Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα

Obesity triggers the genesis of non-alcoholic fatty liver diseases (NAFLD), which involves alterations of regulatory transcription networks and of hepatocyte-selective epigenomes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR)/ histone deacetylase 3 (HDAC3) complex, is a central component of such networks and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor alpha (PPARa, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that GPS2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARa partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be therapeutically important.

肥胖可诱发非酒精性脂肪性肝病（non-alcoholic fatty liver diseases, NAFLD）的发生，该疾病伴随调控性转录网络及肝细胞选择性表观基因组的改变。本研究证实，作为核受体辅阻遏因子（nuclear receptor corepressor, NCOR）/组蛋白去乙酰化酶3（histone deacetylase 3, HDAC3）复合物的亚基，G蛋白通路抑制因子2（G protein pathway suppressor 2, GPS2）是此类调控网络的核心组分，并可加速NAFLD向非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）进展。小鼠肝细胞特异性敲除Gps2可缓解膳食诱导的脂肪变性与纤维化进程，并激活脂质分解代谢相关基因的表达。整合顺基因组、表观基因组与转录组的联合分析显示，脂质感知分子过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor alpha, PPARα, NR1C1）是GPS2的直接靶标。人类患者的肝脏基因表达数据显示，GPS2的表达水平与NASH/纤维化基因特征呈正相关。综上，本研究数据表明，肝细胞中GPS2与PPARα的协同互作可调控小鼠及人类NAFLD的进展，因此具备潜在的治疗价值。