Human genetic studies have identified several MARC1 variants as protective against non-alcoholic fatty liver diseases (NAFLD). The MARC1 variants are associated with reduced lipid profiles, liver enzymes, and liver-related mortality. However, the role of mitochondrial amidoxime reducing component 1 (mARC1), encoded by MARC1, in NAFLD is still unknown and the therapeutic potential of this target has never been developed. Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine conjugated mouse mARC1 siRNA to address this. In ob/ob mice, knockdown of mARC1 in mouse hepatocytes resulted in decreased liver weight, serum lipid enzymes, low-density lipoprotein cholesterol, and liver triglycerides. Loss of mARC1 also improved the lipid profiles and attenuated liver pathological changes in two diet-induced nonalcoholic steatohepatitis (NASH) mouse models. A comprehensive analysis of mARC1-deficient liver in NASH by metabolomics, proteomics, and lipidomics showed that mARC1 knockdown partially restored metabolites and lipids altered by diets. Taken together, loss of mARC1 protects mouse liver from NASH, suggesting a potential therapeutic approach of NASH by downregulation of mARC1 in hepatocytes.
[doi:10.25345/C57S7J31Q]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: MARC1 ; NASH ; TMT
Principal Investigators: (in alphabetical order) |
Matthew Rardin, Amgen, United States |
Submitting User: | mrardin1 |
Guo Y, Gao Z, LaGory EL, Kristin LW, Gupte J, Gong Y, Rardin MJ, Liu T, Nguyen TT, Long J, Hsu YH, Murray JK, Lade J, Jackson S, Zhang J.
Liver-specific mitochondrial amidoxime-reducing component 1 (Mtarc1) knockdown protects the liver from diet-induced MASH in multiple mouse models.
Hepatol Commun. Epub 2024 May 2.
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