TY - JOUR
T1 - The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals
AU - Moon, Young Ah
AU - Liang, Guosheng
AU - Xie, Xuefen
AU - Frank-Kamenetsky, Maria
AU - Fitzgerald, Kevin
AU - Koteliansky, Victor
AU - Brown, Michael S.
AU - Goldstein, Joseph L.
AU - Horton, Jay D.
N1 - Funding Information:
This work was supported by grants from the Moss Heart Foundation and the National Institutes of Health HL-20948 and DK081182. The authors thank Norma Anderson, Tuyet Dang, Katherine Lim, Monica Mendoza, Judy Sanchez, and Isis Soto for technical assistance and Akin Akinc, Muthiah Manoharan, Martin Maier, and Satya Kuchimanchi at Alnylam for formulations and chemistry.
PY - 2012/2/8
Y1 - 2012/2/8
N2 - 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.
AB - 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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U2 - 10.1016/j.cmet.2011.12.017
DO - 10.1016/j.cmet.2011.12.017
M3 - Article
C2 - 22326225
AN - SCOPUS:84863393589
SN - 1550-4131
VL - 15
SP - 240
EP - 246
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -