Insulin plays a crucial role in the metabolic priming and proliferation of neural stem cells(NSCs).However,insulin resistance(IR)is associated with impaired NSC proliferation and cognitive dysfunction,which are the ha...Insulin plays a crucial role in the metabolic priming and proliferation of neural stem cells(NSCs).However,insulin resistance(IR)is associated with impaired NSC proliferation and cognitive dysfunction,which are the hallmarks of psychiatric disorders(PDs).In addition to insulin,de novo lipogenesis(DNL)also plays an essential role in NSC proliferation and function as it supplies fatty acids for membrane phospholipid synthesis and cell signaling.However,enhanced DNL is associated with lipid/fatty acid accumulation,IR,and impaired NSC proliferation.Intriguingly,data from lipidomic studies suggest that DNL could be enhanced before the onset of classical symptoms in patients with PDs.Further,evidence suggests that patients with PDs may develop IR during childhood or before adolescence;therefore,DNL could be enhanced preceding the development of IR.Regarding treatment,while most antidepressants and antipsychotic drugs have been shown to further deteriorate IR and stimulate DNL,various adjunctive drugs/therapies,including chemical,physical,and stem cell therapy,which have shown promising success in treating PDs,reduce DNL while enhancing insulin sensitivity,NSC proliferation,and cognitive function in laboratory animals.Preliminary clinical outcomes and future prospects of these adjunctive drugs/therapies,especially stem cell therapy in treating PDs including schizophrenia and depression,are discussed.展开更多
Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegen...Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.展开更多
This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same da...This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.展开更多
Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully unders...Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood,especially in teleosts.In this study,cyp17a1-/-zebrafish(Danio rerio)exhibited excessive visceral adipose tissue(VAT),lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis(DNL)enzymes.The assay for transposase accessible chromatinwithsequencing(ATAC-seq)results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/-fish compared to cyp17a1+/+male fish,including stearoyl-CoA desaturase(scd)and fatty acid synthase(fasn).Androgen response element(ARE)motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+male fish but not in cyp17a1-/-fish.Both androgen receptor(ar)-/-and wildtype(WT)zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue,lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis enzymes.The Ar agonist BMS-564929 reduced the content of VAT and lipid content,and down-regulated acetyl-CoA carboxylase a(acaca),fasn,and scd expression.Mechanistically,the rescue effect of testosterone on cyp17a1-/-fish in terms of phenotypes was abolished when ar was additionally depleted.Collectively,these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish,thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.展开更多
Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-bi...Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-binding protein a （C/EBPa） and sterol regulatory element binding protein-1 （SREBP1）, play fundamental roles in metabolic pathways. And they are also important in adipocyte differentiation. Expressions of these factors are regulated by some compounds such as fatty acids or some steroid hormones （insulin） which is stimulated by the nutritional level. Furthermore, these factors are related to some metabolic diseases including type II diabetes and obesity, Lots of researches have focused on relationships between the factors and the genetic diseases. Different functions of factors on inducing the adipocyte differentiation are other hot spots according to previous studies. This paper summarized these studies and gave a limpid description of structures and functions of these genes.展开更多
The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic r...The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic reticulum (ER) is critically involved in lipid homeostasis and the development of metabolic disease. The ER is a site where newly-synthesized proteins are folded and assembled into their three-dimensional structures, modified and transported to their precise cellular destinations. A wide range of biochemical, physiological and pathological stimuli can interrupt the protein folding process in the ER and cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition referred to as ER stress. To cope with this stress condition, the ER has evolved highly-specifi c signaling pathways collectively termed Unfolded Protein Response (UPR) or ER stress response. The UPR regulates transcriptionaland translational programs, affecting broad aspects of cellular metabolism and cell fate. Lipogenesis, the metabolic process of de novo lipid biosynthesis, occurs primarily in the liver where metabolic signals regulate expression of key enzymes in glycolytic and lipogenic pathways. Recent studies suggest that the UPR plays crucial roles in modulating lipogenesis under metabolic conditions. Here we address some of recent representative evidence regarding the role of the UPR in lipogenesis.展开更多
Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical sy...Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.展开更多
Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional ...Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional AM extract was recently developed. The objective of this study was to examine the effect of AM-Ex on adipogenesis and its action mechanisms in vitro using 3T3-L1 adipocytes. To examine the anti-obesity effect of AM-Ex, 3T3-L1 cells were induced adipocyte differentiation and incubated with various concentration of AM-Ex. Lipid accumulation, cellular triglyceride content, mRNA expression of transcription factors and adipogenic genes were analyzed. Treatment with 100 - 400 μg/mL of AM-Ex resulted in a dose-dependent decrease in adipocyte differentiation and triglyceride accumulation. mRNA expression of adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1 were decreased. The level of gene expression of adipogenesis and lipogenesis-related genes, such as adipocyte protein 2, lipoprotein lipase, acetyl-CoA carboxylase, ATP-citrate lyase and fatty acid synthase were decreased. These results suggest that AM-Ex alleviated risk factors related to obesity by modulating multiple pathways associated with adipogenesis.展开更多
This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regu...This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regulation of mTORC1.Initially,SKOV3 cells were cultured in the humidified conditions in DMEM media for 24 h with or without increasing concentration of Pterostilbene.Then,the cells were incubated with Pterostilbene(IC_(50)=50μM)under similar conditions with or without pre-incubation with Dorsomorphin,an AMPK inhibitor.In a dose-dependent manner,Pterostilbene inhibited SKOV3 cell survival and increased their lysate levels of lactate dehydrogenase(LDH)and single-stranded DNA(ssDNA).When SKOV3 cells were treated with 50μM Pterostilbene,Pterostilbene significantly suppressed cell migration and invasion,reduced lysate levels of lactic acid and the optical density of Oil Red O staining,and increased lysate glucose levels.It also increased levels of malondialdehyde(MDA),reactive oxygen species(ROS),and induced intrinsic cell apoptosis by upregulating protein levels of Bax and cleaved caspase-3 and reducing protein levels of Bcl-2.Besides,Pterostilbene reduced mRNA levels of sterol regulatory element-binding protein 1(SREBP-1),fatty acid synthase(FAS),acetyl CoA carboxylase-1(ACC-1),and AMP-activated protein kinase(AMPK).Furthermore,Pterostilbene increased the protein levels of p-AMPK,p-p53,p-raptor,p-TSC-2,but significantly decreased protein levels of p-Akt,p-TSC-2,p-mTOR,p-S6K1,and p-4E-BP.Treatment with Dorsomorphin(CC)abolished all the anti-tumorigenesis effects afforded by Pterostilbene and prevented Pterostilbene-induced phosphorylation of Akt,p53,and mTOR.In conclusion,the tumorsuppressive effect of Pterostilbene in SKOV3 cells involves the induction of ROS and inhibition of dysregulation cell metabolism mainly due to AMPK-induced Akt-dependent or independent suppression of mTOR.展开更多
Background: De novo lipogenesis (DNL) is a critical event for the development of tumors, in the present work,we revealed the role of propofol in colorectal cancer (CRC) cell proliferation. Methods: Western blotting (W...Background: De novo lipogenesis (DNL) is a critical event for the development of tumors, in the present work,we revealed the role of propofol in colorectal cancer (CRC) cell proliferation. Methods: Western blotting (WB), Real-timePCR, and luciferase combined with chromatin immunoprecipitation (ChIP) were used to identify the mechanismunderlying propofol-modulated cell proliferation in CRC cells. Results: Herein, we showed that propofol suppressedcell proliferation, which was attributed to the inhibition of DNL characterized by reduced fatty acid synthase (FASN),acetyl-coA carboxylase alpha (ACCA), and stearoyl-coA desaturase-1 (SCD1) expression. Mechanically, propofolstimulation decreased sterol regulatory element-binding proteins-1c (SREBP-1c) mature and nuclear translocation,which further decreased SCD1 transactivation confirmed by luciferase and ChIP analysis, while no significantdifference in total SREBP1c was observed. What’s more, supplementation of Monounsaturated fatty acid (MuFA)could reverse the inhibitory effect of propofol on cell proliferation. Conclusion: Taken together, these resultssuggested propofol modulated cell proliferation is dependent on SREBP1c-mediated DNL.展开更多
Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acety...Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acetyltransferase 1(HAT1)confers reprogramming of gluconeogenesis/lipogenesis in liver cancer.Diethylnitrosamine(DEN)/carbon tetrachloride(CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice.Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver.Protein phosphatase 2 scaffold subunit alpha(PPP2R1A)promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1(PCK1)serine 90 dephosphorylation to suppress the tumor growth.HAT1 succinylated PPP2R1A at lysine 541(K541)to block the assembly of protein phosphatase 2A(PP2A)holoenzyme and interaction with PCK1,resulting in the depression of dephosphorylation of PCK1.HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation,leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1(SREBP1)nuclear accumulation-induced lipogenesis gene expression,which enhanced the tumor growth.In conclusion,succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer.Our finding provides new insights into the mechanism by which post-translational modifications(PTMs)confer the conversion of tumor suppressor function to oncogene.展开更多
Alternative polyadenylation(APA)is a pervasive mechanism that is emerging as a formidable player in post-transcriptional regulation.The transcriptional landscape can be altered via APA in response to various stimulati...Alternative polyadenylation(APA)is a pervasive mechanism that is emerging as a formidable player in post-transcriptional regulation.The transcriptional landscape can be altered via APA in response to various stimulating factors.Using the Pac Bio single-molecule long-read sequencing method,we present for the first time the 3′UTR landscape and reveal a global increase of APA events in prostate cancer(PCa)LNCa P cells in response to androgen dihydrotestosterone(DHT),a critical regulator of PCa progression.With evidence from differential gene expression analyses of Illumina RNA-sequencing data,we demonstrated that genes with DHT-induced changes in both expression and APA were enriched in lipid metabolism.These genes predominantly supported de novo fatty acid synthesis,such as FASN and ACSL3.Furthermore,we showed that an isoform switch to the proximal poly(A)site of these genes depended on the androgen receptor,and the expression of cancer-associated genes was upregulated by the escape of mi RNA-regulated repression machinery.To address the role of key gene shortening in PCa,we prepared 22RV1-FS cells missing the distal poly(A)signal of FASN in the AR+PCa cell line 22RV1 using CRISPR/Cas9 technology.As expected,the edited 22RV1-FS cells overexpressed FASN m RNA and protein and were inclined to cell proliferation in vitro and tumorigenesis in vivo.Interestingly,we found that FASN transcripts with a shortened 3′UTR were significantly increased in advanced PCa and castration-resistant prostate cancer compared with benign prostate hyperplasia,suggesting a possible association between usage of the proximal poly(A)site and disease progression.Therefore,our study highlights the importance of the APA mechanism in response to DHT stimulation in PCa cells and provides a novel regulatory mechanism through which DHT-induced APA causes altered expression of de novo lipogenesis genes,with a possible association with the progression of PCa.展开更多
The endometrium is a proliferative tissue controlled by the menstrual cycle.Endometrial hyperplasia(EH)is a type of neoplastic disease that may develop into endometrial hyperplasia with atypia(EHA)or endometrial adeno...The endometrium is a proliferative tissue controlled by the menstrual cycle.Endometrial hyperplasia(EH)is a type of neoplastic disease that may develop into endometrial hyperplasia with atypia(EHA)or endometrial adenocarcinoma(EA).We performed a multi-omics analysis of a collection of endometrial tissues with four different proliferative statuses from two independent cohorts of patients.A positive association between the level of glutamine and malignancy,as well as addiction of EHA/EA neoplasms to glutamine,was identified.Further investigation revealed the dual mechanism by which glutamine influences the development of endometrial neoplasms.On one hand,glutamine regulates the level of c-MYC by controlling its translational process.On the other hand,glutamine is a major source of energy for endometrial neoplasms.Reprogramming the glutamine metabolism towards de novo lipogenesis affects the growth of endometrial adenocarcinoma in vitro,ex vivo and in vivo.Our study revealed the importance of maintaining metabolic homeostasis in endometrial tissues.The enhancement of de novo lipogenesis is a promising therapeutic strategy for treating endometrial adenocarcinoma.展开更多
Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in ...Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ± 0.04,P =0.04）,and ACC （0.38 ± 0.03 vs.0.95 ± 0.06,P 〈 0.01） decreased.Conversely,levels of triglyceride （4.22 ± 0.54 μmol/g vs.2.41 ± 0.35 μmol/g,P 〈 0.001）,mRNA expression of SREBP-1c （2.70 ± 0.33 vs.1.00 ± 0.00,P 〈 0.0 1）,and protein expression of SCD-1 （0.93 ± 0.06 vs.0.26 ± 0.05,P 〈 0.01）,ACC （0.98 ± 0.09 vs.0.43 ± 0.03,P 〈 0.01）,and FAS （0.90 ± 0.33 vs.0.71 ±4 0.02,P =0.04） in XBP-ls-upregulated group increased compared with the untransfected group.Conclusions：ERS is associated with de novo lipogenesis,and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.展开更多
Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often...Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.展开更多
Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.C.cathayensis leaf ext...Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.C.cathayensis leaf extract(CCE)was rich in flavonoids.Oral administration of CCE reduced the serum lipids and hepatic lipids,alleviated liver steatosis in ovariectomized rats.Objective:To investigate whether CCE has estrogenic effects on reproductive tissue and influences lipid metabolism in ovariectomized rats,and whether CCE has a direct effect on regulation of lipid synthesis and/or oxidation and adipocyte differentiation of ovariectomized(OVX)rats.Methods:Female Sprague-Dawley rats were ovariectomized and treated with CCE or estradiol in combination with a normal diet(ND),a high-fat diet(HFD)for 8 weeks.Histological analysis of uterus were performed and the lipid metabolism-related enzyme activity were examined.Expression of liver lipogenesis-related genes,adipocyte differentiation-and fat accumulation-related genes and protein were measured.Rusults:Ovariectomy accelerated the uterine atrophy,development of dyslipidemia and hepatic steatosis,which were effectively mitigated by CCE supplementation.CCE significantly elevated ovariectomy-induced reduction in the cross-section area of the uterus and uterine glands.Compared with the OVX group,CCE increased the activities of lipoprtein lipase(LPL)and hepatic lipase(HL),decreased the hepatic mRNA expressions of Fas,Srebf1,Sla2a2,and increased Ppar𝛼expressions at the mRNA levels under both ND and HFD conditions.CCE also decreased the Pck1 and G6pc mRNA expressions under HFD conditions,and show no significant effects on Hmgcr.The expressions of SREBF1,CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation.Conclusion:CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by mod-ulating hepatic lipogenesis and adipocyte differentiation.Furthermore,CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.展开更多
Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver ca...Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver can originate from various sources,including de novo lipogenesis(DNL).Research indicates that DNL significantly escalates in NAFLD,worsening steatosis.However,the precise regulatory mechanism of DNL in the development of this disease is not fully understood.Therefore,the targeted reduction of DNL could be a crucial therapeutic strategy.Currently,numerous pharmaceutical agents targeting DNL have been developed,attracting significant attention.This review examines the mechanism of DNL upregulation in NAFLD,assessing its potential as a therapeutic target for hepatic steatosis.Furthermore,we thoroughly examine hepatocellular lipotoxicity and provide an extensive review of the application and limitations of relevant therapeutic drugs,with a focus on key enzymes involved in DNL.The implementation of these pharmacological strategies is expected to significantly improve the management and overall outcomes for patients with NAFLD.展开更多
Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin me...Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin mediator (M. W. 3700—4000 daltons) which had a significant lipogenesis-stimulatlug activity. The other was fraction 2 of insulin mediator (M. W. about 1000 daltons) which exhibited a lipogenesis-inhibitory activity.The ratio of yield between the two mediators produced from the membranes was not only dependent on the concentration but also on the potency of insulin and its analogs added. The result showed that there was more production of fraction 2 than fraction 1 with the inducer at low concentration (100 μU/ml), while the production of fraction 1 from the plasma membranes incubated with high concentration of insulin (300 μU/ml) was higher than fraction 2. On the other hand, insulin and its analogs which have different biological activities and receptor bindtng activities have been used to induce the insulin mediators. The results obtained were similar to those mentioned above. This suggested that the generation of the mediators was dependent on the biological potences but not the binding activities.展开更多
Obesity and diabetes have become global health crises,with rising prevalence and a strong association with various chronic diseases such as cardiovascular disease,stroke,and certain cancers.These conditions contribute...Obesity and diabetes have become global health crises,with rising prevalence and a strong association with various chronic diseases such as cardiovascular disease,stroke,and certain cancers.These conditions contribute to significant morbidity and mortality,highlighting the urgent need for effective therapeutic interventions.Marine products,including fish oils and marine plants,have been increasingly recognized for their potential in mitigating these diseases.Among these,seaweed stands out due to their diverse bioactive compounds and promising therapeutic effects.This comprehensive review explores the mechanisms of action through which seaweeds,and their compounds exert anti-diabetic and anti-obesity effects,including the regulation of adipogenesis,appetite control,modulation of gut microbiota,enhancement of insulin sensitivity,and reduction of inflammation,oxidative stress,andβ-cell dysfunction.Despite the promising potential,challenges such as variability of bioactive compounds and low bioavailability remain there.Advances in bioactive delivery systems and along with large-scale clinical trials,are crucial for optimizing the therapeutic use of bioactive compounds from seaweeds.Future research should also explore synergistic strategies combining seaweed compounds with other bioactive substances.Overall,seaweed offers a promising foundation for developing functional foods and nutraceuticals aimed at promoting long-term metabolic health,providing an innovative approach to addressing obesity and diabetes.展开更多
Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the tr...Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.展开更多
文摘Insulin plays a crucial role in the metabolic priming and proliferation of neural stem cells(NSCs).However,insulin resistance(IR)is associated with impaired NSC proliferation and cognitive dysfunction,which are the hallmarks of psychiatric disorders(PDs).In addition to insulin,de novo lipogenesis(DNL)also plays an essential role in NSC proliferation and function as it supplies fatty acids for membrane phospholipid synthesis and cell signaling.However,enhanced DNL is associated with lipid/fatty acid accumulation,IR,and impaired NSC proliferation.Intriguingly,data from lipidomic studies suggest that DNL could be enhanced before the onset of classical symptoms in patients with PDs.Further,evidence suggests that patients with PDs may develop IR during childhood or before adolescence;therefore,DNL could be enhanced preceding the development of IR.Regarding treatment,while most antidepressants and antipsychotic drugs have been shown to further deteriorate IR and stimulate DNL,various adjunctive drugs/therapies,including chemical,physical,and stem cell therapy,which have shown promising success in treating PDs,reduce DNL while enhancing insulin sensitivity,NSC proliferation,and cognitive function in laboratory animals.Preliminary clinical outcomes and future prospects of these adjunctive drugs/therapies,especially stem cell therapy in treating PDs including schizophrenia and depression,are discussed.
文摘Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.
文摘This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.
基金supported by the National Key Research and Development Program,China (2022YFF1000300 to Z.Y.and2022YFD2401800 to G.Z.)Pilot Program A Project from the Chinese Academy of Sciences (XDA24010206 to Z.Y.)+3 种基金Foundation of Hubei Hongshan Laboratory (2021hskf013 to G.Z.and 2021hszd021 to Z.Y.)National Natural Science Foundation of China (31972779 to G.Z.)Youth Innovation Promotion Association of CAS (2020336 to G.Z.)State Key Laboratory of Freshwater Ecology and Biotechnology (2016FBZ05 to Z.Y.)。
文摘Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood,especially in teleosts.In this study,cyp17a1-/-zebrafish(Danio rerio)exhibited excessive visceral adipose tissue(VAT),lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis(DNL)enzymes.The assay for transposase accessible chromatinwithsequencing(ATAC-seq)results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/-fish compared to cyp17a1+/+male fish,including stearoyl-CoA desaturase(scd)and fatty acid synthase(fasn).Androgen response element(ARE)motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+male fish but not in cyp17a1-/-fish.Both androgen receptor(ar)-/-and wildtype(WT)zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue,lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis enzymes.The Ar agonist BMS-564929 reduced the content of VAT and lipid content,and down-regulated acetyl-CoA carboxylase a(acaca),fasn,and scd expression.Mechanistically,the rescue effect of testosterone on cyp17a1-/-fish in terms of phenotypes was abolished when ar was additionally depleted.Collectively,these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish,thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.
基金Supported by National Natural Science Foundation Key Project of China(30430510)Natural Science Foundation Key Project of Heilongjiang Province(ZJN0604-01)National 973 Project of China(2006CB102105)
文摘Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-binding protein a （C/EBPa） and sterol regulatory element binding protein-1 （SREBP1）, play fundamental roles in metabolic pathways. And they are also important in adipocyte differentiation. Expressions of these factors are regulated by some compounds such as fatty acids or some steroid hormones （insulin） which is stimulated by the nutritional level. Furthermore, these factors are related to some metabolic diseases including type II diabetes and obesity, Lots of researches have focused on relationships between the factors and the genetic diseases. Different functions of factors on inducing the adipocyte differentiation are other hot spots according to previous studies. This paper summarized these studies and gave a limpid description of structures and functions of these genes.
基金Supported partially by the American Heart Association (AHA) Scientist Development Award (0635423Z)the AHA Grant-in-Aid (09GRNT2280479)+1 种基金the Department of Defense Breast Cancer Research Program (BC095179P1)the Karmanos Cancer Institute Pilot Grant
文摘The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic reticulum (ER) is critically involved in lipid homeostasis and the development of metabolic disease. The ER is a site where newly-synthesized proteins are folded and assembled into their three-dimensional structures, modified and transported to their precise cellular destinations. A wide range of biochemical, physiological and pathological stimuli can interrupt the protein folding process in the ER and cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition referred to as ER stress. To cope with this stress condition, the ER has evolved highly-specifi c signaling pathways collectively termed Unfolded Protein Response (UPR) or ER stress response. The UPR regulates transcriptionaland translational programs, affecting broad aspects of cellular metabolism and cell fate. Lipogenesis, the metabolic process of de novo lipid biosynthesis, occurs primarily in the liver where metabolic signals regulate expression of key enzymes in glycolytic and lipogenic pathways. Recent studies suggest that the UPR plays crucial roles in modulating lipogenesis under metabolic conditions. Here we address some of recent representative evidence regarding the role of the UPR in lipogenesis.
文摘Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.
文摘Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional AM extract was recently developed. The objective of this study was to examine the effect of AM-Ex on adipogenesis and its action mechanisms in vitro using 3T3-L1 adipocytes. To examine the anti-obesity effect of AM-Ex, 3T3-L1 cells were induced adipocyte differentiation and incubated with various concentration of AM-Ex. Lipid accumulation, cellular triglyceride content, mRNA expression of transcription factors and adipogenic genes were analyzed. Treatment with 100 - 400 μg/mL of AM-Ex resulted in a dose-dependent decrease in adipocyte differentiation and triglyceride accumulation. mRNA expression of adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1 were decreased. The level of gene expression of adipogenesis and lipogenesis-related genes, such as adipocyte protein 2, lipoprotein lipase, acetyl-CoA carboxylase, ATP-citrate lyase and fatty acid synthase were decreased. These results suggest that AM-Ex alleviated risk factors related to obesity by modulating multiple pathways associated with adipogenesis.
