Polyphenols Stimulate AMP-Activated Protein Kinase, Lower Lipids, and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor–Deficient Mice

By Mengwei Zang, Shanqin Xu, Karlene A. Maitland-Toolan, A. Zuccollo, X. Hou, B. Jiang, M. Wierzbicki, T. Verbeuren, R. Cohen. Diabetes, 2006

696 citations recorded by the source corpus.

Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMP-activated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor–deficient mice (DMLDLR−/−). In HepG2 hepatocytes, polyphenols, including resveratrol (a major polyphenol in red wine), apigenin, and S17834 (a synthetic polyphenol), increased phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC), and they increased activity of AMPK with 200 times the potency of metformin. The polyphenols also prevented the lipid accumulation that occurred in HepG2 cells exposed to high glucose, and their ability to do so was mimicked and abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Furthermore, treatment of DMLDLR−/− mice with S17834 prevented the decrease in AMPK and ACC phosphorylation and the lipid accumulation in the liver, and it also inhibited hyperlipidemia and the acceleration of aortic lesion development. These studies 1) reveal that inactivation of hepatic AMPK is a key event in the pathogenesis of hyperlipidemia in diabetes, 2) point to a novel mechanism of action of polyphenols to lower lipids by activating AMPK, and 3) emphasize a new therapeutic avenue to benefit hyperlipidemia and atherosclerosis specifically in diabetes via activating AMPK.

Subfields: Endocrinology, Diabetes and Metabolism, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/5563431c9e1392c6b95c45f726cd626e3975c6ae

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In Endocrinology, Diabetes and Metabolism

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Citations in the corpus

Flavonoids and Their Anti-Diabetic Effects: Cellular Mechanisms and Effects to Improve Blood Sugar Levels (2019, background): “Apigenin treatment could prevent induced apoptosis through the inhibition of NF-κB activation [150].”
Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors (2008, background): “Polyphenols reduce hyperlipemia and inhibit lipid peroxidation and atherosclerosis development in diabetic LDL receptor KO mice (Zang et al., 2006).”
Resveratrol and health--a comprehensive review of human clinical trials. (2011, background): “In vivo, resveratrol treatment stimulates the activities of sirtuin 1 (SIRT1) and adenosine monophosphateactivated protein kinase (AMPK), both of which influence the regulation of metabolism in multiple tissues [8, 14, 15].”
The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism (2011, background): “Finally, a number of naturally occurring compounds, including resveratrol, a polyphenol found in the skin of red grapes, have been shown to activate AMPK and yield similarly beneficial effects on metabolic disease as AICAR and metformin treatmen”
AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol (2009, background): “Resveratrol also has a number of indirect effects (11), including stimulation of 5 AMP-activated protein kinase (AMPK) (5,12,13).”
AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin Resistant Mice (2011, positive): “, 2005), in human HepG2 hepatocytes and in type 1 diabetic mouse livers (Zang et al., 2006).”