Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation

作者：Mary P. Moore, Xiaobo Wang, John P. Kennelly, Hongxue Shi, Yuki Ishino, Kuniyuki Kano, Junken Aoki, Alessandro Cherubini, Luisa Ronzoni, Xiuqing Guo, Naga Chalasani, Shareef Khalid, Danish Saleheen, Matthew A. Mitsche, Jerome I. Rotter, Katherine P. Yates, Luca Valenti, Nozomu Kono, Peter Tontonoz, Ira Tabas · 发表于：Hepatology · 年份：2024 · DOI：10.1097/hep.0000000000000933 · 被引用次数：18 · 研究领域：Hippo pathway signaling and YAP/TAZ、Liver Disease Diagnosis and Treatment、Liver physiology and pathology

BACKGROUND AND AIMS: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, ...