Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury ...Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.展开更多
Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cel...Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cell dysfunction remains unclear.This study aims to study its role.Methods:Pancreas slices were prepared from mice subjected to a high-fat-diet(HFD)at different time points,and TRPM5 expression in the pancreaticβcells was examined using immunofluorescence staining.Glucose-stimulated insulin secretion(GSIS)defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate(Palm).Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm,and the TRPM5 expression was detected using qRT-PCR and Western blotting.Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown.The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5(Ad-Trpm5).Results:HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets.Palm reduced TRPM5 protein expression in a time-and dose-dependent manner in MIN6 cells.Palm also inhibited TRPM5 expression in primary mouse islets.Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis.Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique toβcells.Conclusion:Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreaticβcells both in vivo and in vitro and,in turn,drivesβ-cell dysfunction.展开更多
Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21stcentury. With the increasing prevalence of obesity, non-alcoholic fatty live...Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21stcentury. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes,recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids,and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors,channels and transporters. However, it also inducesendoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis.This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses.展开更多
One of the leading therapies for acute lymphoblastic leukemia(ALL)is the chemotherapeutic agent PEGylated E.coli-derived-l-asparaginase(PEG-ASNase).Due to the high risk of dose-limiting liver injury,characterized by c...One of the leading therapies for acute lymphoblastic leukemia(ALL)is the chemotherapeutic agent PEGylated E.coli-derived-l-asparaginase(PEG-ASNase).Due to the high risk of dose-limiting liver injury,characterized by clinically elevated levels of hepatic transaminases,PEG-ASNase therapy is generally avoided in adult patients.Our preclinical investigations have indicated that PEG-ASNase-induced liver injury is associated with the release of free fatty acids(FFAs)from white adipose tissue(WAT),suggesting potential lipotoxic effects.However,it remains uncertain whether PEG-ASNase directly induces hepatotoxicity or sensitizes hepatocytes to FFA-induced toxicity.Our results show that PEG-ASNase treatment results in hepatocyte apoptosis and lipid peroxidation.Ex vivo and in vitro studies in mouse and human WAT suggest that PEG-ASNase induces the expression of adipose triglyceride lipase(ATGL),activates the lipase,and stimulates adipose tissue lipolysis,suggesting that the FFAs from WAT may contribute to the observed liver injury.Moreover,treatment with PEG-ASNase sensitizes hepatocytes to FFA-induced lipotoxicity.Mechanistically,our RNA-sequencing(RNA-seq)analyses reveal that PEG-ASNase-induced sensitization to lipotoxicity is accompanied by the induction of Cyp2e1.We demonstrated that this sensitization effect is attenuated by both pharmacological and genetic inhibition of Cyp2e1.Our findings suggest that PEG-ASNase therapy induces WAT lipolysis and sensitizes hepatocytes to hepatic lipotoxicity in a Cyp2e1-dependent manner.展开更多
Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors...Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.展开更多
Diabetic cardiomyopathy(DCM)is a major cause of heart failure in diabetic patients.It progresses asymptomatically prior to the onset of severe cardiac symptoms[1];therefore,elucidating the underlying mechanisms of DCM...Diabetic cardiomyopathy(DCM)is a major cause of heart failure in diabetic patients.It progresses asymptomatically prior to the onset of severe cardiac symptoms[1];therefore,elucidating the underlying mechanisms of DCM is critical to providing early treatment options.This commentary elaborates on the findings of Jiang et al.[2],who investigated the role of adipokine hormone,Adipsin,as a cardioprotective factor in DCM.We provide an exposition and alternative treatment considerations,like Fisetin,and discuss the potential of investigating other cellular targets implicated in cardiac dysfunction,like the interleukin-1 receptor-associated kinaselike 2(Irak2)protein[3]and protein kinase R[4].展开更多
Over the last 20 years,intensive research has been focused on the specific mechanisms mediating the pancreatic β-cell injury.Both the decreased viability and the dysfunction of β-cells have become the key factors in...Over the last 20 years,intensive research has been focused on the specific mechanisms mediating the pancreatic β-cell injury.Both the decreased viability and the dysfunction of β-cells have become the key factors in the development of dia betes mellitus.Thus,it is of utmost importance to elucidate the discrete pathological changes in pancreatic β-cells within the context of the various lipotoxicity models.The goal of these studies is to generate evidence to improve not only the clinical treatment for dia betics,but also modulate the diet and activities of groups at high risk for diabetes.In this regard,we review the role of lipotoxicity in pancreatic β-cell injury and identify potential therapeutic targets in this cell model.展开更多
Fructus Gardeniae(FG)is the dried ripe fruit of Gardenia jasminoides Ellis,having beneficial effects for human health.In this study,we discovered that the most relevant pathway influenced by Fructus Gardeniae extract(...Fructus Gardeniae(FG)is the dried ripe fruit of Gardenia jasminoides Ellis,having beneficial effects for human health.In this study,we discovered that the most relevant pathway influenced by Fructus Gardeniae extract(FGE)is lipid metabolism according to the analysis of network pharmacology.Furthermore,the protective effect of FGE against palmitic acid-induced lipotoxicity was investigated.In L02 cells,FGE significantly promoted cellular proliferation after being treated with palmitic acid,and reduced the accumulation of lipid droplets and triglyceride level.Palmitic acid led to an increase of ROS content,which was reduced by FGE.Additionally,FGE could facilitate Nrf2 localized to nuclear and followed by activating its downstream targets.ML385(a Nrf2 inhibitor)treatment further proved that FGE attenuated lipotoxicity through regulating Nrf2/ARE pathway.Consequently,we demonstrated for the first time FGE could be regarded as potential functional food materials for hepatic protection.展开更多
