{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:39:29Z","timestamp":1772156369290,"version":"3.50.1"},"posted":{"date-parts":[[2023,9,27]]},"group-title":"Pathology","reference-count":48,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,1,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Several recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNPs) near the gene encoding membrane-bound\n                  <jats:italic>O<\/jats:italic>\n                  -acyltransferase 7 (\n                  <jats:italic>MBOAT7<\/jats:italic>\n                  ) that is associated with advanced liver diseases. In fact, a common\n                  <jats:italic>MBOAT7<\/jats:italic>\n                  variant (rs641738), which is associated with reduced\n                  <jats:italic>MBOAT7<\/jats:italic>\n                  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\n                  <jats:italic>MBOAT7<\/jats:italic>\n                  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\n                  <jats:italic>Mboat7<\/jats:italic>\n                  promoted non-alcoholic fatty liver disease (NAFLD) in mice (Helsley et al., 2019). Here, we provide mechanistic insights into how\n                  <jats:italic>MBOAT7<\/jats:italic>\n                  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 (\n                  <jats:italic>Mboat7<\/jats:italic>\n                  <jats:sup>HSKO<\/jats:sup>\n                  ), but not myeloid-specific deletion (\n                  <jats:italic>Mboat7<\/jats:italic>\n                  <jats:sup>MSKO<\/jats:sup>\n                  ), of\n                  <jats:italic>Mboat7<\/jats:italic>\n                  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\n                  <jats:italic>Mboat7<\/jats:italic>\n                  <jats:sup>HSKO<\/jats:sup>\n                  mice. Specifically, we observed large increases in the levels of endosomal\/lysosomal lipids including bis(monoacylglycero)phosphates (BMP) and phosphatidylglycerols (PGs) in ethanol-exposed\n                  <jats:italic>Mboat7<\/jats:italic>\n                  <jats:sup>HSKO<\/jats:sup>\n                  mice. In parallel, ethanol-fed\n                  <jats:italic>Mboat7<\/jats:italic>\n                  <jats:sup>HSKO<\/jats:sup>\n                  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\n                  <jats:italic>MBOAT7<\/jats:italic>\n                  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.\n                <\/jats:p>","DOI":"10.1101\/2023.09.26.559533","type":"posted-content","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T03:51:04Z","timestamp":1695873064000},"source":"Crossref","is-referenced-by-count":1,"title":["Membrane Bound O-Acyltransferase 7 (MBOAT7) Shapes Lysosomal Lipid Homeostasis and Function to Control Alcohol-Associated Liver Injury"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4557-9840","authenticated-orcid":false,"given":"Venkateshwari","family":"Varadharajan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0271-5478","authenticated-orcid":false,"given":"lyappan","family":"Ramachandiran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-6048","authenticated-orcid":false,"given":"William J.","family":"Massey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghav","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2299-7177","authenticated-orcid":false,"given":"Rakhee","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2024-3679","authenticated-orcid":false,"suffix":"3rd","given":"Anthony J.","family":"Horak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan R.","family":"McMullen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annette","family":"Bellar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7206-5243","authenticated-orcid":false,"given":"Shuhui W.","family":"Lorkowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-7370","authenticated-orcid":false,"given":"Kailash","family":"Guilshan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5000-3187","authenticated-orcid":false,"given":"Robert N.","family":"Helsley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella","family":"James","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vai","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaividhya","family":"Dasarathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Welch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1774-0104","authenticated-orcid":false,"given":"Srinivasan","family":"Dasarathy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5804-7598","authenticated-orcid":false,"given":"David","family":"Streem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0075-6871","authenticated-orcid":false,"given":"Ofer","family":"Reizes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela S.","family":"Allende","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan D.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7350-6342","authenticated-orcid":false,"given":"Judith","family":"Simcox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2708-7487","authenticated-orcid":false,"given":"J. 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