Membrane Bound O-Acyltransferase 7 (MBOAT7) Shapes Lysosomal Lipid Homeostasis and Function to Control Alcohol-Associated Liver Injury
Authors: Varadharajan Venkateshwari , Ramachandiran lyappan , Massey William J. , Jain Raghav , Banerjee Rakhee , Horak Anthony J. , McMullen Megan R. , Huang Emily , Bellar Annette , Lorkowski Shuhui W. , Guilshan Kailash , Helsley Robert N. , James Isabella , Pathak Vai , Dasarathy Jaividhya , Welch Nicole , Dasarathy Srinivasan , Streem David , Reizes Ofer , Allende Daniela S. , Smith Jonathan D. , Simcox Judith , Nagy Laura E. , Brown J. Mark 
Published: March 2024

Several recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNPs) near the gene encoding membrane-bound
O
-acyltransferase 7 (
MBOAT7
) that is associated with advanced liver diseases. In fact, a common
MBOAT7
variant (rs641738), which is associated with reduced
MBOAT7
expression, confers increased susceptibility to non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis in those chronically infected with hepatitis viruses B and C. The
MBOAT7
gene encodes a lysophosphatidylinositol (LPI) acyltransferase enzyme that produces the most abundant form of phosphatidylinositol 38:4 (PI 18:0/20:4). Although these recent genetic studies clearly implicate MBOAT7 function in liver disease progression, the mechanism(s) by which MBOAT7-driven LPI acylation regulates liver disease is currently unknown. Previously we showed that antisense oligonucleotide (ASO)-mediated knockdown of
Mboat7
promoted non-alcoholic fatty liver disease (NAFLD) in mice (Helsley et al., 2019). Here, we provide mechanistic insights into how
MBOAT7
loss of function promotes alcohol-associated liver disease (ALD). In agreement with GWAS studies, we find that circulating levels of metabolic product of MBOAT7 (PI 38:4) are significantly reduced in heavy drinkers compared to age-matched healthy controls. Hepatocyte specific genetic deletion (
Mboat7
HSKO
), but not myeloid-specific deletion (
Mboat7
MSKO
), of
Mboat7
in mice results in enhanced ethanol-induced hepatic steatosis and high concentrations of plasma alanine aminotransferase (ALT). Given MBOAT7 is a lipid metabolic enzyme, we performed comprehensive lipidomic profiling of the liver and identified a striking reorganization of the hepatic lipidome upon ethanol feeding in
Mboat7
HSKO
mice. Specifically, we observed large increases in the levels of endosomal/lysosomal lipids including bis(monoacylglycero)phosphates (BMP) and phosphatidylglycerols (PGs) in ethanol-exposed
Mboat7
HSKO
mice. In parallel, ethanol-fed
Mboat7
HSKO
mice exhibited marked dysregulation of autophagic flux and lysosomal biogenesis when exposed to ethanol. This was associated with impaired transcription factor EB (TFEB)-mediated lysosomal biogenesis and accumulation of autophagosomes. Collectively, this works provides new molecular insights into how genetic variation in
MBOAT7
impacts ALD progression in humans and mice. This work is the first to causally link MBOAT7 loss of function in hepatocytes, but not myeloid cells, to ethanol-induced liver injury via dysregulation of lysosomal biogenesis and autophagic flux.