基金supported by the Deputyship for Research&Innovation,Ministry of Education in Saudi Arabia for funding this research work through the project number PNU-DRI-RI-20-012.
文摘This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regulation of mTORC1.Initially,SKOV3 cells were cultured in the humidified conditions in DMEM media for 24 h with or without increasing concentration of Pterostilbene.Then,the cells were incubated with Pterostilbene(IC_(50)=50μM)under similar conditions with or without pre-incubation with Dorsomorphin,an AMPK inhibitor.In a dose-dependent manner,Pterostilbene inhibited SKOV3 cell survival and increased their lysate levels of lactate dehydrogenase(LDH)and single-stranded DNA(ssDNA).When SKOV3 cells were treated with 50μM Pterostilbene,Pterostilbene significantly suppressed cell migration and invasion,reduced lysate levels of lactic acid and the optical density of Oil Red O staining,and increased lysate glucose levels.It also increased levels of malondialdehyde(MDA),reactive oxygen species(ROS),and induced intrinsic cell apoptosis by upregulating protein levels of Bax and cleaved caspase-3 and reducing protein levels of Bcl-2.Besides,Pterostilbene reduced mRNA levels of sterol regulatory element-binding protein 1(SREBP-1),fatty acid synthase(FAS),acetyl CoA carboxylase-1(ACC-1),and AMP-activated protein kinase(AMPK).Furthermore,Pterostilbene increased the protein levels of p-AMPK,p-p53,p-raptor,p-TSC-2,but significantly decreased protein levels of p-Akt,p-TSC-2,p-mTOR,p-S6K1,and p-4E-BP.Treatment with Dorsomorphin(CC)abolished all the anti-tumorigenesis effects afforded by Pterostilbene and prevented Pterostilbene-induced phosphorylation of Akt,p53,and mTOR.In conclusion,the tumorsuppressive effect of Pterostilbene in SKOV3 cells involves the induction of ROS and inhibition of dysregulation cell metabolism mainly due to AMPK-induced Akt-dependent or independent suppression of mTOR.
基金supported by Zhuhai Science and Technology Plan Project in the Field of Social Development(2320004000157)National Natural Science Foundation of China(82072215,82272219)+1 种基金Shenzhen Science and Technology Program(JCYJ20210324134602006)Natural Science Foundation of Guangdong Province(2214050001873).
文摘Background: De novo lipogenesis (DNL) is a critical event for the development of tumors, in the present work,we revealed the role of propofol in colorectal cancer (CRC) cell proliferation. Methods: Western blotting (WB), Real-timePCR, and luciferase combined with chromatin immunoprecipitation (ChIP) were used to identify the mechanismunderlying propofol-modulated cell proliferation in CRC cells. Results: Herein, we showed that propofol suppressedcell proliferation, which was attributed to the inhibition of DNL characterized by reduced fatty acid synthase (FASN),acetyl-coA carboxylase alpha (ACCA), and stearoyl-coA desaturase-1 (SCD1) expression. Mechanically, propofolstimulation decreased sterol regulatory element-binding proteins-1c (SREBP-1c) mature and nuclear translocation,which further decreased SCD1 transactivation confirmed by luciferase and ChIP analysis, while no significantdifference in total SREBP1c was observed. What’s more, supplementation of Monounsaturated fatty acid (MuFA)could reverse the inhibitory effect of propofol on cell proliferation. Conclusion: Taken together, these resultssuggested propofol modulated cell proliferation is dependent on SREBP1c-mediated DNL.
基金supported by the National Natural Science Foundation of China(Nos.82103066,82372818,82303210,and 82302887)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-009A,China).
文摘Metabolic reprogramming plays a central role in tumors.However,the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood.Here,we try to identify the mechanism by which histone acetyltransferase 1(HAT1)confers reprogramming of gluconeogenesis/lipogenesis in liver cancer.Diethylnitrosamine(DEN)/carbon tetrachloride(CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice.Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver.Protein phosphatase 2 scaffold subunit alpha(PPP2R1A)promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1(PCK1)serine 90 dephosphorylation to suppress the tumor growth.HAT1 succinylated PPP2R1A at lysine 541(K541)to block the assembly of protein phosphatase 2A(PP2A)holoenzyme and interaction with PCK1,resulting in the depression of dephosphorylation of PCK1.HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation,leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1(SREBP1)nuclear accumulation-induced lipogenesis gene expression,which enhanced the tumor growth.In conclusion,succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer.Our finding provides new insights into the mechanism by which post-translational modifications(PTMs)confer the conversion of tumor suppressor function to oncogene.
基金supported by the Key Research and Development Program of Yunnan(202203AC100010)the National Natural Science Foundation of China(32371463,32160236)Spring City Plan:The High-level Talent Promotion and Training Project of Kunming(2022SCP001)。
文摘Alternative polyadenylation(APA)is a pervasive mechanism that is emerging as a formidable player in post-transcriptional regulation.The transcriptional landscape can be altered via APA in response to various stimulating factors.Using the Pac Bio single-molecule long-read sequencing method,we present for the first time the 3′UTR landscape and reveal a global increase of APA events in prostate cancer(PCa)LNCa P cells in response to androgen dihydrotestosterone(DHT),a critical regulator of PCa progression.With evidence from differential gene expression analyses of Illumina RNA-sequencing data,we demonstrated that genes with DHT-induced changes in both expression and APA were enriched in lipid metabolism.These genes predominantly supported de novo fatty acid synthesis,such as FASN and ACSL3.Furthermore,we showed that an isoform switch to the proximal poly(A)site of these genes depended on the androgen receptor,and the expression of cancer-associated genes was upregulated by the escape of mi RNA-regulated repression machinery.To address the role of key gene shortening in PCa,we prepared 22RV1-FS cells missing the distal poly(A)signal of FASN in the AR+PCa cell line 22RV1 using CRISPR/Cas9 technology.As expected,the edited 22RV1-FS cells overexpressed FASN m RNA and protein and were inclined to cell proliferation in vitro and tumorigenesis in vivo.Interestingly,we found that FASN transcripts with a shortened 3′UTR were significantly increased in advanced PCa and castration-resistant prostate cancer compared with benign prostate hyperplasia,suggesting a possible association between usage of the proximal poly(A)site and disease progression.Therefore,our study highlights the importance of the APA mechanism in response to DHT stimulation in PCa cells and provides a novel regulatory mechanism through which DHT-induced APA causes altered expression of de novo lipogenesis genes,with a possible association with the progression of PCa.
基金supported by the National Key Research and Development Program of China(2022YFC3600901,2020YFA0803800,2020YFA0803601,2018YFA0801300 and 2019YFA0801900)the National Natural Science Foundation of China(82171633,32071138 and 92057115)+1 种基金Natural Science Foundation of Shanghai(20ZR1408800)Shanghai Sailing Program(20YF1402600).
文摘The endometrium is a proliferative tissue controlled by the menstrual cycle.Endometrial hyperplasia(EH)is a type of neoplastic disease that may develop into endometrial hyperplasia with atypia(EHA)or endometrial adenocarcinoma(EA).We performed a multi-omics analysis of a collection of endometrial tissues with four different proliferative statuses from two independent cohorts of patients.A positive association between the level of glutamine and malignancy,as well as addiction of EHA/EA neoplasms to glutamine,was identified.Further investigation revealed the dual mechanism by which glutamine influences the development of endometrial neoplasms.On one hand,glutamine regulates the level of c-MYC by controlling its translational process.On the other hand,glutamine is a major source of energy for endometrial neoplasms.Reprogramming the glutamine metabolism towards de novo lipogenesis affects the growth of endometrial adenocarcinoma in vitro,ex vivo and in vivo.Our study revealed the importance of maintaining metabolic homeostasis in endometrial tissues.The enhancement of de novo lipogenesis is a promising therapeutic strategy for treating endometrial adenocarcinoma.
文摘Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ± 0.04,P =0.04）,and ACC （0.38 ± 0.03 vs.0.95 ± 0.06,P 〈 0.01） decreased.Conversely,levels of triglyceride （4.22 ± 0.54 μmol/g vs.2.41 ± 0.35 μmol/g,P 〈 0.001）,mRNA expression of SREBP-1c （2.70 ± 0.33 vs.1.00 ± 0.00,P 〈 0.0 1）,and protein expression of SCD-1 （0.93 ± 0.06 vs.0.26 ± 0.05,P 〈 0.01）,ACC （0.98 ± 0.09 vs.0.43 ± 0.03,P 〈 0.01）,and FAS （0.90 ± 0.33 vs.0.71 ±4 0.02,P =0.04） in XBP-ls-upregulated group increased compared with the untransfected group.Conclusions：ERS is associated with de novo lipogenesis,and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.
基金supported by the National Natural Science Foundation of China(32171381 and 81973254)the National Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology)grant(2021ZD0204004,China)+1 种基金Jiangsu Key Laboratory of Neuropsychiatric Diseases Research Major Program(No.ZZ2101,China)the Priority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD),Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and the Suzhou Science and Technology Development Project(No.SJC2022021,China).
文摘Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.
基金This project was financially supported by the Natural Science Foun-dation of China(Grant No:81303258).
