Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse

• Published in: PLoS genetics Vol. 20; no. 3; p. e1011179
• Main Authors: Smagris, Eriks, Shihanian, Lisa M., Mintah, Ivory J., Bigdelou, Parnian, Livson, Yuliya, Brown, Heather, Verweij, Niek, Hunt, Charleen, Johnson, Reid O’Brien, Greer, Tyler J., Hartford, Suzanne A., Hindy, George, Sun, Luanluan, Nielsen, Jonas B., Halasz, Gabor, Lotta, Luca A., Murphy, Andrew J., Sleeman, Mark W., Gusarova, Viktoria
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.03.2024
• Subjects: Animals; Biology and Life Sciences; Cirrhosis; Cytochrome; Engineering and Technology; Enzymes; Fatty liver; Fibrosis; Genetic aspects; Genome-wide association studies; Genome-Wide Association Study; Genomes; Health aspects; Humans; Lipids; Liver; Liver Cirrhosis; Liver diseases; Localization; Magnetic resonance imaging; Medicine and Health Sciences; Mice; Mitochondria; Oximes; Phenotypes; Protein expression; Proteins; Research and Analysis Methods; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1011179

Recent human genome-wide association studies have identified common missense variants in MARC1 , p.Ala165Thr and p.Met187Lys, associated with lower hepatic fat, reduction in liver enzymes and protection from most causes of cirrhosis. Using an exome-wide association study we recapitulated earlier MARC1 p.Ala165Thr and p.Met187Lys findings in 540,000 individuals from five ancestry groups. We also discovered novel rare putative loss of function variants in MARC1 with a phenotype similar to MARC1 p.Ala165Thr/p.Met187Lys variants. In vitro studies of recombinant human MARC1 protein revealed Ala165Thr substitution causes protein instability and aberrant localization in hepatic cells, suggesting MARC1 inhibition or deletion may lead to hepatoprotection. Following this hypothesis, we generated Marc1 knockout mice and evaluated the effect of Marc1 deletion on liver phenotype. Unexpectedly, our study found that whole-body Marc1 deficiency in mouse is not protective against hepatic triglyceride accumulation, liver inflammation or fibrosis. In attempts to explain the lack of the observed phenotype, we discovered that Marc1 plays only a minor role in mouse liver while its paralogue Marc2 is the main Marc family enzyme in mice. Our findings highlight the major difference in MARC1 physiological function between human and mouse.