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Fatty liver disease protective MTARC1 p.A165T variant reduces the protein stability of MTARC1
Mengyue Wu1, Meng Tie2, Liwei Hu2
1Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Anhui Medical University, Hefei, 230032, Anhui, China.
Abstract:
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.
Insights
The MTARC1 p.A165T variant significantly reduces MTARC1 protein stability, offering a potential therapeutic target for non-alcoholic fatty liver disease (NAFLD). This finding supports MTARC1 inhibition as a strategy to combat NAFLD.
Area of Science:
- Biochemistry
- Genetics
- Hepatology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a prevalent global liver condition.
- MTARC1, a mitochondrial enzyme, is implicated in NAFLD pathogenesis.
- The MTARC1 p.A165T variant (rs2642438) is linked to reduced NAFLD risk.
Purpose of the Study:
- To investigate the impact of the MTARC1 p.A165T variant on MTARC1 protein stability.
- To explore the potential of MTARC1 as a therapeutic target for NAFLD.
Main Methods:
- Generation of MTARC1 mutants, including p.A165T.
- Assessment of protein stability using in vitro and in vivo reporter systems across cell lines and mouse models.
- Analysis of various alanine substitution mutants at MTARC1 position 165.
Main Results:
- The MTARC1 p.A165T variant markedly decreased MTARC1 protein stability in multiple cell lines.
- The equivalent mouse mutant (A168T) also showed diminished stability in liver tissue.
- Other alanine mutants at position 165 (A165S, A165N, A165V, A165G, A165D) also exhibited significantly reduced stability, highlighting the importance of alanine at this site.
- The rs2642438 variant's protective effect against NAFLD correlates with reduced MTARC1 stability.
Conclusions:
- The MTARC1 p.A165T variant (rs2642438) leads to significantly reduced MTARC1 protein stability.
- MTARC1 stability is crucial, with alanine at position 165 being essential.
- These findings suggest that MTARC1 inhibition could be a viable therapeutic strategy for managing NAFLD.
