Fatty liver disease protective MTARC1 p.A165T variant reduces the protein stability of MTARC1

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. MTARC1, encoded by the MTARC1 gene, is a mitochondrial outer membrane-anchored enzyme. Interestingly, the MTARC1 p.A165T (rs2642438) variant is associated with a decreased risk of NAFLD, indicating that MTARC1 might be an effective target. It has been reported that the rs2642438 variant does not have altered enzymatic activity so we reasoned that this variation may affect MTARC1 stability. In this study, MTARC1 mutants were generated and stability was assessed using a protein stability reporter system both in vitro and in vivo. We found that the MTARC1 p.A165T variant has dramatically reduced the stability of MTARC1, as assessed in several cell lines. In mice, the MTARC1 A168T mutant, the equivalent of human MTARC1 A165T, had diminished stability in mouse liver. Additionally, several MTARC1 A165 mutants, including A165S, A165 N, A165V, A165G, and A165D, had dramatically decreased stability as well, suggesting that the alanine residue of MTARC1 165 site is essential for MTARC1 protein stability. Collectively, our data indicates that the MTARC1 p.A165T variant (rs2642438) leads to reduced stability of MTARC1. Given that carriers of rs2642438 show a decreased risk of NAFLD, the findings herein support the notion that MTARC1 inhibition may be a therapeutic target to combat NAFLD.