文摘Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.C.cathayensis leaf extract(CCE)was rich in flavonoids.Oral administration of CCE reduced the serum lipids and hepatic lipids,alleviated liver steatosis in ovariectomized rats.Objective:To investigate whether CCE has estrogenic effects on reproductive tissue and influences lipid metabolism in ovariectomized rats,and whether CCE has a direct effect on regulation of lipid synthesis and/or oxidation and adipocyte differentiation of ovariectomized(OVX)rats.Methods:Female Sprague-Dawley rats were ovariectomized and treated with CCE or estradiol in combination with a normal diet(ND),a high-fat diet(HFD)for 8 weeks.Histological analysis of uterus were performed and the lipid metabolism-related enzyme activity were examined.Expression of liver lipogenesis-related genes,adipocyte differentiation-and fat accumulation-related genes and protein were measured.Rusults:Ovariectomy accelerated the uterine atrophy,development of dyslipidemia and hepatic steatosis,which were effectively mitigated by CCE supplementation.CCE significantly elevated ovariectomy-induced reduction in the cross-section area of the uterus and uterine glands.Compared with the OVX group,CCE increased the activities of lipoprtein lipase(LPL)and hepatic lipase(HL),decreased the hepatic mRNA expressions of Fas,Srebf1,Sla2a2,and increased Ppar𝛼expressions at the mRNA levels under both ND and HFD conditions.CCE also decreased the Pck1 and G6pc mRNA expressions under HFD conditions,and show no significant effects on Hmgcr.The expressions of SREBF1,CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation.Conclusion:CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by mod-ulating hepatic lipogenesis and adipocyte differentiation.Furthermore,CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.
基金the National Natural Science Foundation of China(82325008).
文摘Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver can originate from various sources,including de novo lipogenesis(DNL).Research indicates that DNL significantly escalates in NAFLD,worsening steatosis.However,the precise regulatory mechanism of DNL in the development of this disease is not fully understood.Therefore,the targeted reduction of DNL could be a crucial therapeutic strategy.Currently,numerous pharmaceutical agents targeting DNL have been developed,attracting significant attention.This review examines the mechanism of DNL upregulation in NAFLD,assessing its potential as a therapeutic target for hepatic steatosis.Furthermore,we thoroughly examine hepatocellular lipotoxicity and provide an extensive review of the application and limitations of relevant therapeutic drugs,with a focus on key enzymes involved in DNL.The implementation of these pharmacological strategies is expected to significantly improve the management and overall outcomes for patients with NAFLD.
基金Project supported by the National Natural Science Foundation of China.
文摘Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin mediator (M. W. 3700—4000 daltons) which had a significant lipogenesis-stimulatlug activity. The other was fraction 2 of insulin mediator (M. W. about 1000 daltons) which exhibited a lipogenesis-inhibitory activity.The ratio of yield between the two mediators produced from the membranes was not only dependent on the concentration but also on the potency of insulin and its analogs added. The result showed that there was more production of fraction 2 than fraction 1 with the inducer at low concentration (100 μU/ml), while the production of fraction 1 from the plasma membranes incubated with high concentration of insulin (300 μU/ml) was higher than fraction 2. On the other hand, insulin and its analogs which have different biological activities and receptor bindtng activities have been used to induce the insulin mediators. The results obtained were similar to those mentioned above. This suggested that the generation of the mediators was dependent on the biological potences but not the binding activities.
基金Supported by India-South Africa Bilateral Research Grant from the National Research Foundation,Pretoria,South Africa,No.133137.
文摘Obesity and diabetes have become global health crises,with rising prevalence and a strong association with various chronic diseases such as cardiovascular disease,stroke,and certain cancers.These conditions contribute to significant morbidity and mortality,highlighting the urgent need for effective therapeutic interventions.Marine products,including fish oils and marine plants,have been increasingly recognized for their potential in mitigating these diseases.Among these,seaweed stands out due to their diverse bioactive compounds and promising therapeutic effects.This comprehensive review explores the mechanisms of action through which seaweeds,and their compounds exert anti-diabetic and anti-obesity effects,including the regulation of adipogenesis,appetite control,modulation of gut microbiota,enhancement of insulin sensitivity,and reduction of inflammation,oxidative stress,andβ-cell dysfunction.Despite the promising potential,challenges such as variability of bioactive compounds and low bioavailability remain there.Advances in bioactive delivery systems and along with large-scale clinical trials,are crucial for optimizing the therapeutic use of bioactive compounds from seaweeds.Future research should also explore synergistic strategies combining seaweed compounds with other bioactive substances.Overall,seaweed offers a promising foundation for developing functional foods and nutraceuticals aimed at promoting long-term metabolic health,providing an innovative approach to addressing obesity and diabetes.
文摘Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.
