Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 34, Pages 13656-13661Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1203218109
Keywords
nonalcoholic fatty liver disease; adenoviral expression; SREBP1c; ChREBP; TLR4
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Funding
- National Research Foundation of Korea [2011-0030711, 2011-0015665]
- World Class University (WCU) [R31-10086]
- Ministry of Education, Science and Technology (MEST) of the Korean government
- National Research Foundation of Korea [R31-2012-000-10086-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Recently, hepatic peroxisome proliferator-activated receptor (PPAR)gamma has been implicated in hepatic lipid accumulation. We found that the C3H mouse strain does not express PPAR gamma in the liver and, when subject to a high-fat diet, is resistant to hepatic steatosis, compared with C57BL/6 (B6) mice. Adenoviral PPAR gamma 2 injection into B6 and C3H mice caused hepatic steatosis, and microarray analysis demonstrated that hepatic PPAR gamma 2 expression is associated with genes involved in fatty acid transport and the triglyceride synthesis pathway. In particular, hepatic PPAR gamma 2 expression significantly increased the expression of monoacylglycerol O-acyltransferase 1 (MGAT1). Promoter analysis by luciferase assay and electrophoretic mobility shift assay as well as chromatin immunoprecipitation assay revealed that PPAR gamma 2 directly regulates the MGAT1 promoter activity. The MGAT1 overexpression in cultured hepatocytes enhanced triglyceride synthesis without an increase of PPAR gamma expression. Importantly, knockdown of MGAT1 in the liver significantly reduced hepatic steatosis in 12-wk-old high-fat-fed mice as well as ob/ob mice, accompanied by weight loss and improved glucose tolerance. These results suggest that the MGAT1 pathway induced by hepatic PPAR gamma is critically important in the development of hepatic steatosis during diet-induced obesity.
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