TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice

JOURNAL OF HEPATOLOGY

卷:62

Article

Jiang, Shiming^1,2,3  Minter, Lindsey Cauthen^1,2,3,7  Stratton, Sabrina A.^1,2,3  Yang, Peirong⁴  Abbas, Hussein A.^4,7  Akdemir, Zeynep Coban^1,2,3,7  Pant, Vinod⁴  Post, Sean⁵  Gagea, Mihai⁶  Lee, Richard G.⁸  Lozano, Guillermina^4,7  Barton, Michelle Craig^1,2,3,7 

[1] UT MD Anderson Canc Ctr, Dept Biochem & Mol Biol, Houston, TX USA

[2] UT MD Anderson Canc Ctr, Ctr Stem Cell & Dev Biol, Houston, TX USA

[3] UT MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX USA

[4] UT MD Anderson Canc Ctr, Dept Genet, Houston, TX USA

[5] UT MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA

[6] UT MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX USA

[7] Univ Texas Grad Sch Biomed Sci Houston, Grad Program Genes & Dev, Houston, TX USA

[8] ISIS Pharmaceut, Carlsbad, CA 92008 USA

关键词: NAFLD;    NASH;    Steatosis;    Hepatic lesions;    HCC;    Histone reader;   

DOI  :  10.1016/j.jhep.2014.09.026

来源: Elsevier

【 摘 要 】

Background & Aims: Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumour suppressor. To address this dichotomy and to uncover direct regulatory functions of TRIM24 in vivo, we developed a new mouse model that lacks expression of all Trim24 isoforms, as the previous model expressed normal levels of Trim24 lacking only exon 4. Methods: To produce germline-deleted Trim24(dlE1) mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24(LoxP) mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24(hep)) was achieved by crossing with an albumin-Cre line. Phenotypic analyses were complemented by protein, gene-specific and global RNA expression analyses and quantitative chromatin immunoprecipitation. Results: Global loss of Trim24 disrupted hepatic homeostasis in 100% of mice with highly significant, decreased expression of oxidation/reduction, steroid, fatty acid, and lipid metabolism genes, as well as increased expression of genes involved in unfolded protein response, endoplasmic reticulum stress and cell cycle pathways. Trim24(dlE1/dlE1) mice have markedly depleted visceral fat and, like Trim24(hep/hep) mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma. Conclusions: TRIM24, an epigenetic co-regulator of transcription, directly and indirectly represses hepatic lipid accumulation, inflammation, fibrosis and damage in the murine liver. Complete loss of Trim24 offers a model of human non-alcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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