The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia
| Autor: | Antonio C. Bianco, Ali Keshavarzian, Lattoya J. Lartey, Miriam O. Ribeiro, Allison B. Goldfine, Sungro Jo, Elizabeth A. McAninch, Balázs Gereben, Christopher B. Forsyth, Terry G. Unterman, Gustavo W. Fernandes, InSug O-Sullivan, Robin M. Voigt, Barbara M L C Bocco, Richárd Sinkó, Nailliw Z. Preite, Tatiana L. Fonseca, Mary E. Patti |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Apolipoprotein E medicine.medical_specialty Hypercholesterolemia Deiodinase FOXO1 Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Animals lcsh:QH301-705.5 Gene knockdown biology Forkhead Box Protein O1 Chemistry medicine.disease DNA-Binding Proteins Fatty Liver 030104 developmental biology Endocrinology medicine.anatomical_structure lcsh:Biology (General) Hepatocyte Hepatic stellate cell biology.protein lipids (amino acids peptides and proteins) Steatosis 030217 neurology & neurosurgery Lipoprotein |
| Zdroj: | Cell Reports, Vol 22, Iss 2, Pp 523-534 (2018) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2017.12.053 |
| Popis: | Summary: 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 ∼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. : Mice with liver-specific disruption of the type 2 deiodinase gene are resistant to both diet-induced obesity and hepatosteatosis. Fernandes et al. show that this is due to a reduction in liver expression of zinc-finger protein-125, a Foxo1-inducible transcriptional repressor that causes lipid accumulation by reducing hepatic secretion of VLDL. Keywords: deiodinase, steatosis, cholesterol, triglycerides, zinc finger protein 125, liver, hepatocytes, transcriptional repressor |
| Databáze: | OpenAIRE |
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