Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis.
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.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA.
Chen-Yu
CY
Wang
Donald S
DS
Stapleton
Kathryn L
KL
Schueler
Mary E
ME
Rabaglia
Angie T
AT
Oler
Mark P
MP
Keller
Christina M
CM
Kendziorski
Karl W
KW
Broman
Brian S
BS
Yandell
Eric E
EE
Schadt
Alan D
AD
Attie
D000483:Alleles; D000818:Animals; D049109:Cell Proliferation; D033481:Chromosomes, Mammalian / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D050417:Insulin-Secreting Cells / Q000473:pathology; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D040641:Quantitative Trait Loci / Q000235:genetics*; D013045:Species Specificity; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins