V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzhei...Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.展开更多
Traditional Chinese medicine(TCM)has demonstrated unique advantages in the prevention and treatment of chronic diseases such as glycolipid metabolism disorder.However,its widespread application has been hindered by th...Traditional Chinese medicine(TCM)has demonstrated unique advantages in the prevention and treatment of chronic diseases such as glycolipid metabolism disorder.However,its widespread application has been hindered by the unclear biological essence of TCM syndromes and therapeutic mechanisms.As an emerging interdisciplinary field,phenomics integrates multi-dimensional data including genome,transcriptome,proteome,metabolome,and microbiome.When combined with TCM's holistic philosophy,it forms TCM phenomics,providing novel approaches to reveal the biological connotation of TCM syndromes and the mechanisms of herbal medicine.Taking glycolipid metabolism disorder as an example,this paper explores the application of TCM phenomics in glycolipid metabolism disorder.By analyzing molecular characteristics of related syndromes,TCM phenomics identifies differentially expressed genes,metabolites,and gut microbiota biomarkers to elucidate the dynamic evolution patterns of syndromes.Simultaneously,it deciphers the multi-target regulatory networks of herbal formulas,demonstrating their therapeutic effects through mechanisms including modulation of insulin signaling pathways,improvement of gut microbiota imbalance,and suppression of inflammatory responses.Current challenges include the subjective nature of syndrome diagnosis,insufficient standardization of animal models,and lack of integrated multi-omics analysis.Future research should employ machine learning,multimodal data integration,and cross-omics longitudinal studies to establish quantitative diagnostic systems for syndromes,promote the integration of precision medicine in TCM and western medicine,and accelerate the modernization of TCM.展开更多
BACKGROUND Diabetes mellitus(DM)and metabolic-associated fatty liver disease(MAFLD)are common metabolic disorders,and their coexistence can exacerbate the progression of either disease.Human umbilical cord mesenchymal...BACKGROUND Diabetes mellitus(DM)and metabolic-associated fatty liver disease(MAFLD)are common metabolic disorders,and their coexistence can exacerbate the progression of either disease.Human umbilical cord mesenchymal stem cell(hUCMSC)therapy has shown promising potential in the treatment of several metabolic diseases.AIM To investigate how hUC-MSCs affect liver metabolism in diabetic rats with MAFLD and assess their therapeutic potential and underlying mechanisms.METHODS A streptozotocin-induced rat model of DM with MAFLD was established,and hUC-MSCs were administered via tail vein injection.Changes in body weight,fasting blood glucose(FBG),and serum triglyceride(TG),alanine aminotransferase,aspartate aminotransferase levels,and pathological changes of liver were evaluated.Receiver operating characteristic analysis was used to assess the diagnostic value of differential metabolites and their ability to predict the therapeutic effects of hUC-MSCs.Spearman correlation was employed to analyze the relationships between liver metabolites and key biochemical markers.RESULTS hUC-MSC treatment significantly reduced FBG and TG levels in diabetic rats with MAFLD and improved histological steatosis and injury in the liver.Metabolomic analysis indicated that hUC-MSCs significantly ameliorated liver metabolic disturbances via their regulatory effect on several key metabolic pathways related to carbohydrate,amino acid,and lipid metabolism.Receiver operating characteristic curve analysis revealed that 70 differential metabolites had good diagnostic value for DM with MAFLD and could effectively predict the therapeutic effect of hUC-MSCs.Moreover,Spearman correlation analysis confirmed that significant correlations existed between differential liver metabolites and the concentrations of biochemical markers(FBG,TG,alanine aminotransferase,aspartate aminotransferase).CONCLUSION hUC-MSCs alleviate liver metabolic disturbances in diabetic rats with MAFLD,thereby mitigating the pathological state of DM and slowing the progression of MAFLD.展开更多
Background and objective:Both type 2 diabetes mellitus(T2DM)and metabolic dysfunction-associated steatotic liver disease(MASLD)are known to be influenced by environmental and lifestyle factors.Ramulus Mori(Sangzhi)alk...Background and objective:Both type 2 diabetes mellitus(T2DM)and metabolic dysfunction-associated steatotic liver disease(MASLD)are known to be influenced by environmental and lifestyle factors.Ramulus Mori(Sangzhi)alkaloids(SZ-A)are effective hypoglycemic agents.Recent studies suggest that SZ-A may improve T2DM,MASLD,and metabolic syndrome,but the underlying mechanisms remain unclear.This study aimed to investigate whether SZ-A can modulate hepatic lipid metabolism and gut microbiota in a mouse model of T2DM combined with MASLD.Methods:A combined T2DM-MASLD mouse model was established using a high-fat diet and streptozotocin injection.Liver morphology and histology were assessed using a portable small-animal ultrasound imaging system,hematoxylin and eosin(H&E)staining,and Oil Red O staining.Serum levels of triglycerides(TG),total cholesterol(TC),low-density lipoprotein(LDL),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were measured using standard assay kits.Gut microbiota composition was analyzed by 16S rRNA sequencing,and hepatic lipid metabolites were profiled using liquid chromatography-mass spectrometry(LC-MS)MS.Results:SZ-A improved liver function by ameliorating morphological and structural abnormalities,reducing lipid droplet accumulation,and lowering serum levels of TG,TC,LDL,ALT,and AST.It also led to decreased hepatic ultrasound echo intensity compared to the kidney.Additionally,SZ-A helped restore gut microbiota balance,including a partial reversal of the Firmicutes/Bacteroidetes ratio.Lipidomic analysis revealed that SZ-A downregulated most TG and diglycerides(DG),while upregulating phosphatidylcholine(PC)and phosphatidylethanolamine(PE)in the model group.Conclusions:SZ-A partially alleviates liver injury in T2DM-MASLD mice by modulating hepatic lipid metabolism and gut microbiota composition.展开更多
An increasing number of studies have characterized the bone as an endocrine organ,and that bone secreted factors may not only regulate local bone remodeling,but also other tissues and whole-body metabolic functions.Th...An increasing number of studies have characterized the bone as an endocrine organ,and that bone secreted factors may not only regulate local bone remodeling,but also other tissues and whole-body metabolic functions.The precise nature of these regulatory factors and their roles at bridging the bone,bone marrow adipose tissue,extramedullary body fat and whole-body energy homeostasis are being explored.In this study,we report that KIAA1199,a secreted factor produced from bone and bone marrow,previously described as an inhibitor of bone formation,also plays a role at promoting adipogenesis.KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue,subcutaneous and visceral fat tissue mass,blood cholesterol,triglycerides,free fatty acids and glycerol,as well as improved insulin sensitivity in skeletal muscle,liver and fat.Moreover,these mice are protected from the detrimental effects of high-fat diet feeding,with decreased obesity,lower blood glucose and glucose tolerance,as well as decreased adipose tissue inflammation,insulin resistance and hepatic steatosis.In human studies,plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol,triglycerides,free fatty acids,glycerol,fasting glucose and HOMA-IR.Mechanistically,KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT/ERK signaling.These findings provide evidence for the role of bone secreted factors on coupling bone,fat and whole-body energy homeostasis.展开更多
Background:The prevalence of circadian misalignment,particularly social jetlag(SJL),contributes significantly to the epidemic of metabolic disorders.However,the precise impact of SJL on the liver has remained poorly e...Background:The prevalence of circadian misalignment,particularly social jetlag(SJL),contributes significantly to the epidemic of metabolic disorders.However,the precise impact of SJL on the liver has remained poorly elucidated.Methods:The rhythmicity of circulating prolactin(PRL)was evaluated in subjects with SJL and mice under SJL.The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and PrI^(-/-) mice.Luciferase reporter assay,electrophoretic mobility shift assay,and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL.RNA-sequencing(RNA-seq)on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism.The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared.Results:SJL increases the risk of metabolic dysfunction-associated steatotic liver disease(MASLD),mediated by the disruption of the rhythmicity of serum PRL.In particular,SJL inhibits the rhythmic transcription of PRL in the pituitary,leading to desynchronized PRL levels in circulation.Under jetlag conditions,the rhythmicity of the hepatic PRL signaling pathway was significantly dampened,which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions.Notably,PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration.Conclusions:Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL,which was mediated through derailed serum PRL rhythm.Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver,providing new insight into treating MASLD.展开更多
Polyamines(putrescine,spermidine,and spermine)are aliphatic compounds ubiquitous in prokaryotes and eukaryotes.Positively charged polyamines bind to negatively charged macromolecules,such as nucleic acids and acidic p...Polyamines(putrescine,spermidine,and spermine)are aliphatic compounds ubiquitous in prokaryotes and eukaryotes.Positively charged polyamines bind to negatively charged macromolecules,such as nucleic acids and acidic phospholipids,and are involved in physiological activities including cell proliferation,differentiation,apoptosis and gene regulation.Intracellular polyamine levels are regulated by biosynthesis,catabolism and transport.Polyamines in the body originate from two primary sources:dietary intake and intestinal microbial metabolism.These polyamines are then transported into the bloodstream,through which they are distributed to various tissues and organs to exert their biological functions.Polyamines synthesized by intestinal microorganisms serve dual critical roles.First,they are essential for maintaining polyamine concentrations within the digestive tract.Second,through transcriptional and post-transcriptional mechanisms,these microbial-derived polyamines modulate the expression of genes governing key processes in intestinal epithelial cells-including proliferation,migration,apoptosis,and cell-cell interactions.Collectively,these regulatory effects help maintain intestinal epithelial homeostasis and ensure the integrity of the gut barrier.In addition,polyamines interact with the gut microbiota to maintain intestinal homeostasis by promoting microbial growth,biofilm formation,swarming,and endocytosis vesicle production,etc.Supplementation with polyamines has been demonstrated to be important in regulating host intestinal microbial composition,enhancing nutrient absorption,and improving metabolism and immunity.In this review,we will focus on recent advances in the study of polyamine metabolism and transport in intestinal microbes and intestinal epithelial cells.We then summarize the scientific understanding of their roles in intestinal homeostasis,exploring the advances in cellular and molecular mechanisms of polyamines and their potential clinical applications,and providing a rationale for polyamine metabolism as an important target for the treatment of intestinal-based diseases.展开更多
The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately...The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues.While circadian clocks regulate metabolic processes and related physiology,emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined.In this review,we highlight the concept of metabolites,including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake,as time cues that drive changes in circadian rhythms,which in turn influence metabolism and aging.Furthermore,we discuss the roles of functional metabolites as circadian cues,paving a new direction on potential intervention targets of circadian disruption,pathological aging,as well as metabolic diseases that are clinically important.展开更多
Background:Intrauterine growth retardation(IUGR)is associated with severely impaired nutrient metabolism and intestinal development of pigs.Our previous study found that IUGR altered intestinal microbiota and metaboli...Background:Intrauterine growth retardation(IUGR)is associated with severely impaired nutrient metabolism and intestinal development of pigs.Our previous study found that IUGR altered intestinal microbiota and metabolites in the colon.However,the consequences of IUGR on bile acid metabolism in pigs remained unclear.The present study aimed to investigate the bile acid metabolism in the liver and the profile of bile acid derivatives in the colon of grow-ing pigs with IUGR using bile acid targeted metabolomics.Furthermore,we determined correlations between colonic microbiota composition and metabolites of IUGR and normal birth weight(NBW)pigs at different growth stages that were 7,21,and 28-day-old,and the average body weight(BW)of 25,50,and 100 kg of the NBW pigs.Results:The results showed that the plasma total bile acid concentration was higher(P<0.05)at the 25 kg BW stage and tended to increase(P=0.08)at 28-day-old in IUGR pigs.The hepatic gene expressions related to bile acid synthe-sis(CYP7A1,CYP27A1,and NTCP)were up-regulated(P<0.05),and the genes related to glucose and lipid metabolism(ATGL,HSL,and PC)were down-regulated(P<0.05)at the 25 kg BW stage in IUGR pigs when compared with the NBW group.Targeted metabolomics analysis showed that 29 bile acids and related compounds were detected in the colon of pigs.The colonic concentrations of dehydrolithocholic acid and apocholic acid were increased(P<0.05),while isodeoxycholic acid and 6,7-diketolithocholic acid were decreased(P<0.05)in IUGR pigs,when compared with the NBW pigs at the 25 kg BW stage.Moreover,Spearman’s correlation analysis revealed that colonic Unclassified_[Mogi-bacteriaceae],Lachnospira,and Slackia abundances were negatively correlated(P<0.05)with dehydrolithocholic acid,as well as the Unclassified_Clostridiaceae abundance with 6,7-diketolithocholic acid at the 25 kg BW stage.Conclusions:These findings suggest that IUGR could affect bile acid and glucolipid metabolism in growing pigs,especially at the 25 kg BW stage,these effects being paralleled by a modification of bile acid derivatives concentra-tions in the colonic content.The plausible links between these modified parameters are discussed.展开更多
The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulatingthe activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microb...The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulatingthe activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probioticstreated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics, synbiotics, and prebiotics, with sufficient nutrition could aid the development of treatments and prevention for liver cirrhosis patients.展开更多
Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase(XDH/XO) is ...Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase(XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid(UA) generation inhibitor in the 1950 s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target forvascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted.展开更多
Activating transcription factor 4 （ATF4） has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed tha...Activating transcription factor 4 （ATF4） has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4- deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 （UCP2） and p-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue （WAT）, suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue （BAT）, suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.展开更多
AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of ...AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS:Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006.RESULTS:Seven classes of drugs were chosen,including gastric proton pump inhibitors,histamine H2-receptor antagonists,benzamide-type gastroprokinetic agents,selective 5-HT3 receptor antagonists,fluoroquinolones,macrolide antibiotics and azole antifungals.They showed significant differences in metabolic profile(i.e.,the fraction of drug metabolized by cytochrome P450(CYP),CYP reaction phenotype,impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential).Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues.CONCLUSION:Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy.The relevant CYP knowledgehelps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.展开更多
Objective：We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease （CAVD） in patients with normal or mildly impaired rena...Objective：We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease （CAVD） in patients with normal or mildly impaired renal function. Methods：We measured serum levels of calcium, phosphate, alkaline phosphatase （AKP）, intact parathyroid hormone （iPTH）, 25-hydroxyvitamin D （25-OHD）, and biomarkers of bone turnover in 260 consecutive patients with normal or mildly impaired renal function and aortic valve sclerosis （AVSc） （n=164） or stenosis （AVS） （n=96） and in 164 age- and gender-matched controls. Logistic regression models were used to determine the association of mineral metabolism parameters with the presence and severity of CAVD. Results：Stepwise increases were observed in serum levels of calcium, phosphate, AKP, and iPTH from the control group to patients with AVS, and with reverse changes for 25-OHD levels （al P〈0.001）. Similarly, osteocalcin, procol agen I N-terminal peptide, andβ-isomerized type I col agen C-telopeptide breakdown products were significantly increased stepwise from the control group to patients with AVS （al P〈0.001）. In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to trans-aortic peak flow velocity and mean pressure gradient. After adjusting for relevant confounding varia-bles, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were in-dependently associated with the presence and severity of CAVD. Conclusions： This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Abnormal bone turnover may be a potential mechanism.展开更多
The adenosine monophosphate-activated protein kinase (AMPK) and p70 ribosomal S6 kinase-1 pathway may serve as a key signaling flow that regulates energy metabolism; thus, this pathway becomes an attractive target for...The adenosine monophosphate-activated protein kinase (AMPK) and p70 ribosomal S6 kinase-1 pathway may serve as a key signaling flow that regulates energy metabolism; thus, this pathway becomes an attractive target for the treatment of liver diseases that result from metabolic derangements. In addition, AMPK emerges as a kinase that controls the redox-state and mitochondrial function, whose activity may be modulated by antioxidants. A close link exists between fuel metabolism and mitochondrial biogenesis. The relationship between fuel metabolism and cell survival strongly implies the existence of a shared signaling network, by which hepatocytes respond to challenges of external stimuli. The AMPK pathway may belong to this network. A series of drugs and therapeutic candidates enable hepatocytes to protect mitochondria from radical stress and increase cell viability, which may be associated with the activation of AMPK, liver kinase B1, and other molecules or components. Consequently, the components downstream of AMPK may contribute to stabilizing mitochondrial membrane potential for hepatocyte survival. In this review, we discuss the role of the AMPK pathway in hepatic energy metabolism and hepatocyte viability. This information may help identify ways to prevent and/or treat hepatic diseases caused by the metabolic syndrome. Moreover, clinical drugs and experimental therapeutic candidates that directly or indirectly modulate the AMPK pathway in distinct manners are discussed here with particular emphasis on their effects on fuel metabolism and mitochondrial function.展开更多
Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known ...Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of "red flags" which should prompt additional evaluation.展开更多
The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remn...The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.展开更多
Objective: To explore the molecular regulation mechanism of carvedilol in attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy induced by coarctation of abdomina...Objective: To explore the molecular regulation mechanism of carvedilol in attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy induced by coarctation of abdominal aorta (CAA) in male Wistar rats. Methods: Hemodynamic and ventricular remodeling parameters, free fatty acid content in the serum were measured in the experimental animals at 16 weeks after the surgical CAA, the rats receiving carvedilol intervention (CAR) after CAA, and those with sham operation (SH). The expressions of muscle carnitine palmitoyltransferaseⅠ (M-CPTⅠ) and medium chain acyl-CoA dehydrogenase (MCAD) mRNA in the cardiac myocytes from every group were studied with RT-PCR. Results: Significant left ventricular hypertrophy were observed in the rats 16 weeks after coarctation operation (P<0.05), together with significant free fatty acids accumulation and downregulation of M-CPTⅠ and MCAD mRNA (P<0.05) in CAA group. Carvedilol at a dose of 30 mg/kg/d for 12 weeks inhibited the left ventricular hypertrophy induced by pressure overload and enhanced the gene expressions of rate-limiting enzyme (M-CPTⅠ) and key enzyme of fatty acid (MCAD) in the CAR group compared with CAA group (P<0.05). Conclusion: Pressure overload-induced hypertrophy in CAA rats causes the reversion back towards fetal enery metabolism, that is, downregulates the expressions of rate-limiting enzyme and key enzyme of fatty acid oxidation. The intervention therapy with carvedilol, a vasodilating alpha- and beta-adrenoreceptor antagonist, attenuates the reversion of the metabolic gene expression to fetal type through upregulating M-CPTⅠ and MCAD mRNA expressions. Thus, carvedilol may exert cardioprotective effects on heart failure by the mechanism of preserving the adult metabolic gene regulation.展开更多
Objective The experiment was conducted to explore the effects of silymarin on reproductive and lactation performance,serum antioxidants,and body metabolism of sows.Methods Sixty pregnant sows(85 d,Large×Landrace)...Objective The experiment was conducted to explore the effects of silymarin on reproductive and lactation performance,serum antioxidants,and body metabolism of sows.Methods Sixty pregnant sows(85 d,Large×Landrace)with similar genetic background,body condition,and parity were randomly divided into three groups,and each group has 20 individually housed sows.The sows in the control group(CG)were fed with basal diet,and those in the experimental group A(EGA)and B(EGB)were fed with basal diet containing 250 and 500 mg/kg silymarin,respectively.The experiment lasted 46 days from day 85 of gestation to the end of lactation(weaning on day 17).The milk composition and serum biochemical para-meters were determined by a milk composition analyzer and a blood biochemical analyzer,respectively.Serum antioxidant indexes and plasma hormone levels were measured using the biochemical kits.The gas chromatograph was applied to detect the fecal short chain fatty acids.Results Compared with the CG,the total feed intake(TFI)and average daily feed intake(ADFI)were significantly increased(P<0.01),and the urea content in regular milk tended to increase(P=0.095)in the EG.The serum malondialdehyde(MDA)contents were decreased on day 90 of gestation and the day of farrowing(P<0.01),and the serum contents of total antioxidant capacity(T-AOC)tended to increase on day 17 of lactation(P=0.099)compared with the CG.Compared with the CG,the serum triglyceride(TG)concentrations in the EG tended to increase on day 90 of gestation(P=0.062),and the content of serum total protein(TP)and albumin(ALB)reduced on day 17 of lactation(P<0.01).Compared with the CG,plasm D-lactic acid content was decreased(P<0.05),and the plasma prostaglandin(PG)level tended to increase(P=0.088)in the EG on the day of farrowing and day 17 of lactation.Compared with the CG,fecal isobutyric acid concentration in the EG significantly decreased on the day of farrowing(P<0.05).Conclusion Adding 250-500 mg/kg silymarin to diets from the late gestation to the end of lactation could improve reproductive and lactation performance of sows via the regulation of nutrient metabolism and serum antioxidant.展开更多
基金support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
基金financially supported by the National Natural Science Foundation of China,No.823 74552 (to WP)the Science and Technology Innovation Program of Hunan Province,No.2022RC1220 (to WP)+1 种基金the Natural Science Foundation of Hunan Province of China,Nos.2020JJ4803 (to WP),2022JJ40723 (to MY)the Scientific Research Launch Project for New Employees of the Second Xiangya Hospital of Central South University (to MY)
文摘Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.
基金National Natural Science Foundation of China(82474323)High Level Chinese Medical Hospital Promotion Project(HLCMHPP20230CZ40907)China Academy of Chinese Medical Sciences Outstanding Young Scientific and Technological Talents Program(ZZ13-YQ-026).
文摘Traditional Chinese medicine(TCM)has demonstrated unique advantages in the prevention and treatment of chronic diseases such as glycolipid metabolism disorder.However,its widespread application has been hindered by the unclear biological essence of TCM syndromes and therapeutic mechanisms.As an emerging interdisciplinary field,phenomics integrates multi-dimensional data including genome,transcriptome,proteome,metabolome,and microbiome.When combined with TCM's holistic philosophy,it forms TCM phenomics,providing novel approaches to reveal the biological connotation of TCM syndromes and the mechanisms of herbal medicine.Taking glycolipid metabolism disorder as an example,this paper explores the application of TCM phenomics in glycolipid metabolism disorder.By analyzing molecular characteristics of related syndromes,TCM phenomics identifies differentially expressed genes,metabolites,and gut microbiota biomarkers to elucidate the dynamic evolution patterns of syndromes.Simultaneously,it deciphers the multi-target regulatory networks of herbal formulas,demonstrating their therapeutic effects through mechanisms including modulation of insulin signaling pathways,improvement of gut microbiota imbalance,and suppression of inflammatory responses.Current challenges include the subjective nature of syndrome diagnosis,insufficient standardization of animal models,and lack of integrated multi-omics analysis.Future research should employ machine learning,multimodal data integration,and cross-omics longitudinal studies to establish quantitative diagnostic systems for syndromes,promote the integration of precision medicine in TCM and western medicine,and accelerate the modernization of TCM.
基金Supported by the National Key Specialty Major Scientific Research Project of the Hunan Provincial Health Commission,No.Z2023158.
文摘BACKGROUND Diabetes mellitus(DM)and metabolic-associated fatty liver disease(MAFLD)are common metabolic disorders,and their coexistence can exacerbate the progression of either disease.Human umbilical cord mesenchymal stem cell(hUCMSC)therapy has shown promising potential in the treatment of several metabolic diseases.AIM To investigate how hUC-MSCs affect liver metabolism in diabetic rats with MAFLD and assess their therapeutic potential and underlying mechanisms.METHODS A streptozotocin-induced rat model of DM with MAFLD was established,and hUC-MSCs were administered via tail vein injection.Changes in body weight,fasting blood glucose(FBG),and serum triglyceride(TG),alanine aminotransferase,aspartate aminotransferase levels,and pathological changes of liver were evaluated.Receiver operating characteristic analysis was used to assess the diagnostic value of differential metabolites and their ability to predict the therapeutic effects of hUC-MSCs.Spearman correlation was employed to analyze the relationships between liver metabolites and key biochemical markers.RESULTS hUC-MSC treatment significantly reduced FBG and TG levels in diabetic rats with MAFLD and improved histological steatosis and injury in the liver.Metabolomic analysis indicated that hUC-MSCs significantly ameliorated liver metabolic disturbances via their regulatory effect on several key metabolic pathways related to carbohydrate,amino acid,and lipid metabolism.Receiver operating characteristic curve analysis revealed that 70 differential metabolites had good diagnostic value for DM with MAFLD and could effectively predict the therapeutic effect of hUC-MSCs.Moreover,Spearman correlation analysis confirmed that significant correlations existed between differential liver metabolites and the concentrations of biochemical markers(FBG,TG,alanine aminotransferase,aspartate aminotransferase).CONCLUSION hUC-MSCs alleviate liver metabolic disturbances in diabetic rats with MAFLD,thereby mitigating the pathological state of DM and slowing the progression of MAFLD.
基金supported by the Fund for Independent Innovation of Hypoglycemic Drugs from Basic Research to Clinical Application(070500020373).
文摘Background and objective:Both type 2 diabetes mellitus(T2DM)and metabolic dysfunction-associated steatotic liver disease(MASLD)are known to be influenced by environmental and lifestyle factors.Ramulus Mori(Sangzhi)alkaloids(SZ-A)are effective hypoglycemic agents.Recent studies suggest that SZ-A may improve T2DM,MASLD,and metabolic syndrome,but the underlying mechanisms remain unclear.This study aimed to investigate whether SZ-A can modulate hepatic lipid metabolism and gut microbiota in a mouse model of T2DM combined with MASLD.Methods:A combined T2DM-MASLD mouse model was established using a high-fat diet and streptozotocin injection.Liver morphology and histology were assessed using a portable small-animal ultrasound imaging system,hematoxylin and eosin(H&E)staining,and Oil Red O staining.Serum levels of triglycerides(TG),total cholesterol(TC),low-density lipoprotein(LDL),alanine aminotransferase(ALT),and aspartate aminotransferase(AST)were measured using standard assay kits.Gut microbiota composition was analyzed by 16S rRNA sequencing,and hepatic lipid metabolites were profiled using liquid chromatography-mass spectrometry(LC-MS)MS.Results:SZ-A improved liver function by ameliorating morphological and structural abnormalities,reducing lipid droplet accumulation,and lowering serum levels of TG,TC,LDL,ALT,and AST.It also led to decreased hepatic ultrasound echo intensity compared to the kidney.Additionally,SZ-A helped restore gut microbiota balance,including a partial reversal of the Firmicutes/Bacteroidetes ratio.Lipidomic analysis revealed that SZ-A downregulated most TG and diglycerides(DG),while upregulating phosphatidylcholine(PC)and phosphatidylethanolamine(PE)in the model group.Conclusions:SZ-A partially alleviates liver injury in T2DM-MASLD mice by modulating hepatic lipid metabolism and gut microbiota composition.
基金supports from Odense University Hospital PhD fellowship(2014)the NovoNordisk Foundations(NNF15OC0016284,NNF19OC0057449)+2 种基金the Innovation Foundation of Denmark(5166-00002B)National Natural Science Foundation of China(No.32060155,82260284)Guangxi Medical and Health Key Discipline Construction Project.
文摘An increasing number of studies have characterized the bone as an endocrine organ,and that bone secreted factors may not only regulate local bone remodeling,but also other tissues and whole-body metabolic functions.The precise nature of these regulatory factors and their roles at bridging the bone,bone marrow adipose tissue,extramedullary body fat and whole-body energy homeostasis are being explored.In this study,we report that KIAA1199,a secreted factor produced from bone and bone marrow,previously described as an inhibitor of bone formation,also plays a role at promoting adipogenesis.KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue,subcutaneous and visceral fat tissue mass,blood cholesterol,triglycerides,free fatty acids and glycerol,as well as improved insulin sensitivity in skeletal muscle,liver and fat.Moreover,these mice are protected from the detrimental effects of high-fat diet feeding,with decreased obesity,lower blood glucose and glucose tolerance,as well as decreased adipose tissue inflammation,insulin resistance and hepatic steatosis.In human studies,plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol,triglycerides,free fatty acids,glycerol,fasting glucose and HOMA-IR.Mechanistically,KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT/ERK signaling.These findings provide evidence for the role of bone secreted factors on coupling bone,fat and whole-body energy homeostasis.
基金supported by the National Natural Science Foundation of China(82030026,81900787,81770819,82300877,and 82450002)the Key Project supported by Medical Science and technology development Foundation,Nanjing Department of Health(YKK24104)+1 种基金the Medical Research Program of Jiangsu Provincial Health Committe(M2024050)the China Postdoctoral Science Foundation(2023M731628).
文摘Background:The prevalence of circadian misalignment,particularly social jetlag(SJL),contributes significantly to the epidemic of metabolic disorders.However,the precise impact of SJL on the liver has remained poorly elucidated.Methods:The rhythmicity of circulating prolactin(PRL)was evaluated in subjects with SJL and mice under SJL.The causative mechanism of SJL on fatty liver was explored using jetlag model in wild-type and PrI^(-/-) mice.Luciferase reporter assay,electrophoretic mobility shift assay,and chromatin immunoprecipitation analysis were used to study the transcriptional mechanism of retinoic acid receptor-related orphan receptor α on PRL.RNA-sequencing(RNA-seq)on human and mice liver as well as circadian analysis were used to study the mechanism of SJL-associated desynchronized PRL on hepatic lipid metabolism.The therapeutic effect of PRL intervention on SJL-induced mice at different time points was compared.Results:SJL increases the risk of metabolic dysfunction-associated steatotic liver disease(MASLD),mediated by the disruption of the rhythmicity of serum PRL.In particular,SJL inhibits the rhythmic transcription of PRL in the pituitary,leading to desynchronized PRL levels in circulation.Under jetlag conditions,the rhythmicity of the hepatic PRL signaling pathway was significantly dampened,which resulted in increased lipogenesis via inhibited hepatic mitogen-activated protein kinase/cyclin D1 expressions.Notably,PRL treatment at PRL nadir in jetlagged mice decreased hepatic lipid content and liver injury markers to a greater extent compared with conventional PRL administration.Conclusions:Reprogrammed hepatic PRL signaling pathway with concomitant dysregulated lipid metabolism homeostasis was the causative mechanism of fatty liver under SJL,which was mediated through derailed serum PRL rhythm.Restoration of PRL rhythm could effectively alleviate SJL-induced fatty liver,providing new insight into treating MASLD.
基金supported by projects from the Xinjiang Production and Construction Corps Major Science and Technology"Revealing the List and Taking Command"Project(2023AB078)the Ministry of Science and Technology High-end Foreign Expert Project(G2023014066L)the Xinjiang Production and Construction Corps Agricultural Science and Technology Innovation Engineering Special Project(NCG202232).
文摘Polyamines(putrescine,spermidine,and spermine)are aliphatic compounds ubiquitous in prokaryotes and eukaryotes.Positively charged polyamines bind to negatively charged macromolecules,such as nucleic acids and acidic phospholipids,and are involved in physiological activities including cell proliferation,differentiation,apoptosis and gene regulation.Intracellular polyamine levels are regulated by biosynthesis,catabolism and transport.Polyamines in the body originate from two primary sources:dietary intake and intestinal microbial metabolism.These polyamines are then transported into the bloodstream,through which they are distributed to various tissues and organs to exert their biological functions.Polyamines synthesized by intestinal microorganisms serve dual critical roles.First,they are essential for maintaining polyamine concentrations within the digestive tract.Second,through transcriptional and post-transcriptional mechanisms,these microbial-derived polyamines modulate the expression of genes governing key processes in intestinal epithelial cells-including proliferation,migration,apoptosis,and cell-cell interactions.Collectively,these regulatory effects help maintain intestinal epithelial homeostasis and ensure the integrity of the gut barrier.In addition,polyamines interact with the gut microbiota to maintain intestinal homeostasis by promoting microbial growth,biofilm formation,swarming,and endocytosis vesicle production,etc.Supplementation with polyamines has been demonstrated to be important in regulating host intestinal microbial composition,enhancing nutrient absorption,and improving metabolism and immunity.In this review,we will focus on recent advances in the study of polyamine metabolism and transport in intestinal microbes and intestinal epithelial cells.We then summarize the scientific understanding of their roles in intestinal homeostasis,exploring the advances in cellular and molecular mechanisms of polyamines and their potential clinical applications,and providing a rationale for polyamine metabolism as an important target for the treatment of intestinal-based diseases.
基金supported by grants from the Chinese Academy of Sciences(XDB39050800)the Major Project of Guangzhou National Laboratory(GZNL2024A03013)the National Natural Science Foundation of China(92357308 and 32321004)。
文摘The circadian clock is a highly hierarchical network of endogenous pacemakers that primarily maintains and directs oscillations through transcriptional and translational feedback loops,which modulates an approximately 24-h cycle of endocrine and metabolic rhythms within cells and tissues.While circadian clocks regulate metabolic processes and related physiology,emerging evidence indicates that metabolism and circadian rhythm are intimately intertwined.In this review,we highlight the concept of metabolites,including lipids and other polar metabolites generated from intestinal microbial metabolism and nutrient intake,as time cues that drive changes in circadian rhythms,which in turn influence metabolism and aging.Furthermore,we discuss the roles of functional metabolites as circadian cues,paving a new direction on potential intervention targets of circadian disruption,pathological aging,as well as metabolic diseases that are clinically important.
基金supported by the National Natural Science Foundation of China(U20A2056)Special Funds for Construction of Innovative Provinces in Hunan Province(2019RS3022).
文摘Background:Intrauterine growth retardation(IUGR)is associated with severely impaired nutrient metabolism and intestinal development of pigs.Our previous study found that IUGR altered intestinal microbiota and metabolites in the colon.However,the consequences of IUGR on bile acid metabolism in pigs remained unclear.The present study aimed to investigate the bile acid metabolism in the liver and the profile of bile acid derivatives in the colon of grow-ing pigs with IUGR using bile acid targeted metabolomics.Furthermore,we determined correlations between colonic microbiota composition and metabolites of IUGR and normal birth weight(NBW)pigs at different growth stages that were 7,21,and 28-day-old,and the average body weight(BW)of 25,50,and 100 kg of the NBW pigs.Results:The results showed that the plasma total bile acid concentration was higher(P<0.05)at the 25 kg BW stage and tended to increase(P=0.08)at 28-day-old in IUGR pigs.The hepatic gene expressions related to bile acid synthe-sis(CYP7A1,CYP27A1,and NTCP)were up-regulated(P<0.05),and the genes related to glucose and lipid metabolism(ATGL,HSL,and PC)were down-regulated(P<0.05)at the 25 kg BW stage in IUGR pigs when compared with the NBW group.Targeted metabolomics analysis showed that 29 bile acids and related compounds were detected in the colon of pigs.The colonic concentrations of dehydrolithocholic acid and apocholic acid were increased(P<0.05),while isodeoxycholic acid and 6,7-diketolithocholic acid were decreased(P<0.05)in IUGR pigs,when compared with the NBW pigs at the 25 kg BW stage.Moreover,Spearman’s correlation analysis revealed that colonic Unclassified_[Mogi-bacteriaceae],Lachnospira,and Slackia abundances were negatively correlated(P<0.05)with dehydrolithocholic acid,as well as the Unclassified_Clostridiaceae abundance with 6,7-diketolithocholic acid at the 25 kg BW stage.Conclusions:These findings suggest that IUGR could affect bile acid and glucolipid metabolism in growing pigs,especially at the 25 kg BW stage,these effects being paralleled by a modification of bile acid derivatives concentra-tions in the colonic content.The plausible links between these modified parameters are discussed.
文摘The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulatingthe activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probioticstreated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics, synbiotics, and prebiotics, with sufficient nutrition could aid the development of treatments and prevention for liver cirrhosis patients.
文摘Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase(XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid(UA) generation inhibitor in the 1950 s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target forvascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted.
文摘Activating transcription factor 4 （ATF4） has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4- deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 （UCP2） and p-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue （WAT）, suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue （BAT）, suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.
基金the Scientific Research Project of Zhejiang Provincial Bureau of Education,No. 20061449,No. 20010535
文摘AIM:To review and summarize drug metabolism and its related interactions in prescribing drugs within the similar therapeutic or structural class for gastrointestinal disease treatment so as to promote rational use of medicines in clinical practice.METHODS:Relevant literature was identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006.RESULTS:Seven classes of drugs were chosen,including gastric proton pump inhibitors,histamine H2-receptor antagonists,benzamide-type gastroprokinetic agents,selective 5-HT3 receptor antagonists,fluoroquinolones,macrolide antibiotics and azole antifungals.They showed significant differences in metabolic profile(i.e.,the fraction of drug metabolized by cytochrome P450(CYP),CYP reaction phenotype,impact of CYP genotype on interindividual pharmacokinetics variability and CYP-mediated drug-drug interaction potential).Many events of severe adverse drug reactions and treatment failures were closely related to the ignorance of the above issues.CONCLUSION:Clinicians should acquaint themselves with what kind of drug has less interpatient variability in clearance and whether to perform CYP genotyping prior to initiation of therapy.The relevant CYP knowledgehelps clinicians to enhance the management of patients with gastrointestinal disease who may require treatment with polytherapeutic regimens.
基金Project supported by the Science and Technology Commission of Shanghai Municipality(No.114119a8800),China
文摘Objective：We investigated whether disturbance of calcium and phosphate metabolism is associated with the presence and severity of calcific aortic valve disease （CAVD） in patients with normal or mildly impaired renal function. Methods：We measured serum levels of calcium, phosphate, alkaline phosphatase （AKP）, intact parathyroid hormone （iPTH）, 25-hydroxyvitamin D （25-OHD）, and biomarkers of bone turnover in 260 consecutive patients with normal or mildly impaired renal function and aortic valve sclerosis （AVSc） （n=164） or stenosis （AVS） （n=96） and in 164 age- and gender-matched controls. Logistic regression models were used to determine the association of mineral metabolism parameters with the presence and severity of CAVD. Results：Stepwise increases were observed in serum levels of calcium, phosphate, AKP, and iPTH from the control group to patients with AVS, and with reverse changes for 25-OHD levels （al P〈0.001）. Similarly, osteocalcin, procol agen I N-terminal peptide, andβ-isomerized type I col agen C-telopeptide breakdown products were significantly increased stepwise from the control group to patients with AVS （al P〈0.001）. In patients with AVS, serum levels of iPTH were positively, in contrast 25-OHD levels were negatively, related to trans-aortic peak flow velocity and mean pressure gradient. After adjusting for relevant confounding varia-bles, increased serum levels of calcium, phosphate, AKP, and iPTH and reduced serum levels of 25-OHD were in-dependently associated with the presence and severity of CAVD. Conclusions： This study suggests an association between mineral metabolism disturbance and the presence and severity of CAVD in patients with normal or mildly impaired renal function. Abnormal bone turnover may be a potential mechanism.
基金Supported by The National Research Foundation of Korea Grant,Funded by the Korea Government(MEST),No.2010-0001706,South Korea
文摘The adenosine monophosphate-activated protein kinase (AMPK) and p70 ribosomal S6 kinase-1 pathway may serve as a key signaling flow that regulates energy metabolism; thus, this pathway becomes an attractive target for the treatment of liver diseases that result from metabolic derangements. In addition, AMPK emerges as a kinase that controls the redox-state and mitochondrial function, whose activity may be modulated by antioxidants. A close link exists between fuel metabolism and mitochondrial biogenesis. The relationship between fuel metabolism and cell survival strongly implies the existence of a shared signaling network, by which hepatocytes respond to challenges of external stimuli. The AMPK pathway may belong to this network. A series of drugs and therapeutic candidates enable hepatocytes to protect mitochondria from radical stress and increase cell viability, which may be associated with the activation of AMPK, liver kinase B1, and other molecules or components. Consequently, the components downstream of AMPK may contribute to stabilizing mitochondrial membrane potential for hepatocyte survival. In this review, we discuss the role of the AMPK pathway in hepatic energy metabolism and hepatocyte viability. This information may help identify ways to prevent and/or treat hepatic diseases caused by the metabolic syndrome. Moreover, clinical drugs and experimental therapeutic candidates that directly or indirectly modulate the AMPK pathway in distinct manners are discussed here with particular emphasis on their effects on fuel metabolism and mitochondrial function.
文摘Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of "red flags" which should prompt additional evaluation.
基金Supported by grant 2001B043 from the Netherlands Heart Foundation
文摘The liver is considered the major “control center” for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.
文摘Objective: To explore the molecular regulation mechanism of carvedilol in attenuating the reversion back towards fetal energy metabolism during the development of cardiac hypertrophy induced by coarctation of abdominal aorta (CAA) in male Wistar rats. Methods: Hemodynamic and ventricular remodeling parameters, free fatty acid content in the serum were measured in the experimental animals at 16 weeks after the surgical CAA, the rats receiving carvedilol intervention (CAR) after CAA, and those with sham operation (SH). The expressions of muscle carnitine palmitoyltransferaseⅠ (M-CPTⅠ) and medium chain acyl-CoA dehydrogenase (MCAD) mRNA in the cardiac myocytes from every group were studied with RT-PCR. Results: Significant left ventricular hypertrophy were observed in the rats 16 weeks after coarctation operation (P<0.05), together with significant free fatty acids accumulation and downregulation of M-CPTⅠ and MCAD mRNA (P<0.05) in CAA group. Carvedilol at a dose of 30 mg/kg/d for 12 weeks inhibited the left ventricular hypertrophy induced by pressure overload and enhanced the gene expressions of rate-limiting enzyme (M-CPTⅠ) and key enzyme of fatty acid (MCAD) in the CAR group compared with CAA group (P<0.05). Conclusion: Pressure overload-induced hypertrophy in CAA rats causes the reversion back towards fetal enery metabolism, that is, downregulates the expressions of rate-limiting enzyme and key enzyme of fatty acid oxidation. The intervention therapy with carvedilol, a vasodilating alpha- and beta-adrenoreceptor antagonist, attenuates the reversion of the metabolic gene expression to fetal type through upregulating M-CPTⅠ and MCAD mRNA expressions. Thus, carvedilol may exert cardioprotective effects on heart failure by the mechanism of preserving the adult metabolic gene regulation.
基金National Key Research and Development Program(2021YFD1300201 and 2021YFD1301004)Science and Technology Innovation Program of Hunan Province(2020RC2063)+2 种基金Natural Science Foundation of Hunan Province(2022JJ40532)Open Fund of Key Laboratory of Agro-ecological Processes in Subtropical Region,Chinese Academy of Sciences(ISA2021103)the cooperation between research institutes and enterprises(E0490205 and E0490207).
文摘Objective The experiment was conducted to explore the effects of silymarin on reproductive and lactation performance,serum antioxidants,and body metabolism of sows.Methods Sixty pregnant sows(85 d,Large×Landrace)with similar genetic background,body condition,and parity were randomly divided into three groups,and each group has 20 individually housed sows.The sows in the control group(CG)were fed with basal diet,and those in the experimental group A(EGA)and B(EGB)were fed with basal diet containing 250 and 500 mg/kg silymarin,respectively.The experiment lasted 46 days from day 85 of gestation to the end of lactation(weaning on day 17).The milk composition and serum biochemical para-meters were determined by a milk composition analyzer and a blood biochemical analyzer,respectively.Serum antioxidant indexes and plasma hormone levels were measured using the biochemical kits.The gas chromatograph was applied to detect the fecal short chain fatty acids.Results Compared with the CG,the total feed intake(TFI)and average daily feed intake(ADFI)were significantly increased(P<0.01),and the urea content in regular milk tended to increase(P=0.095)in the EG.The serum malondialdehyde(MDA)contents were decreased on day 90 of gestation and the day of farrowing(P<0.01),and the serum contents of total antioxidant capacity(T-AOC)tended to increase on day 17 of lactation(P=0.099)compared with the CG.Compared with the CG,the serum triglyceride(TG)concentrations in the EG tended to increase on day 90 of gestation(P=0.062),and the content of serum total protein(TP)and albumin(ALB)reduced on day 17 of lactation(P<0.01).Compared with the CG,plasm D-lactic acid content was decreased(P<0.05),and the plasma prostaglandin(PG)level tended to increase(P=0.088)in the EG on the day of farrowing and day 17 of lactation.Compared with the CG,fecal isobutyric acid concentration in the EG significantly decreased on the day of farrowing(P<0.05).Conclusion Adding 250-500 mg/kg silymarin to diets from the late gestation to the end of lactation could improve reproductive and lactation performance of sows via the regulation of nutrient metabolism and serum antioxidant.
