کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
6102601 1211118 2015 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Research ArticleTRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی بیماری‌های گوارشی
پیش نمایش صفحه اول مقاله
Research ArticleTRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice
چکیده انگلیسی

Background & AimsAberrantly 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.MethodsTo produce germline-deleted Trim24dlE1 mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24LoxP mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24hep) 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.ResultsGlobal 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. Trim24dlE1/dlE1 mice have markedly depleted visceral fat and, like Trim24hep/hep mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma.ConclusionsTRIM24, 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Hepatology - Volume 62, Issue 2, February 2015, Pages 371-379
نویسندگان
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