Article

The Scap/SREBP Pathway Is Essential for Developing Diabetic Fatty Liver and Carbohydrate-Induced Hypertriglyceridemia in Animals

Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
Cell metabolism (Impact Factor: 17.57). 02/2012; 15(2):240-6. DOI: 10.1016/j.cmet.2011.12.017
Source: PubMed

ABSTRACT

Insulin resistance leads to hypertriglyceridemia and hepatic steatosis and is associated with increased SREBP-1c, a transcription factor that activates fatty acid synthesis. Here, we show that steatosis in insulin-resistant ob/ob mice was abolished by deletion of Scap, an escort protein necessary for generating nuclear isoforms of all three SREBPs. Scap deletion reduced lipid synthesis and prevented fatty livers despite persistent obesity, hyperinsulinemia, and hyperglycemia. Scap deficiency also prevented steatosis in mice fed high-fat diets. Steatosis was also prevented when siRNAs were used to silence Scap in livers of sucrose-fed hamsters, a model of diet-induced steatosis and hypertriglyceridemia. This silencing reduced all three nuclear SREBPs, decreasing lipid biosynthesis and abolishing sucrose-induced hypertriglyceridemia. These results demonstrate that SREBP activation is essential for development of diabetic hepatic steatosis and carbohydrate-induced hypertriglyceridemia, but not insulin resistance. Inhibition of SREBP activation has therapeutic potential for treatment of hypertriglyceridemia and fatty liver disease.

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Available from: Kevin Fitzgerald, Feb 11, 2015
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    • "Choose right candidate for gene therapy is vitally essential. SREBP, a sterol regulatory element-binding protein, plays a central role in cholesterol and fatty acid metabolism [22] [23]. Many reports indicate that inhibition of SREBP either by small molecules or gene disruption renders health benefits to animals with hyperlipidemia and greatly lowers the risk of T2D [24e26]. "
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    • "For example, a bifurcation point at mTORC1 in the insulin signaling pathway separated the insulin-induced Srebp-1c expression and the insulin-suppressed Pck1 expression [23]. The knockout of SREBP cleaving-activating protein gene in ob/ob mice resulted in the amelioration of hepatic lipogenesis without the improvement of hepatic gluconeogenesis [24]. Additionally in primary rat hepatocytes treated with insulin, the Gck expression reached the peak level 6 hours earlier than did the Srebp-1c expression [10]. "
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    • "Nonetheless, this observation is of particular interest in light of the potentially causal role that hepatic SREBP-1c activation has been proposed to play in metabolic disease in humans. Others have shown that genetic or pharmacological inhibition of SREBP maturation improves hepatic and whole-body metabolism (Moon et al., 2012; Tang et al., 2011). We therefore propose that SREBP-1c activation by PASK is an important Figure 6. "
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