8 research outputs found

    The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia

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    Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an similar to 60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like'' metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.NIDDKEUHungarian Brain Research ProgramFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Coordenadoria de Apoio a Pesquisa (CAPES), BrazilRush Univ, Med Ctr, Div Endocrinol & Metab, Chicago, IL 60612 USAUniv Fed Sao Paulo, Program Translat Med, Sao Paulo, BrazilUniv Illinois, Coll Med, Dept Med, Sect Endocrinol Diabet & Metab, Chicago, IL USARush Univ, Div Digest Dis & Nutr, Med Ctr, Chicago, IL 60612 USAHarvard Med Sch, Joslin Diabet Ctr, Boston, MA USAUniv Prebiteriana Mackenzie, Ctr Biol Sci & Hlth, Dev Disorders Program, Sao Paulo, BrazilHungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest, HungaryUniv Fed Sao Paulo, Program Translat Med, Sao Paulo, BrazilNIDDK: DK65055, R01DK106193, P30DK036836EU: 666869Hungarian Brain Research Program: KTIA_13_NAP_A_I/4FAPESP: 2011/21847-6Web of Scienc
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