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Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
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Hepatocyte mARC1 promotes fatty liver disease
Lara C Lewis1, Lingyan Chen1, L Shahul Hameed1
1Novo Nordisk Research Centre Oxford, Oxford, UK.
JHEP Reports : Innovation in Hepatology
|May 1, 2023
Summary
Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) are linked to non-alcoholic fatty liver disease (NAFLD). Inhibiting MTARC1 in liver cells shows promise for treating NAFLD.
Area of Science:
- Hepatology
- Human Genetics
- Metabolic Disease Research
Background:
- Non-alcoholic fatty liver disease (NAFLD) affects 25% globally, with limited treatments.
- Genetic variants in MTARC1 are associated with NAFLD and liver mortality.
- The precise role of MTARC1 and its mediating cell types in NAFLD are unclear.
Purpose of the Study:
- Investigate the role of MTARC1 in NAFLD pathogenesis.
- Integrate human genetics with in vitro and in vivo studies.
- Assess the potential of MTARC1 as a therapeutic target for NAFLD.
Main Methods:
- Utilized multi-trait colocalization and Mendelian randomization to analyze MTARC1 genetic associations.
- Established a primary human hepatocyte model for in vitro studies.
- Employed a NASH mouse model with hepatocyte-specific MTARC1 knockdown for in vivo validation.
Main Results:
- MTARC1 variants are associated with liver enzymes, fat, lipids, and body composition, driven by a shared causal variant (p.A165T).
- Increased MTARC1 mRNA showed adverse effects on these traits, suggesting therapeutic inhibition benefits.
- MTARC1 knockdown reduced hepatic lipid accumulation and altered triglyceride secretion in vitro and in vivo.
Conclusions:
- Findings support MTARC1's role in NAFLD pathogenesis.
- Hepatocyte-specific targeting of MTARC1 shows potential for NAFLD treatment.
- Genetic insights and experimental models underscore MTARC1 as a therapeutic target.
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