TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice.
TRIM24 suppresses development of spontaneous hepatic lipid accumulation and hepatocellular carcinoma in mice.
复制标题
DOI：
10.1016/j.jhep.2014.09.026
复制
发表时间：
2015-02
影响因子：
25.7
通讯作者：
Barton MC
中科院分区：
文献类型：
--
作者：
Jiang S;Minter LC;Stratton SA;Yang P;Abbas HA;Akdemir ZC;Pant V;Post S;Gagea M;Lee RG;Lozano G;Barton MC
TRIM 24的异常高表达发生在人类癌症中，包括肝细胞癌。相比之下，据报道小鼠中的TRIM 24是肝脏特异性肿瘤抑制因子。为了解决这种二分法并揭示TRIM 24在体内的直接调控功能，我们开发了一种新的小鼠模型，该模型缺乏所有Trim 24亚型的表达，因为先前的模型表达仅缺乏外显子4的正常水平的Trim 24。为了产生种系缺失的Trim 24 dlE 1小鼠，通过与用于整体缺失的透明带3-Cre系杂交，在Trim 24 LoxP小鼠中诱导Trim 24的启动子和外显子1的缺失。通过与白蛋白-Cre系杂交实现肝脏特异性缺失（Trim 24 hep）。表型分析的补充蛋白质，基因特异性和全球RNA表达分析和定量染色质免疫沉淀。Trim 24的整体缺失破坏了100%小鼠的肝脏稳态，氧化/还原、类固醇、脂肪酸和脂质代谢基因的表达显著降低，以及未折叠蛋白、内质网应激和细胞周期途径中的基因表达增加。Trim 24 dlE 1/dlE 1小鼠的内脏脂肪显著减少，并且与Trim 24 hep/hep小鼠一样，自发地发生肝脏脂质填充病变、脂肪变性、肝损伤、纤维化和肝细胞癌。TRIM 24是一种表观遗传转录共调节因子，直接和间接抑制小鼠肝脏中的肝脏脂质积累、炎症、纤维化和损伤。Trim 24的完全丧失提供了在不存在高脂肪饮食或肥胖的情况下人类非酒精性脂肪肝疾病、脂肪变性、纤维化和肝细胞癌发展的模型。
Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumor suppressor. To address this dichotomy and 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 expresses normal levels of Trim24 lacking only exon 4. To 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. 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 in unfolded protein, 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. 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 nonalcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity.