Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis |
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Authors: | Wang Chen-Yu Stapleton Donald S Schueler Kathryn L Rabaglia Mary E Oler Angie T Keller Mark P Kendziorski Christina M Broman Karl W Yandell Brian S Schadt Eric E Attie Alan D |
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Institution: | Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. |
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Abstract: | Nonalchoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction and is associated with metabolic diseases, including obesity, insulin resistance, and type 2 diabetes. We mapped a quantitative trait locus (QTL) for NAFLD to chromosome 17 in a cross between C57BL/6 (B6) and BTBR mouse strains made genetically obese with the Lep(ob/ob) mutation. We identified Tsc2 as a gene underlying the chromosome 17 NAFLD QTL. Tsc2 functions as an inhibitor of mammalian target of rapamycin, which is involved in many physiological processes, including cell growth, proliferation, and metabolism. We found that Tsc2(+/-) mice have increased lipogenic gene expression in the liver in an insulin-dependent manner. The coding single nucleotide polymorphism between the B6 and BTBR strains leads to a change in the ability to inhibit the expression of lipogenic genes and de novo lipogenesis in AML12 cells and to promote the proliferation of Ins1 cells. This difference is due to a different affinity of binding to Tsc1, which affects the stability of Tsc2. |
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Keywords: | diabetes fatty acid/metabolism genetics triglycerides cell proliferation nonalcoholic fatty liver disease |
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