Loss of cisPTase function in the liver promotes a highly penetrant form of fatty liver disease that rapidly transitions to hepatocellular carcinoma [scRNA-seq]

In developed countries, obesity-linked fatty liver is a significant risk factor for hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying the transition from non-alcoholic fatty liver disease (NAFLD) to HCC remains unclear. The present study explores the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme, in chronic liver disease. Here we show that genetic depletion of NgBR in hepatocytes ofmice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and liver fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Comprehensive genomic and single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in hepatic TAG synthesis, abrogates diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish NgBR/cisPTase as a critical suppressor of NAFLD- HCC conversion and suggests that DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in patients with advanced non-alcoholic steatohepatitis (NASH). Overall design: Comparative gene expression in Wild type (WT) and Liver specific NgBR KO mice fed with Western type of diet (WD) for 16 weeks.

在发达国家，与肥胖相关的脂肪肝是肝细胞癌（hepatocellular carcinoma, HCC）的重要危险因素，但从非酒精性脂肪性肝病（non-alcoholic fatty liver disease, NAFLD）进展至HCC的分子机制仍不明确。本研究探讨了内质网（endoplasmic reticulum, ER）相关蛋白NgBR——顺式异戊烯基转移酶（cis-prenyltransferases, cis-PTase）复合物的关键组成部分——在慢性肝脏疾病中的作用。研究结果显示，在小鼠肝细胞中特异性敲除NgBR（N-LKO小鼠）后，喂食高脂饮食四个月时可100%外显率诱发HCC，其机制为加剧三酰甘油（triacylglycerol, TAG）蓄积、炎症反应、内质网/氧化应激及肝纤维化。我们通过对受累肝脏开展全基因组与单细胞转录组图谱分析，详细解析了从肝脏病理生理改变到HCC发生的分子转化过程。值得注意的是，靶向抑制肝脏三酰甘油合成的关键酶二酰甘油酰基转移酶-2（diacylglycerol acyltransferase-2, DGAT2），可阻断N-LKO小鼠中饮食诱导的肝脏损伤与HCC负荷增加。综上，本研究证实NgBR/cis-PTase是NAFLD向HCC转化的关键抑制因子，并提示抑制DGAT2或可成为延缓晚期非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）患者HCC发生的潜在治疗策略。实验整体设计：对喂食西式饮食（Western diet, WD）16周的野生型（Wild type, WT）与肝脏特异性NgBR敲除小鼠进行基因表达对比分析。