Journal ArticleDOI
Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c
Pascal Ferré,Fabienne Foufelle +1 more
TLDR
Inhibition of the ER stress in obese rodents decreases SREBP‐1c activation and lipogenesis and improves markedly hepatic steatosis and insulin sensitivity, thus explaining the paradoxical stimulation of lipogenesis in an insulin‐resistant liver.Abstract:
Steatosis is an accumulation of triglycerides in the liver. Although an excessive availability of plasma fatty acids is an important determinant of steatosis, lipid synthesis from glucose (lipogenesis) is now also considered as an important contributing factor. Lipogenesis is an insulin- and glucose-dependent process that is under the control of specific transcription factors, sterol regulatory element binding protein 1c (SREBP-1c), activated by insulin and carbohydrate response element binding protein (ChREBP) activated by glucose. Insulin induces the maturation of SREBP-1c by a proteolytic mechanism initiated in the endoplasmic reticulum (ER). SREBP-1c in turn activates glycolytic gene expression, allowing glucose metabolism, and lipogenic genes in conjunction with ChREBP. Lipogenesis activation in the liver of obese markedly insulin-resistant steatotic rodents is then paradoxical. Recent data suggest that the activation of SREBP-1c and thus of lipogenesis is secondary in the steatotic liver to an ER stress. The ER stress activates the cleavage of SREBP-1c independent of insulin, thus explaining the paradoxical stimulation of lipogenesis in an insulin-resistant liver. Inhibition of the ER stress in obese rodents decreases SREBP-1c activation and lipogenesis and improves markedly hepatic steatosis and insulin sensitivity. ER is thus a new partner in steatosis and metabolic syndrome which is worth considering as a potential therapeutic target.read more
Citations
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Journal ArticleDOI
Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.
TL;DR: The transcriptional activation and repression mechanisms by PPAR α, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, are discussed, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response.
Journal ArticleDOI
Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease
Yuki Kawano,David E. Cohen +1 more
TL;DR: The molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions are discussed, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.
OtherDOI
Triglyceride Metabolism in the Liver
TL;DR: The current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease is described, identifying potential directions for future research.
Journal ArticleDOI
Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production
Arya E. Mehran,Nicole M. Templeman,G. Stefano Brigidi,Gareth E. Lim,Kwan-Yi Chu,Xiaoke Hu,José Diego Botezelli,Ali Asadi,Bradford G. Hoffman,Timothy J. Kieffer,Shernaz X. Bamji,Susanne M. Clee,James D. Johnson +12 more
TL;DR: Genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications is provided and white adipose tissue is reprogrammed to express uncoupling protein 1 and increase energy expenditure.
Journal ArticleDOI
A Conserved SREBP-1/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans
Amy K. Walker,René L. Jacobs,Jennifer L. Watts,Veerle Rottiers,Karen Jiang,Deirdre M. Finnegan,Toshi Shioda,Malene Hansen,Fajun Yang,Lorissa J. Niebergall,Dennis E. Vance,Monika Tzoneva,Anne C. Hart,Anders M. Näär +13 more
TL;DR: The studies identify a conserved regulatory circuit in which SREBP-1 controls genes in the one-carbon cycle, which produces the methyl donor S-adenosylmethionine (SAMe), and suggest a feedback mechanism whereby maturation of nuclear, transcriptionally active SRE BP-1 is controlled by levels of PC.
References
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Journal ArticleDOI
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Fumihiko Urano,Xiaozhong Wang,Anne Bertolotti,Yuhong Zhang,Peter Chung,Heather P. Harding,David Ron +6 more
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