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- Title
A Synthetic Polyphenol, S17834, Protects Against Hepatic Lipid Accumulation in Type 1 Diabetic Mice: Role of AMPK and SREBP.
- Authors
Hou, Xiuyun; Xu, Shanqin; Maitland-Toolan, Karlene; Jiang, Bingbing; Wierzbicki, Michel; Verbeuren, Tony J.; Cohen, Richard A.; Zang, Mengwei
- Abstract
Sterol regulatory element binding protein (SREBP) is a key lipogenic transcription factor that has been implicated in the pathogenesis of dyslipidemia. We previously demonstrated that high glucose and streptozotocin (STZ)-induced type 1 diabetes decrease AMPK activity and cause lipid accumulation both in HepG2 hepatocytes in vitro, and in mouse liver in vivo, associated with hyperlipidemia. These changes were prevented by metformin or a synthetic polyphenol, S17834. We have further investigated the role of S 17834 in regulating SREBP and lipid metabolism. In STZ-induced diabetic mice, the nuclear active form (∼68 kDa) of liver SREBP-1 was increased 5-fold, and the increase was significantly prevented by S17834 (130 mg/kg/day), suggesting that the lipid-lowering effect of S17834 is associated with suppression of SREBP-1. Exposure of HepG2 cells to high glucose in culture resulted in increased expression of the precursor and nuclear active form of SREBP-1, as well as enhanced nuclear translocation of SREBP- 1 as detected by immunofluorescent staining. An increase in the SREBP-1 target enzyme, fatty acid synthase (FAS), was associated with an increase in hepatocellular triglyceride accumulation. In contrast, S17834 (l0 micro;M) or metformin (2 mM) significantly increased AMPK activity and inhibited activation of SREBP and induction of FAS, and thereby lowered hepatocellular triglyceride levels. Moreover, the ability of S17834 to downregulate SREBP-1 and FAS is mimicked by overexpression of the constitutively active AMPK, and largely prevented by a dominant-negative AMPK. These results indicate that polyphenols attenuate hepatic lipid accumulation associated with high glucose via inhibition of de novo fatty acid synthesis via activation of AMPK and suppression of SREBP-1, and point to new approaches using small molecules for treating dyslipidemia associated with diabetes.
- Subjects
POLYPHENOLS; DIABETES; PROTEIN kinases; STEROLS; TRANSCRIPTION factors; LABORATORY mice
- Publication
Diabetes, 2007, Vol 56, pA392
- ISSN
0012-1797
- Publication type
Article