OBJECTIVE:To investigate the mechanism of Dan Ze mixture(丹泽合剂,DZM)in the treatment of lipotoxic cardiomyopathy.METHODS:Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize ...OBJECTIVE:To investigate the mechanism of Dan Ze mixture(丹泽合剂,DZM)in the treatment of lipotoxic cardiomyopathy.METHODS:Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize the serum migration constituents of DZM.A lipotoxic cardiomyopathy rat model was established through high-fat diet and intervened by different doses of DZM.The cardiac function was assessed using echocardiography,and hematoxylin and eosin,oil red O,and Masson staining were conducted to evaluate morphological changes,lipid accumulation,and fibrosis in myocardial tissue.Serum myocardial enzyme activity,lipid levels,and lipid content of myocardial tissue were measured,while fluorescent staining and colorimetry were used to assess oxidation levels in myocardial tissue.Mitochondrial membrane potential was detected by 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanineiodide(JC-1).Transmission electron microscopy was employed to observe ultrastructure and mitochondrial structure changes in myocardial tissue.Fluorescence double staining and colocalization were utilized to observe the binding of autophagosomes and mitochondria,while immunohistochemical staining was used to detect the expression of mitophagy-related proteins.Terminal deoxynucleoitidyl transferase mediated nick end labeling staining was employed for the identification of apoptosis in myocardial tissue,while quantitative real-time reverse transcriptase polymerase chain reaction(q RT-PCR)and Western blot were utilized for the detection of apoptosis,B-cell lymphoma-2 adenovirus E1B 19 k Da-interacting protein 3(BNIP3)/mitophagy signaling pathway-related genes and proteins.In palmitic acid-induced Rat H9C2 cardiomyocytes(H9c2)cells,various cellular parameters including cell viability,lactate dehydrogenase release,apoptosis rate,oxidative stress level,mitochondrial structure and function,and mitophagy level were assessed after the treatment of DZM drug-containing serum for a duration of 24 h.The cellular expressions of BNIP3/mitophagy signaling pathway relevant genes and proteins were further evaluated using q RT-PCR and Western blot techniques.RESULTS:A total of 295 prototypes(e.g.,phenolic acids,quinones,terpenoids)were identified in serum of rats after oral administration of DZM.In vivo,DZM therapy has been shown to effectively enhance cardiac function,mitigate high-fat diet-induced myocardial structural damage and lipid accumulation.Furthermore,DZM has demonstrated the ability to reduce lipid levels,attenuate cell apoptosis,combat oxidative stress,enhance mitochondrial structure and function,and activate the BNIP3/mitophagy signaling pathway.Furthermore,the silencing of BNIP3 has been shown to exacerbate palmitic acid-induced damages in H9c2 cells,while inhibiting the BNIP3/mitophagy signaling pathway can mitigate the inhibitory effects of DZM on palmitic acidinduced apoptosis,lipid deposition and oxidative stress.CONCLUSION:This study presents preliminary evidence for the therapeutic efficacy of DZM on lipotoxic cardiomyopathy through the activating BNIP3/mitophagy signaling pathway.展开更多
Fatty acids are the primary fuel for cardiac muscle.The physiological equilibrium of lipid uptake and oxidation may aid in the prevention of excessive lipid accumulation.Several pathological states,such as myocardial ...Fatty acids are the primary fuel for cardiac muscle.The physiological equilibrium of lipid uptake and oxidation may aid in the prevention of excessive lipid accumulation.Several pathological states,such as myocardial ischemia,obesity,and insulin resistance,are routinely associated with disorders of lipid metabolism.There is growing evidence that certain types of lipids trigger cardiac lipotoxicity and ultimately heart failure.This review focuses on recent advances in the pathogenesis of lipotoxic cardiomyopathy and the treatment prospects for the repair of cardiac damage caused by lipotoxicity.展开更多
Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated b...Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index(BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome(MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods(fat). However, high-carbohydrate rich(CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering highdensity lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS.展开更多
Leptin is an adipokine that has been linked with the cardiovascular complications resulting from obesity such as hypertension and heart disease. Obese patients have high levels of circulating leptin due to increased f...Leptin is an adipokine that has been linked with the cardiovascular complications resulting from obesity such as hypertension and heart disease. Obese patients have high levels of circulating leptin due to increased fat mass. Clinical and population studies have correlated high levels of circulating leptin with the development of cardiac hypertrophy in obesity. Leptin has also been demonstrated to increase the growth of cultured cardiomyocytes. However, several animal studies of obese leptin deficient mice have not supported a role for leptin in promoting cardiac hypertrophy so the role of leptin in this pathological process remains unclear. Leptin is also an important hormone in the regulation of cardiac metabolism where it supports oxidation of glucose and fatty acids. In addition, leptin plays a critical role in protecting the heart from excess lipid accumulation and the formation of toxic lipids in obesity a condition known as cardiac lipotoxicity. This paper focuses on the data supporting and refuting leptin's role in promoting cardiac hypertrophy as well as its important role in the regulation of cardiac metabolism and protection against cardiac lipotoxicity.展开更多
Non-alcoholic fatty liver disease(NAFLD),the most common chronic liver disorder in Western countries,comprises steatosis to nonalcoholic steatohepatitis(NASH),with the latter having the potential to progress to cirrho...Non-alcoholic fatty liver disease(NAFLD),the most common chronic liver disorder in Western countries,comprises steatosis to nonalcoholic steatohepatitis(NASH),with the latter having the potential to progress to cirrhosis.The transition from isolated steatosis to NASH is still poorly understood,but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression.Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD.Changes in glycerophospholipid,sphingolipid,and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD,implicating that specific lipid species are involved in oxidative stress,inflammation,and cell death.In this article,we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.展开更多
Sangguayin preparation(SGY-P) is refined from the traditional Chinese medicinal compound Sangguayin, which"clears heat and promotes fluid" and "tonifies kidney and spleen" for "Xiaoke", c...Sangguayin preparation(SGY-P) is refined from the traditional Chinese medicinal compound Sangguayin, which"clears heat and promotes fluid" and "tonifies kidney and spleen" for "Xiaoke", commonly known as ‘Diabetes mellitus’ in clinics.Previous studies have shown that SGY-P could reduce insulin resistance and repair damaged pancreas in db/db mice, but the underlying mechanisms were unclear. Here, we investigated whether treatment with SGY-P could protect pancreatic β-cells from apoptosis and uncovered the underlying mechanisms. db/db mice were used to observe the hypoglycemic and islet protective effect in vivo. Apoptosis was induced in mouse insulinoma 6(MIN6) cells by palmitate, following which the cells were treated with SGY-P for elucidating the anti-apoptotic mechanism in vitro. Cell viability and nuclear morphology were detected by CCK-8 assay and Hoechst 33258 staining. The expression levels of apoptosis-, endoplasmic reticulum(ER) stress-, and autophagy-related proteins were measured by western blot. The results showed that SGY-P reduced fasting blood glucose, pancreatic pathological changes, and islet β-cell apoptosis in db/db mice. Palmitate-induced apoptosis in MIN6 cells was decreased by SGY-P treatment. Hence, SGY-P therapy exhibited a protective effect on pancreatic β-cells by decreasing the expression of cleaved caspase-3, cleaved PARP and Bax, and increasing Bcl-2 by suppressing ER stress(Bip/XBP1/IRE1α/CHOP/Caspase-12) and autophagy(LC3/p62/Atg5) pathways.2/Atg5 pathways.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and no...Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and non-alcoholic steatohepatitis(NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms,such as,insulin resistance(IR),lipotoxicity,inflammation,oxidative stress,and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1(GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion,inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted,GLP-1 is quickly degraded by dipeptidyl peptidase-4(DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1. Currently,GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors,such as the farsenoid X receptor,also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid(UDCA) is a hydrophilic bile acid with immunomodulatory,antiinflammatory,antiapoptotic,antioxidant and antifibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as,TGR5,farnesoid X receptor-a,or the small heterodimeric partner. Finally,pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion,inhibit mucosal adherence by bacteria,and stimulate host immunity. In animal models,probiotics prevent obesity,decrease transaminase levels,and improve IR and liver histology in NASH.展开更多
Objective The aim of this study is by observing the number change of islets beta cells in gestational rats exposed to high fat diet, tofurther reveal the mechanism of gestational diabetes mellitus. Methods Female Wist...Objective The aim of this study is by observing the number change of islets beta cells in gestational rats exposed to high fat diet, tofurther reveal the mechanism of gestational diabetes mellitus. Methods Female Wistar rats were exposed to high fat diet for five weeks, and then became pregnant. During pregnancy dynamically detected indicators of glucose and fat. Until the third trimester of pregnancy evaluated the sensitivity of insulin and glucose tolerance. After executed rats, selected pancreatic tail tissue and fixed, further slides were stained with insulin antibody by immunohistochemistry to confirm the location of beta cells. Image analysis system determined mean area stained positive cells in each islet, which stood for total number of beta cells. The apoptotic beta cells in islet were detected and quantified by the Tunel technology to calculate apoptosis ratio. Results The level of free fatty acids in rats exposed to high fat diet was significantly higher than the control groups, and insulin resistance was more serious. Compared mean stained positive area among each group, the largest was gestational rats fed high fat diet, and gestational rats was larger than virgin rats, but the difference had no statistical significance. About apoptoticratio of beta cells was higher in diet intervened rats, gestational rats were higher than virgin rats. The same trend happened in the number of positive cells, but discrepancy was not remarkable. Conclusion Based on insulin resistance, apoptosis of pancreatic beta cellsincreased in gestational ratstaking high fat diet, through changing the number of beta cells to down regulate the pancreas endocrine function. That may be the mechanism of gestational mellitus.展开更多
With the arrival of the new millennium,gastroenterologists have been faced with the problem of metabolic liver diseases associated with obesity.The active role of the liver in metabolism and inflammation make it a key...With the arrival of the new millennium,gastroenterologists have been faced with the problem of metabolic liver diseases associated with obesity.The active role of the liver in metabolism and inflammation make it a key organ in the war against the rapidly-spreading worldwide epidemic of obesity.Many lives and much money could be saved if the work of hepatologists led to the development of effective diagnostic and therapeutic strategies against this growing leader of cirrhosis.展开更多
Background: Impaired insulin sensitivity may partly arise from a dysregulated lipid metabolism in human skeletal muscle. This study investigates the expression levels of perilipin 2, 3, and 5, and four key lipases in ...Background: Impaired insulin sensitivity may partly arise from a dysregulated lipid metabolism in human skeletal muscle. This study investigates the expression levels of perilipin 2, 3, and 5, and four key lipases in human skeletal muscle from the subjects that exhibit a range from normal to very low insulin sensitivity. Methods: 25 middle aged male participants were matched for lean body mass and recruited into three groups;type 2 diabetes patients (T2D), impaired glucose tolerance (IGT), and healthy sedentary controls (CON) according to their glucose tolerance and VO2peak. A muscle biopsy was obtained from vastus lateralis, and a two-step sequential euglycaemic-hyperinsulinaemic clamp was performed. Muscle samples were analyzed by Western blot for expression of perilipin 2, 3, 5, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), endothelial lipase (EL) and lipoprotein lipase (LPL). Results: Perilipin 3 expression was higher in T2D compared to CON. Perilipin 2 expression was higher in CON than T2D. We observed no difference in expression of perili pin 5, ATGL, HSL, EL or LPL between the groups. Conclusions: In the present study the muscle perilipin 3 expression and perilipin 2 expression varied markedly with insulin sensitivity. This difference in perilipin expression may indicate that the lipid droplet function and thus storage and release of fatty acid-vary with insulin sensitivity.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)poses a sub-stantial global health burden,progressing from simple steatosis to metabolic dysfunction-associated steatohepatitis and cirrhosis.A deeper und...Metabolic dysfunction-associated steatotic liver disease(MASLD)poses a sub-stantial global health burden,progressing from simple steatosis to metabolic dysfunction-associated steatohepatitis and cirrhosis.A deeper understanding of the underlying mechanisms and associated complications is crucial for developing effective therapies.Extracellular vesicles(EVs),nanoscale membrane-enclosed particles carrying bioactive cargoes such as proteins and noncoding RNAs,including microRNAs and long noncoding RNAs,play crucial roles in intercel-lular communication and have emerged as critical mediators of MASLD patho-genesis.This article details the current understanding of the function of EVs in MASLD progression,emphasizing specific cell-derived EVs implicated in disease development.We elucidate how EVs facilitate intercellular communication and influence key pathological processes,including lipotoxicity,inflammation,and fibrosis.Furthermore,we examine the involvement of EVs in MASLD-associated complications and evaluate their potential as minimally invasive tools for disease diagnosis,staging,and prognosis.We also explore EV-based therapeutic stra-tegies,encompassing preclinical studies,while acknowledging current challenges and future opportunities.Finally,we discuss emerging research trends,the po-tential for personalized medicine,and areas necessitating further investigation,particularly the utilization of EVs as therapeutic targets or delivery vehicles.This review underscores the pivotal role of EVs in MASLD,providing insights into their translational potential for improved patient outcomes.展开更多
This study evaluated the effects of different proportions of palmitic(C16:0)and oleic(cis-9 C18:1)acids in fat supplements on rumen fermentation,glucose(GLU)and lipid metabolism,antioxidant function,and visceral fat f...This study evaluated the effects of different proportions of palmitic(C16:0)and oleic(cis-9 C18:1)acids in fat supplements on rumen fermentation,glucose(GLU)and lipid metabolism,antioxidant function,and visceral fat fatty acid(FA)composition in Angus bulls.The design of the experiment was a randomized block design with 3 treatments of 10 animals each.A total of 30 finishing Angus bulls(21±0.5 months)with an initial body weight of 626±69 kg were blocked by weight into 10 blocks,with 3 bulls per block.The bulls in each block were randomly assigned to one of three experimental diets:(1)control diet without additional fat(CON),(2)CON+2.5%palmitic calcium salt(PA;90%C16:0),(3)CON+2.5%mixed FA calcium salts(MA;60%C16:0+30%cis-9 C18:1).Both fat supplements increased C18:0 and cis-9 C18:1 in visceral fat(P<0.05)and up-regulated the expression of liver FA transport protein 5(FATP5;P<0.001).PA increased the insulin concentration(P<0.001)and aspartate aminotransferase activity(AST;P=0.030)in bull's blood while reducing the GLU concentration(P=0.009).PA increased the content of triglycerides(TG;P=0.014)in the liver,the content of the C16:0 in visceral fat(P=0.004),and weight gain(P=0.032),and up-regulated the expression of liver diacylglycerol acyltransferase 2(DGAT2;P<0.001)and stearoyl-CoA desaturase 1(SCD1;P<0.05).MA increased plasma superoxide dismutase activity(SOD;P=0.011),reduced the concentration of acetate and total volatile FA(VFA)in rumen fluid(P<0.05),and tended to increase plasma non-esterified FA(NEFA;P=0.069)concentrations.Generally,high C16:0 fat supplementation increased weight gain in Angus bulls and triggered the risk of fatty liver,insulin resistance,and reduced antioxidant function.These adverse effects were alleviated by partially replacing C16:0 with cis-9 C18:1.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071376(to ZC)and 82001471(to CJ)the Natural Science Foundation of Shanghai,No.20ZR1410500(to ZC).
文摘Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.
基金supported by grants from the National Natural Science Foundation of China(No.81830024,No.82270844 and No.82070843).
文摘Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cell dysfunction remains unclear.This study aims to study its role.Methods:Pancreas slices were prepared from mice subjected to a high-fat-diet(HFD)at different time points,and TRPM5 expression in the pancreaticβcells was examined using immunofluorescence staining.Glucose-stimulated insulin secretion(GSIS)defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate(Palm).Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm,and the TRPM5 expression was detected using qRT-PCR and Western blotting.Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown.The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5(Ad-Trpm5).Results:HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets.Palm reduced TRPM5 protein expression in a time-and dose-dependent manner in MIN6 cells.Palm also inhibited TRPM5 expression in primary mouse islets.Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis.Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique toβcells.Conclusion:Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreaticβcells both in vivo and in vitro and,in turn,drivesβ-cell dysfunction.
基金Supported by Hungarian Scientific Research Fund(OTKA 104113 and 106060)the Hungarian Research and Technological Innovation Fund(KMR_12-1-2012-0074)
文摘Obesity due to excessive food intake and the lack of physical activity is becoming one of the most serious public health problems of the 21stcentury. With the increasing prevalence of obesity, non-alcoholic fatty liver disease is also emerging as a pandemic. While previously this pathophysiological condition was mainly attributed to triglyceride accumulation in hepatocytes,recent data show that the development of oxidative stress, lipid peroxidation, cell death, inflammation and fibrosis are mostly due to accumulation of fatty acids,and the altered composition of membrane phospholipids. In fact, triglyceride accumulation might play a protective role, and the higher toxicity of saturated or trans fatty acids seems to be the consequence of a blockade in triglyceride synthesis. Increased membrane saturation can profoundly disturb cellular homeostasis by impairing the function of membrane receptors,channels and transporters. However, it also inducesendoplasmic reticulum stress via novel sensing mechanisms of the organelle's stress receptors. The triggered signaling pathways in turn largely contribute to the development of insulin resistance and apoptosis. These findings have substantiated the lipotoxic liver injury hypothesis for the pathomechanism of hepatosteatosis.This minireview focuses on the metabolic and redox aspects of lipotoxicity and lipoapoptosis, with special regards on the involvement of endoplasmic reticulum stress responses.
