Department of Cancer Biology, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Iyappan Ramachandiran
Department of Cancer Biology, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Department of Cancer Biology, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
Rakhee Banerjee
Department of Cancer Biology, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Anthony J Horak
Department of Cancer Biology, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Megan R McMullen
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Emily Huang
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Annette Bellar
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Shuhui W Lorkowski
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States
Kailash Gulshan
Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, United States
Department of Cancer Biology, Lerner Research Institute of the Cleveland Clinic, Cleveland, United States; Department of Pharmacology & Nutritional Sciences, Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, United States
Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
Vai Pathak
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Jaividhya Dasarathy
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Family Medicine, Metro Health Medical Center, Case Western Reserve University, Cleveland, United States
Nicole Welch
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
David Streem
Lutheran Hospital, Cleveland Clinic, Cleveland, United States
Ofer Reizes
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Daniela S Allende
Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Anatomical Pathology, Cleveland Clinic, Cleveland, United States
Department of Biochemistry, University of Wisconsin-Madison, Madison, United States
Laura E Nagy
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Northern Ohio Alcohol Center (NOAC), Lerner Research Institute, Cleveland Clinic, Cleveland, United States
Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive. Previously, we identified MBOAT7-driven acylation of lysophosphatidylinositol lipids as key mechanism suppressing the progression of NAFLD (Gwag et al., 2019). Here, we show that MBOAT7 loss of function promotes ALD via reorganization of lysosomal lipid homeostasis. Circulating levels of MBOAT7 metabolic products are significantly reduced in heavy drinkers compared to healthy controls. Hepatocyte- (Mboat7-HSKO), but not myeloid-specific (Mboat7-MSKO), deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling reveals a reorganization of the hepatic lipidome in Mboat7-HSKO mice, characterized by increased endosomal/lysosomal lipids. Ethanol-exposed Mboat7-HSKO mice exhibit dysregulated autophagic flux and lysosomal biogenesis, associated with impaired transcription factor EB-mediated lysosomal biogenesis and autophagosome accumulation. This study provides mechanistic insights into how MBOAT7 influences ALD progression through dysregulation of lysosomal biogenesis and autophagic flux, highlighting hepatocyte-specific MBOAT7 loss as a key driver of ethanol-induced liver injury.
