mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

Autor:	Jones AK; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Bajrami B; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Campbell MK; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Erzurumluoglu AM; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Guo Q; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Chen H; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Zhang X; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Zeveleva S; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Kvaskoff D; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Brunner AD; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Muller S; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Gathey V; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Dave RM; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Tanner JW; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Rixen S; Department of Pharmacy, Pharmaceutical Institute, Christian Albrechts University, Kiel, Germany., Struwe MA; Department of Pharmacy, Pharmaceutical Institute, Christian Albrechts University, Kiel, Germany.; Department of Biology, Institute of Zoology-Structural Biology, Christian Albrechts University, Kiel, Germany., Phoenix K; Department of Biotherapeutics Discovery, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Klumph KJ; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Robinson H; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Veyel D; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Muller A; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Noyvert B; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Bartholdy BA; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Steixner-Kumar AA; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Stutzki J; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany.; Data Science Chapter, BI X GmbH, Ingelheim am Rhein, Germany., Drichel D; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany.; Data Science Chapter, BI X GmbH, Ingelheim am Rhein, Germany., Omland S; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany.; Data Science Chapter, BI X GmbH, Ingelheim am Rhein, Germany., Sheehan R; Department of Immunology and Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Hill J; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Bretschneider T; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Gottschling D; Department of Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Scheidig AJ; Department of Biology, Institute of Zoology-Structural Biology, Christian Albrechts University, Kiel, Germany., Clement B; Department of Pharmacy, Pharmaceutical Institute, Christian Albrechts University, Kiel, Germany., Giera M; Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany.; The Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands., Ding Z; Department of Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany., Broadwater J; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA., Warren CR; Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA.
Jazyk:	angličtina
Zdroj:	Hepatology communications [Hepatol Commun] 2024 Apr 12; Vol. 8 (5). Date of Electronic Publication: 2024 Apr 12 (Print Publication: 2024).
DOI:	10.1097/HC9.0000000000000365
Abstrakt:	Background: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. Methods and Results: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models. Conclusions: Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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