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Androgen signaling inhibits de novo lipogenesis to alleviate lipid deposition in zebrafish
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作者 Jing-Yi Jia Guang-Hui Chen +6 位作者 Ting-Ting Shu Qi-Yong Lou Xia Jin Jiang-Yan He Wu-Han Xiao Gang Zhai Zhan Yin 《Zoological Research》 SCIE CSCD 2024年第2期355-366,共12页
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
关键词 Cyp17a1 TESTOSTERONE Androgen receptor de novo lipogenesis Fatty acid synthesis
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Metabolic complications of psychotropic medications in psychiatric disorders:Emerging role of de novo lipogenesis and therapeutic consideration
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作者 Mohammad M Khan Zaw Ali Khan Mohsin Ali Khan 《World Journal of Psychiatry》 SCIE 2024年第6期767-783,共17页
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
关键词 Psychotropic medications Metabolic complications de novo lipogenesis OBESITY DIABETES Non-alcoholic fatty liver disease
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In-depth analysis of de novo lipogenesis in non-alcoholic fatty liver disease:Mechanism and pharmacological interventions
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作者 Zhixian Zhu Xiaoxun Zhang +2 位作者 Qiong Pan Liangjun Zhang Jin Chai 《Liver Research》 CSCD 2023年第4期285-295,共11页
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
关键词 Non-alcoholic fatty liver disease(NAFLD) de novo lipogenesis(DNL) THERAPEUTICS Molecular mechanism
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The significance of SREBP1 expression in HBV-related hepatocellular carcinoma
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作者 DENG Hui-zi ZHENG Jing +1 位作者 WENG Yang WEI Shang 《Journal of Hainan Medical University》 CAS 2023年第15期30-30,共1页
Objective:To investigate the relationship between SREBP1 protein expression and clinicopathological features of hepatitis B virus infection-related hepatocellular carcinoma.Methods:A total of 91 cases of hepatocellula... Objective:To investigate the relationship between SREBP1 protein expression and clinicopathological features of hepatitis B virus infection-related hepatocellular carcinoma.Methods:A total of 91 cases of hepatocellular carcinoma associated with hepatitis B virus infection and paired adjacent liver tissue samples were collected from the Department of Pathology,the First Affiliated Hospital of Hainan Medical College.The expression of SREBP1 protein in cancer and paired adjacent tissues was detected by immunohistochemical staining.The relationship between SREBP1 protein expression and clinicopathological features of hepatocellular carcinoma was analyzed by chi-square test.Results:The results of immunohistochemical staining showed that the ex-pression of SREBP1 protein in hepatocellular carcinoma was significantly higher than that in adjacent liver tissues(P<0.001).The expression level of SREBP1 protein was significantly correlated with tumor differentiation,distant metastasis or local recurrence in patients with hepatocellular carcinoma(P<0.05).The expression of SREBP1 protein was significantly up-regulated in the high HBV-related HCC virus load group(>103 IU/mL)compared with the low HBV-related HCC virus load group 3(0~10 IU/mL)(P<0.05).Conclusion:1.The expression of SREBP1 protein is correlated with hepatocellular carcinoma,and shows a high expression trend,which provides direction and theoretical basis for the study of lipid metabolism regulation mechnism related to the occurrence and development of hepatocellular carcinoma.2.The expression of SREBP1 protein is correlated with the replication activity of hepatitis B virus,which provides a new research direction for the exploration of the mechanism of the occurrence and development of hepatitis B virus infection-related liver cancer. 展开更多
关键词 SREBP1 Hepatocellular carcinoma HBV de novo lipogenesis
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Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to Fatty Acid Synthase
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作者 Yang Song Wei Zhong +9 位作者 Harry Cheuk-Hay Lau Yating Zhang Huayu Guan Mingxu Xie Suki Ha Diwen Shou Yongjian Zhou Hongzhi Xu Jun Yu Xiang Zhang 《Engineering》 SCIE EI CAS 2024年第10期204-215,共12页
Carboxyl ester lipase(CEL),a pivotal enzyme involved in lipid metabolism,is recurrently mutated in obese mice.Here,we aimed to elucidate the functional significance,molecular mechanism,and therapeutic potential of CEL... Carboxyl ester lipase(CEL),a pivotal enzyme involved in lipid metabolism,is recurrently mutated in obese mice.Here,we aimed to elucidate the functional significance,molecular mechanism,and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis(MASH).Hepatocyte-specific carboxyl ester lipase gene(Cel)knockout(Cel^(DHEP))and wildtype(WT)littermates were fed with cholinedeficient high-fat diet(CD-HFD)for 16 weeks,or methionine-and choline-deficient diet(MCD)for three weeks to induce MASH.Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL.CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral,serotype 8(AAV8)to induce specific overexpression of CEL in the liver.We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice.Cel^(DHEP) mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis,inflammation,lipid peroxidation,and liver injury compared to WT littermates,accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell(NF-jB)activation.Consistently,Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation,whereas CEL overexpression exerted the opposite effect.Mechanistically,CEL directly bound to fatty acid synthase(FASN),resulting in reduced FASN SUMOylation,which in turn promoted FASN degradation through the proteasome pathway.Furthermore,inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro.Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD.CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis.CEL overexpression confers a therapeutic benefit in steatohepatitis. 展开更多
关键词 Metabolic dysfunction-associated steatohepatitis Carboxyl ester lipase Fatty acid synthase de novo lipogenesis Treatment
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Nutrient mTORC1 signaling contributes to hepatic lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease 被引量:2
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作者 Hanqing Chen 《Liver Research》 2020年第1期15-22,共8页
Energy metabolism is maintained by the complex homeostatic system in multiple cells and organs involving“nutrient signaling”or“nutrient sensor”.Overnutrient-induced chronic metabolic diseases,as the hallmarks of t... Energy metabolism is maintained by the complex homeostatic system in multiple cells and organs involving“nutrient signaling”or“nutrient sensor”.Overnutrient-induced chronic metabolic diseases,as the hallmarks of the 21st century’s public health,are growing threat worldwide.In the past two decades,non-alcoholic fatty liver disease(NAFLD)has emerged as the most prevalent form of chronic liver dis-ease,affecting globally,and increases the risk of incident obesity,type 2 diabetes,and insulin resistance.NAFLD begins with the excessive triglyceride accumulation in hepatocytes,and develops to hepatocel-lular steatosis with inflammation(non-alcoholic steatohepatitis,NASH),fibrosis,cirrhosis,and ultimately hepatocellular carcinoma(HCC).The liver is the central mediator of lipid metabolism by regulation of fatty acid(FA)uptake,manufacture,store,export,and oxidation in response to physiological fluctuations of nutrient.Sterol regulatory element-binding protein c(SREBP-1c)-mediated de novo lipogenesis(DNL)is an important nutritional regulator in biosynthesis of FAs and triglyceride in the liver.Mechanistic target of rapamycin complex 1(mTORC1),as a central hub of nutrient signaling,controls cellular metabolism and growth mainly via increasing anabolic processes and inhibiting catabolic processes in response to physiological fluctuations of nutrient.mTORC1 activation contributes to regulation of DNL by increasing SREBP1 transcription,which contributes to NAFLD pathogenesis and accelerates NAFLD-related HCC development.In this review,we provide the comprehensive understanding of the molec-ular mechanism of SREBPs and autophagy to control hepatic lipid homeostasis under nutrient availability in physiological and pathophysiological states,and highlight how nutrient mTORC1 signaling coordi-nately to integrate the lipid metabolic regulation and therapeutic targets in NAFLD and HCC. 展开更多
关键词 Nutrient signaling Non-alcoholic fatty liver disease Mechanistic target of rapamycin Sterol regulatory element-binding proteins de novo lipogenesis Autophagy
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Functionalized gadofullerene ameliorates impaired glycolipid metabolism in type 2 diabetic mice
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作者 Jin Wu Yingbo Chen +10 位作者 Xue Li Liyuan Ran Xiangdong Liu Xiaoshuang Wang Mingming Zhen Shanshan Shao Li Zeng Chunru Wang Bin Liang Jiajun Zhao Yingjie Wu 《Journal of Genetics and Genomics》 SCIE CAS CSCD 2022年第4期364-376,共13页
The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety.Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical ap... The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety.Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application.In the present study,we investigated the anti-diabetic effects of a functionalized gadofullerene(GF)using obese db/db and non-obese mouse model of type 2 diabete mellitus(MKR)mouse type 2 diabetes mellitus(T2DM)models.In both mouse models,the diabetic phenotypes,including hyperglycemia,impaired glucose tolerance,and insulin sensitivity,were ameliorated after two or four weeks of intraperitoneal administration of GF.GF lowered blood glucose levels in a dose-dependent manner.Importantly,the restored blood glucose levels could persist ten days after withdrawal of GF treatment.The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro.Furthermore,GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through m TOR/S6K/SREBP1 pathway.Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM. 展开更多
关键词 Functionalized gadofullerene Type 2 diabetes Glycolipid metabolism AKT de novo lipogenesis
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