基金supported by the University of Pittsburgh School of Pharmacy and NIH Grants R01CA216815 and R01DK140079(USA).
文摘One of the leading therapies for acute lymphoblastic leukemia(ALL)is the chemotherapeutic agent PEGylated E.coli-derived-l-asparaginase(PEG-ASNase).Due to the high risk of dose-limiting liver injury,characterized by clinically elevated levels of hepatic transaminases,PEG-ASNase therapy is generally avoided in adult patients.Our preclinical investigations have indicated that PEG-ASNase-induced liver injury is associated with the release of free fatty acids(FFAs)from white adipose tissue(WAT),suggesting potential lipotoxic effects.However,it remains uncertain whether PEG-ASNase directly induces hepatotoxicity or sensitizes hepatocytes to FFA-induced toxicity.Our results show that PEG-ASNase treatment results in hepatocyte apoptosis and lipid peroxidation.Ex vivo and in vitro studies in mouse and human WAT suggest that PEG-ASNase induces the expression of adipose triglyceride lipase(ATGL),activates the lipase,and stimulates adipose tissue lipolysis,suggesting that the FFAs from WAT may contribute to the observed liver injury.Moreover,treatment with PEG-ASNase sensitizes hepatocytes to FFA-induced lipotoxicity.Mechanistically,our RNA-sequencing(RNA-seq)analyses reveal that PEG-ASNase-induced sensitization to lipotoxicity is accompanied by the induction of Cyp2e1.We demonstrated that this sensitization effect is attenuated by both pharmacological and genetic inhibition of Cyp2e1.Our findings suggest that PEG-ASNase therapy induces WAT lipolysis and sensitizes hepatocytes to hepatic lipotoxicity in a Cyp2e1-dependent manner.
基金This study was supported by National Natural Science Foundation of China(82260674 to Yong Rao,82160653 to Ling Huang)Fundamental Research Funds for Hainan University(KYQD(ZR)-21114 to Yong Rao,KYQD(ZR)-21089 to Ling Huang,China)+2 种基金Hainan Provincial Natural Science Foundation of China(822MS054 to Yong Rao)Natural Science Foundation of Guangdong Province(2021A1515010488 to Yong Rao,China)Central Public-interest Scientific Institution Basal Research Fund for CATAS-ITBB(1630052022016,1630052019011,China).
文摘Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease(MAFLD).However,there are few reported lipotoxicity inhibitors.Here,we identified a natural anti-lipotoxicity candidate,HN-001,from the marine fungus Aspergillus sp.C1.HN-001 dose-and time-dependently reversed palmitic acid(PA)-induced hepatocyte death.This protection was associated with IRE-1a-mediated XBP-1 splicing inhibition,which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation.Knockdown of XBP-1s attenuated lipotoxicity,but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes.Notably,the ER stress and lipotoxicity amelioration was associated with PLA2.Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity,reduced lysophosphatidylcholine(LPC)level,subsequently ameliorated lipotoxicity.In contrast,overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001.Additionally,HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway.In vivo,chronic administration of HN-001(i.p.)in mice alleviated all manifestations of MAFLD,including hepatic steatosis,liver injury,inflammation,and fibrogenesis.These effects were correlated with PLA2/IRE-1a/XBP-1s axis and JNK signaling suppression.These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity,and provide a natural structural basis for developing anti-MAFLD candidates.
基金supported by the Office of Naval Research Grant(N00014-22-1-2184)。
文摘Diabetic cardiomyopathy(DCM)is a major cause of heart failure in diabetic patients.It progresses asymptomatically prior to the onset of severe cardiac symptoms[1];therefore,elucidating the underlying mechanisms of DCM is critical to providing early treatment options.This commentary elaborates on the findings of Jiang et al.[2],who investigated the role of adipokine hormone,Adipsin,as a cardioprotective factor in DCM.We provide an exposition and alternative treatment considerations,like Fisetin,and discuss the potential of investigating other cellular targets implicated in cardiac dysfunction,like the interleukin-1 receptor-associated kinaselike 2(Irak2)protein[3]and protein kinase R[4].
基金This work was supported by the National Natural Science Foundation of China(Nos.91129727,81020108031,and 30973558)the Major Specialized Research Fund from the Ministry of Science and Technology in China(No.2009ZX09103-144).
文摘Over the last 20 years,intensive research has been focused on the specific mechanisms mediating the pancreatic β-cell injury.Both the decreased viability and the dysfunction of β-cells have become the key factors in the development of dia betes mellitus.Thus,it is of utmost importance to elucidate the discrete pathological changes in pancreatic β-cells within the context of the various lipotoxicity models.The goal of these studies is to generate evidence to improve not only the clinical treatment for dia betics,but also modulate the diet and activities of groups at high risk for diabetes.In this regard,we review the role of lipotoxicity in pancreatic β-cell injury and identify potential therapeutic targets in this cell model.
基金supported by grants from National Natural Science Foundation of China(32172192)Zhejiang Provincial Key R&D Pro-gram of China(2021C02018)Open Project of Wencheng Joint Research Center of Big Health Industry of Zhejiang University(Zdwc2205).
