Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse
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. Overall design: Marc1-/- mice were generated using Regeneron's (Tarrytown, NY) VelociGene® technology (ID #20561), and  Wild-type (Marc1+/+) littermates were used as controls. All experiments were performed on 100% C57BL/6NTac background. Marc2 knockout mice (ID #20646) were generated similarly as Marc1 KO mouse using Regeneron VelociGene® technology, where second exon of Marc2 gene was replaced with LacZ reporter. Marc2 mice were bred on 100% C57BL/6NTac background. RNA-Seq was performed on RNA purified  from wild-type and homozygous Marc1 or Marc2 knockout mice tissues (heart, kidney, liver, lung, and white adipose).