Singh Abhishek K, Chaube Balkrishna, Citrin Kathryn M, Fowler Joseph Wayne, Lee Sungwoon, Catarino Jonatas, Knight James, Lowery Sarah, Shree Sonal, Boutagy Nabil, Ruz-Maldonado Inmaculada, Harry Kathy, Shanabrough Marya, Ross Trenton Thomas, Malaker Stacy, Suárez Yajaira, Fernández-Hernando Carlos, Grabinska Kariona, Sessa William C
Department of Pharmacology, and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, 06520, USA.
Department of Comparative Medicine, Yale Center for Molecular and Systems Metabolism and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
bioRxiv. 2023 Nov 15:2023.11.13.566870. doi: 10.1101/2023.11.13.566870.
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 of mice (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/cis-PTase 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).
肥胖相关的脂肪肝是肝细胞癌（HCC）的一个重要危险因素；然而，从非酒精性脂肪性肝病（NAFLD）转变为HCC的潜在分子机制仍不清楚。本研究探讨内质网（ER）相关蛋白NgBR（顺式异戊二烯转移酶（cis-PTase）的一个重要组成部分）在慢性肝病中的作用。在此我们表明，小鼠肝细胞中NgBR的基因缺失（N-LKO）会加剧甘油三酯（TAG）积累、炎症反应、内质网/氧化应激和肝纤维化，最终在高脂饮食四个月后导致HCC发生，发生率达100%。来自受影响肝脏的综合基因组和单细胞转录组图谱提供了从肝脏病理生理学到HCC发生转变的详细分子分析。重要的是，对肝脏TAG合成中的关键酶二酰甘油酰基转移酶-2（DGAT2）进行药理抑制，可消除N-LKO小鼠饮食诱导的肝损伤和HCC负担。总体而言，我们的研究结果确立了NgBR/cis-PTase作为NAFLD-HCC转化的关键抑制因子，并表明抑制DGAT2可能是延缓晚期非酒精性脂肪性肝炎（NASH）患者HCC形成的一种有前景的治疗方法。