文摘Fructus Gardeniae(FG)is the dried ripe fruit of Gardenia jasminoides Ellis,having beneficial effects for human health.In this study,we discovered that the most relevant pathway influenced by Fructus Gardeniae extract(FGE)is lipid metabolism according to the analysis of network pharmacology.Furthermore,the protective effect of FGE against palmitic acid-induced lipotoxicity was investigated.In L02 cells,FGE significantly promoted cellular proliferation after being treated with palmitic acid,and reduced the accumulation of lipid droplets and triglyceride level.Palmitic acid led to an increase of ROS content,which was reduced by FGE.Additionally,FGE could facilitate Nrf2 localized to nuclear and followed by activating its downstream targets.ML385(a Nrf2 inhibitor)treatment further proved that FGE attenuated lipotoxicity through regulating Nrf2/ARE pathway.Consequently,we demonstrated for the first time FGE could be regarded as potential functional food materials for hepatic protection.
基金Scientific Research Project of Hebei Province Administration of Traditional Chinese Medicine:to Explore the Protective Effect and Mechanism of Zexie Decoction on Lipotoxic Cardiomyopathy based on the p-mitogen-activated protein kinases/Peroxisome proliferator-activated receptorγcoactivator 1-alpha(p MAPK/PGC-1α)Signaling Pathway(No.2022096)Medical Science Research Project of Hebei Province:the Effect of 23-acetyl Alismol-B on Mitochondrial Function in Palmitic Acid-induced H9c2 Cells Was Investigated based on the Ca2+-Cyclic Adenosine Monophosphate(c AMP)-Response Element Binding Protein/c AMP Response Element(CREB/CRE)-PGC-1αSignaling Pathway(No.20221490)+1 种基金Hebei province natural science fund project:Study on the Mechanism of Danshen Zexie Decoction in Activating Nuclear Factor Erythroid 2-related Factor 2 Signaling Pathway to Trigger 0mi/Htr A2,Restoring Autophagic Flux and Enhancing Metabolism-Related Fatty Liver Disease(No.H2023423064)Hebei graduate student innovation ability funding training project:to Investigate the Protective Effects and Underlying Mechanisms of Zexie Decoction on Lipotoxic Cardiomyopathy,with A Focus on the PGC-1a Signaling Pathway(No.CXZZBS2022096)。
文摘OBJECTIVE:To investigate the mechanism of Dan Ze mixture(丹泽合剂,DZM)in the treatment of lipotoxic cardiomyopathy.METHODS:Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize the serum migration constituents of DZM.A lipotoxic cardiomyopathy rat model was established through high-fat diet and intervened by different doses of DZM.The cardiac function was assessed using echocardiography,and hematoxylin and eosin,oil red O,and Masson staining were conducted to evaluate morphological changes,lipid accumulation,and fibrosis in myocardial tissue.Serum myocardial enzyme activity,lipid levels,and lipid content of myocardial tissue were measured,while fluorescent staining and colorimetry were used to assess oxidation levels in myocardial tissue.Mitochondrial membrane potential was detected by 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanineiodide(JC-1).Transmission electron microscopy was employed to observe ultrastructure and mitochondrial structure changes in myocardial tissue.Fluorescence double staining and colocalization were utilized to observe the binding of autophagosomes and mitochondria,while immunohistochemical staining was used to detect the expression of mitophagy-related proteins.Terminal deoxynucleoitidyl transferase mediated nick end labeling staining was employed for the identification of apoptosis in myocardial tissue,while quantitative real-time reverse transcriptase polymerase chain reaction(q RT-PCR)and Western blot were utilized for the detection of apoptosis,B-cell lymphoma-2 adenovirus E1B 19 k Da-interacting protein 3(BNIP3)/mitophagy signaling pathway-related genes and proteins.In palmitic acid-induced Rat H9C2 cardiomyocytes(H9c2)cells,various cellular parameters including cell viability,lactate dehydrogenase release,apoptosis rate,oxidative stress level,mitochondrial structure and function,and mitophagy level were assessed after the treatment of DZM drug-containing serum for a duration of 24 h.The cellular expressions of BNIP3/mitophagy signaling pathway relevant genes and proteins were further evaluated using q RT-PCR and Western blot techniques.RESULTS:A total of 295 prototypes(e.g.,phenolic acids,quinones,terpenoids)were identified in serum of rats after oral administration of DZM.In vivo,DZM therapy has been shown to effectively enhance cardiac function,mitigate high-fat diet-induced myocardial structural damage and lipid accumulation.Furthermore,DZM has demonstrated the ability to reduce lipid levels,attenuate cell apoptosis,combat oxidative stress,enhance mitochondrial structure and function,and activate the BNIP3/mitophagy signaling pathway.Furthermore,the silencing of BNIP3 has been shown to exacerbate palmitic acid-induced damages in H9c2 cells,while inhibiting the BNIP3/mitophagy signaling pathway can mitigate the inhibitory effects of DZM on palmitic acidinduced apoptosis,lipid deposition and oxidative stress.CONCLUSION:This study presents preliminary evidence for the therapeutic efficacy of DZM on lipotoxic cardiomyopathy through the activating BNIP3/mitophagy signaling pathway.
基金C.B.L.from the National Natural Science Foundation of China(82070388)Taishan Pandeng Scholar Program of Shandong Province(tspd20181220)the National Natural Science Foundation of Shandong Province(ZR2020MH035).
文摘Fatty acids are the primary fuel for cardiac muscle.The physiological equilibrium of lipid uptake and oxidation may aid in the prevention of excessive lipid accumulation.Several pathological states,such as myocardial ischemia,obesity,and insulin resistance,are routinely associated with disorders of lipid metabolism.There is growing evidence that certain types of lipids trigger cardiac lipotoxicity and ultimately heart failure.This review focuses on recent advances in the pathogenesis of lipotoxic cardiomyopathy and the treatment prospects for the repair of cardiac damage caused by lipotoxicity.
文摘Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index(BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome(MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods(fat). However, high-carbohydrate rich(CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering highdensity lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS.
基金the National Heart,Lung and Blood Institute,Nos.PO1HL-051971 and R00HL112952the National Institute of General Medical Sciences,No.P20GM-104357the American Heart Association,No.14SDG20490339
文摘Leptin is an adipokine that has been linked with the cardiovascular complications resulting from obesity such as hypertension and heart disease. Obese patients have high levels of circulating leptin due to increased fat mass. Clinical and population studies have correlated high levels of circulating leptin with the development of cardiac hypertrophy in obesity. Leptin has also been demonstrated to increase the growth of cultured cardiomyocytes. However, several animal studies of obese leptin deficient mice have not supported a role for leptin in promoting cardiac hypertrophy so the role of leptin in this pathological process remains unclear. Leptin is also an important hormone in the regulation of cardiac metabolism where it supports oxidation of glucose and fatty acids. In addition, leptin plays a critical role in protecting the heart from excess lipid accumulation and the formation of toxic lipids in obesity a condition known as cardiac lipotoxicity. This paper focuses on the data supporting and refuting leptin's role in promoting cardiac hypertrophy as well as its important role in the regulation of cardiac metabolism and protection against cardiac lipotoxicity.
文摘Non-alcoholic fatty liver disease(NAFLD),the most common chronic liver disorder in Western countries,comprises steatosis to nonalcoholic steatohepatitis(NASH),with the latter having the potential to progress to cirrhosis.The transition from isolated steatosis to NASH is still poorly understood,but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression.Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD.Changes in glycerophospholipid,sphingolipid,and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD,implicating that specific lipid species are involved in oxidative stress,inflammation,and cell death.In this article,we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.
基金Chinese Medicine Research Program of Hunan Province(No.201999)。
文摘Sangguayin preparation(SGY-P) is refined from the traditional Chinese medicinal compound Sangguayin, which"clears heat and promotes fluid" and "tonifies kidney and spleen" for "Xiaoke", commonly known as ‘Diabetes mellitus’ in clinics.Previous studies have shown that SGY-P could reduce insulin resistance and repair damaged pancreas in db/db mice, but the underlying mechanisms were unclear. Here, we investigated whether treatment with SGY-P could protect pancreatic β-cells from apoptosis and uncovered the underlying mechanisms. db/db mice were used to observe the hypoglycemic and islet protective effect in vivo. Apoptosis was induced in mouse insulinoma 6(MIN6) cells by palmitate, following which the cells were treated with SGY-P for elucidating the anti-apoptotic mechanism in vitro. Cell viability and nuclear morphology were detected by CCK-8 assay and Hoechst 33258 staining. The expression levels of apoptosis-, endoplasmic reticulum(ER) stress-, and autophagy-related proteins were measured by western blot. The results showed that SGY-P reduced fasting blood glucose, pancreatic pathological changes, and islet β-cell apoptosis in db/db mice. Palmitate-induced apoptosis in MIN6 cells was decreased by SGY-P treatment. Hence, SGY-P therapy exhibited a protective effect on pancreatic β-cells by decreasing the expression of cleaved caspase-3, cleaved PARP and Bax, and increasing Bcl-2 by suppressing ER stress(Bip/XBP1/IRE1α/CHOP/Caspase-12) and autophagy(LC3/p62/Atg5) pathways.2/Atg5 pathways.
文摘Non-alcoholic fatty liver disease(NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as nonalcoholic fatty liver(NAFL) or simple steatosis,and non-alcoholic steatohepatitis(NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms,such as,insulin resistance(IR),lipotoxicity,inflammation,oxidative stress,and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon-like peptide-1(GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose-stimulated insulin secretion,inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted,GLP-1 is quickly degraded by dipeptidyl peptidase-4(DPP-4). Therefore,DPP-4 inhibitors are able to extend the activity of GLP-1. Currently,GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors,such as the farsenoid X receptor,also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid(UDCA) is a hydrophilic bile acid with immunomodulatory,antiinflammatory,antiapoptotic,antioxidant and antifibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as,TGR5,farnesoid X receptor-a,or the small heterodimeric partner. Finally,pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion,inhibit mucosal adherence by bacteria,and stimulate host immunity. In animal models,probiotics prevent obesity,decrease transaminase levels,and improve IR and liver histology in NASH.
文摘Objective The aim of this study is by observing the number change of islets beta cells in gestational rats exposed to high fat diet, tofurther reveal the mechanism of gestational diabetes mellitus. Methods Female Wistar rats were exposed to high fat diet for five weeks, and then became pregnant. During pregnancy dynamically detected indicators of glucose and fat. Until the third trimester of pregnancy evaluated the sensitivity of insulin and glucose tolerance. After executed rats, selected pancreatic tail tissue and fixed, further slides were stained with insulin antibody by immunohistochemistry to confirm the location of beta cells. Image analysis system determined mean area stained positive cells in each islet, which stood for total number of beta cells. The apoptotic beta cells in islet were detected and quantified by the Tunel technology to calculate apoptosis ratio. Results The level of free fatty acids in rats exposed to high fat diet was significantly higher than the control groups, and insulin resistance was more serious. Compared mean stained positive area among each group, the largest was gestational rats fed high fat diet, and gestational rats was larger than virgin rats, but the difference had no statistical significance. About apoptoticratio of beta cells was higher in diet intervened rats, gestational rats were higher than virgin rats. The same trend happened in the number of positive cells, but discrepancy was not remarkable. Conclusion Based on insulin resistance, apoptosis of pancreatic beta cellsincreased in gestational ratstaking high fat diet, through changing the number of beta cells to down regulate the pancreas endocrine function. That may be the mechanism of gestational mellitus.
文摘With the arrival of the new millennium,gastroenterologists have been faced with the problem of metabolic liver diseases associated with obesity.The active role of the liver in metabolism and inflammation make it a key organ in the war against the rapidly-spreading worldwide epidemic of obesity.Many lives and much money could be saved if the work of hepatologists led to the development of effective diagnostic and therapeutic strategies against this growing leader of cirrhosis.
基金Financial support from The 1991 Pharmacy Foundation,NOVO Nordic Foundation,Direktor Verner Richter and Hustrus foundation,the foundation of 1870,Direktor Jacob and Olga Madsens foundation,Aase and Ejnar Danielsens foundation and EU project EXGENESIS 005272 is gratefully acknowledged
文摘Background: Impaired insulin sensitivity may partly arise from a dysregulated lipid metabolism in human skeletal muscle. This study investigates the expression levels of perilipin 2, 3, and 5, and four key lipases in human skeletal muscle from the subjects that exhibit a range from normal to very low insulin sensitivity. Methods: 25 middle aged male participants were matched for lean body mass and recruited into three groups;type 2 diabetes patients (T2D), impaired glucose tolerance (IGT), and healthy sedentary controls (CON) according to their glucose tolerance and VO2peak. A muscle biopsy was obtained from vastus lateralis, and a two-step sequential euglycaemic-hyperinsulinaemic clamp was performed. Muscle samples were analyzed by Western blot for expression of perilipin 2, 3, 5, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), endothelial lipase (EL) and lipoprotein lipase (LPL). Results: Perilipin 3 expression was higher in T2D compared to CON. Perilipin 2 expression was higher in CON than T2D. We observed no difference in expression of perili pin 5, ATGL, HSL, EL or LPL between the groups. Conclusions: In the present study the muscle perilipin 3 expression and perilipin 2 expression varied markedly with insulin sensitivity. This difference in perilipin expression may indicate that the lipid droplet function and thus storage and release of fatty acid-vary with insulin sensitivity.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)poses a sub-stantial global health burden,progressing from simple steatosis to metabolic dysfunction-associated steatohepatitis and cirrhosis.A deeper understanding of the underlying mechanisms and associated complications is crucial for developing effective therapies.Extracellular vesicles(EVs),nanoscale membrane-enclosed particles carrying bioactive cargoes such as proteins and noncoding RNAs,including microRNAs and long noncoding RNAs,play crucial roles in intercel-lular communication and have emerged as critical mediators of MASLD patho-genesis.This article details the current understanding of the function of EVs in MASLD progression,emphasizing specific cell-derived EVs implicated in disease development.We elucidate how EVs facilitate intercellular communication and influence key pathological processes,including lipotoxicity,inflammation,and fibrosis.Furthermore,we examine the involvement of EVs in MASLD-associated complications and evaluate their potential as minimally invasive tools for disease diagnosis,staging,and prognosis.We also explore EV-based therapeutic stra-tegies,encompassing preclinical studies,while acknowledging current challenges and future opportunities.Finally,we discuss emerging research trends,the po-tential for personalized medicine,and areas necessitating further investigation,particularly the utilization of EVs as therapeutic targets or delivery vehicles.This review underscores the pivotal role of EVs in MASLD,providing insights into their translational potential for improved patient outcomes.
基金supported by the earmarked fund for CARS36,the Natural Science Foundation of Heilongjiang Province,China (YQ2023C011)the"Academic Backbone"Project of Northeast Agricultural University.China (22XG35).
文摘This study evaluated the effects of different proportions of palmitic(C16:0)and oleic(cis-9 C18:1)acids in fat supplements on rumen fermentation,glucose(GLU)and lipid metabolism,antioxidant function,and visceral fat fatty acid(FA)composition in Angus bulls.The design of the experiment was a randomized block design with 3 treatments of 10 animals each.A total of 30 finishing Angus bulls(21±0.5 months)with an initial body weight of 626±69 kg were blocked by weight into 10 blocks,with 3 bulls per block.The bulls in each block were randomly assigned to one of three experimental diets:(1)control diet without additional fat(CON),(2)CON+2.5%palmitic calcium salt(PA;90%C16:0),(3)CON+2.5%mixed FA calcium salts(MA;60%C16:0+30%cis-9 C18:1).Both fat supplements increased C18:0 and cis-9 C18:1 in visceral fat(P<0.05)and up-regulated the expression of liver FA transport protein 5(FATP5;P<0.001).PA increased the insulin concentration(P<0.001)and aspartate aminotransferase activity(AST;P=0.030)in bull's blood while reducing the GLU concentration(P=0.009).PA increased the content of triglycerides(TG;P=0.014)in the liver,the content of the C16:0 in visceral fat(P=0.004),and weight gain(P=0.032),and up-regulated the expression of liver diacylglycerol acyltransferase 2(DGAT2;P<0.001)and stearoyl-CoA desaturase 1(SCD1;P<0.05).MA increased plasma superoxide dismutase activity(SOD;P=0.011),reduced the concentration of acetate and total volatile FA(VFA)in rumen fluid(P<0.05),and tended to increase plasma non-esterified FA(NEFA;P=0.069)concentrations.Generally,high C16:0 fat supplementation increased weight gain in Angus bulls and triggered the risk of fatty liver,insulin resistance,and reduced antioxidant function.These adverse effects were alleviated by partially replacing C16:0 with cis-9 C18:1.
