Abstract
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.
Highlights
Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMPactivated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor– deficient mice (DMLDLR؊/؊)
Because our preliminary studies found that like metformin (2 mmol/l), S17834 (5–10 mol/l), a synthetic polyphenol, decreased lipid content in these cells at 24 h, we tested whether S17834 activates AMPK in these cells
Concentrations as low as 2.5 mol/l S17834 were found to significantly increase AMPK and acetyl-CoA carboxylase (ACC) phosphorylation by twofold in 1 h, reaching levels that were similar to those induced by AICAR (1 mmol/l) or metformin (2 mmol/l) in 1 h (Fig. 1A and B)
Summary
Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMPactivated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor– deficient mice (DMLDLR؊/؊). To determine whether two other polyphenols have similar actions as S17834, the ability of apigenin and resveratrol to activate AMPK and inhibit hepatocellular lipids was studied in HepG2 cells exposed to elevated glucose.
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