The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals

Young Ah Moon, Guosheng Liang, Xuefen Xie, Maria Frank-Kamenetsky, Kevin Fitzgerald, Victor Koteliansky, Michael S. Brown, Joseph L. Goldstein, Jay D. Horton

Research output: Contribution to journalArticle

177 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)240-246
Number of pages7
JournalCell Metabolism
Volume15
Issue number2
DOIs
StatePublished - Feb 8 2012

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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