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Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury

التفاصيل البيبلوغرافية
العنوان: Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury
المؤلفون: Venkateshwari Varadharajan, Iyappan Ramachandiran, William J Massey, Raghav Jain, Rakhee Banerjee, Anthony J Horak, Megan R McMullen, Emily Huang, Annette Bellar, Shuhui W Lorkowski, Kailash Gulshan, Robert N Helsley, Isabella James, Vai Pathak, Jaividhya Dasarathy, Nicole Welch, Srinivasan Dasarathy, David Streem, Ofer Reizes, Daniela S Allende, Jonathan D Smith, Judith Simcox, Laura E Nagy, J Mark Brown
المصدر: eLife, Vol 12 (2024)
بيانات النشر: eLife Sciences Publications Ltd, 2024.
سنة النشر: 2024
المجموعة: LCC:Medicine
LCC:Science
LCC:Biology (General)
مصطلحات موضوعية: MBOAT7, alcohol-associated liver disease, autophagy, Medicine, Science, Biology (General), QH301-705.5
الوصف: 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2050-084X
Relation: https://elifesciences.org/articles/92243; https://doaj.org/toc/2050-084X
DOI: 10.7554/eLife.92243
URL الوصول: https://doaj.org/article/3c5d86faa2f749f9b1ff225029440203
رقم الأكسشن: edsdoj.3c5d86faa2f749f9b1ff225029440203
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:2050084X
DOI:10.7554/eLife.92243