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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. [ABSTRACT FROM AUTHOR]

Our recent studies show that the synthetic polyphenol, S 17834, stimulates AMP-activated protein kinase (AMPK) more potently than resveratrol or metformin. Stimulation of AMPK by S17834 was shown to attenuate high glucose-induced lipid accumulation in HepG2 cells, as well as to be associated with a reduction in hepatic and serum lipids, and atherosclerosis in type 1 diabetic LDL receptor deficient (LDLR-/-) mice. To determine the effect of S17834 in obesity-induced insulin resistance and type 2 diabetes, LDLR-/- mice were fed a high fat, high sucrose (HFHS) diet for 16 weeks. Compared with normal chow, body weight gain increased ∼3-fold, and insulin resistance index, as determined by the homeostasis model assessment for insulin resistance (HOMAIR), was increased ∼2.5-fold. Hepatic steatosis caused by the HFHS diet was accompanied in the liver by decreased phosphorylation of AMPK and the AMPK downstream effector, acetyl CoA carboxylase (ACC) compared with chow fed mice. The HFHS diet caused a ∼2-fold increase in plasma cholesterol levels as well as a 4-fold increase in oil red O stained atherosclerotic lesions in aortic mot cross sections. S17834 administration (130 mg/kg/day, 16 weeks) significantly protected mice against diet-induced obesity and systemic insulin resistance. Treatment with S 17834 was accompanied by increased AMPK and ACC phosphorylation in the liver and improvement in hepatic steatosis. S17834 also significantly decreased plasma cholesterol levels and attenuated the development of aortic atherosclerotic lesions. These data show that protection afforded by S17834 from the exaggerated hyperlipidemia and vascular disease caused by type 1 diabetes extends to type 2 diabetes in LDLR-/- mice. Improvements in body weight, insulin resistance, hepatic steatosis, hyperlipidemia, and atherosclerosis may be attributed to the ability of the polyphenol to stimulate AMPK as demonstrated here to occur in the mouse liver. Activation of AMPK by polyphenols, like S17834, represents a major new avenue for treatment of hyperlipidemia and vascular disease in both type 1 and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: S18886 is an orally active thromboxane A2 (TXA2) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice by a mechanism independent of platelet-derived TXA2. Atherosclerosis is accelerated by diabetes and is associated with increased TXA(2) and other eicosanoids that stimulate TP. The purpose of this study was to determine whether S18886 lessens the enhanced atherogenesis in diabetic apoE(-/-) mice., Methods and Results: Diabetes mellitus was induced in apoE(-/-) mice with streptozotocin and was treated or not with S18886 (5 mg.kg(-1).d(-1)). After 6 weeks, aortic lesion area was increased >4-fold by diabetes in apoE(-/-) mice, associated with similar increases in serum glucose and cholesterol. S18886 largely prevented the diabetes-related increase in lesion area without affecting the hyperglycemia or hypercholesterolemia. S18886 prevented deterioration of endothelial function and endothelial nitric oxide synthase expression, as well as increases in intimal markers of inflammation associated with diabetes. In human aortic endothelial cells in culture, S18886 also prevented the induction of vascular cell adhesion molecule-1 and prevented the decrease in endothelial nitric oxide synthase expression caused by high glucose., Conclusions: The TP antagonist inhibits inflammation and accelerated atherogenesis caused by diabetes, most likely by counteracting effects on endothelial function and adhesion molecule expression of eicosanoids stimulated by the diabetic milieu.