AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin Resistant Mice

By Yu Li, Shanqin Xu, Maria M. Mihaylova, B. Zheng, X. Hou, B. Jiang, Ogyi Park, Zhijun Luo, E. Lefai, J. Shyy and 6 more. Cell Metabolism, 2011

1,696 citations recorded by the source corpus.

Summary AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. We demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and −2). Ser372 phosphorylation of SREBP-1c by AMPK is sufficient and necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin resistant LDL receptor deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c and −2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer novel therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/3ada70fd4f2c1ff66737f66dc066331665816f4d

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Citations in the corpus

AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, positive): “In many cases, AMPK also downregulates expression of the proteins involved in these pathways, including ACC1 and other lipogenic enzymes (probably via phosphorylation of the lipogenic transcription factor sterol regulatory element-binding protein 1C (SREBP1C”
Energy Metabolism in the Liver (2014, positive): “cleavage and nuclear translocation of SREBP-1c, thus suppressing hepatic lipogenesis (147).”
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. (2011, background): “AMPK down-regulates expression of enzymes of fatty acid synthesis at the transcriptional level by a mechanism involving phosphorylation of the transcription factor SREBP-1c, inhibiting its proteolytic processing to the active, nuclear form (Zhou et al. 2001; Li et al. 2011).”
The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism (2011, positive): “One example that was recently discovered is the lipogenic transcriptional factor SREBP1 (ref”
Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development (2013, background): “AMPK phosphorylates SREBP and inhibits its proteolytic cleavage, thereby preventing hepatic steatosis and hyperlipidaemia in insulin-resistant mice (Li et al., 2011).”
AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo (2012, background): “AMPK may also influence lipid biosynthesis through regulation of ACC and other lipogenic enzymes, possibly through its effects on SREBP-1 (Li et al., 2011).”