Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-oxidation.

ABSTRACT:

Background/aims

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic. The disease has a strong genetic component, and a common missense variant (rs2642438) in the mitochondrial amidoxime-reducing component 1 (MARC1) gene confers protection against its onset and severity. However, there are contrasting results regarding the mechanisms that promote this protection.

Methods

We downregulated MARC1 in primary human hepatocytes (PHHs) using short interfering RNA (siRNA). We measured neutral lipid content by Oil-Red O staining and fatty acid oxidation by radiolabeled tracers. We also performed RNA-sequencing and proteomic analysis using LC-MS. Additionally, we analyzed data from 239,075 participants from the UK Biobank.

Results

Downregulation

SUBMITTER: Ciociola E 

PROVIDER: S-EPMC12016604 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature