# MRPL44 regulates lipid metabolism in metabolic dysfunction-associated steatotic liver disease through BNIP3-mediated mitophagy

## TL;DR

MRPL44 helps reduce liver fat buildup by boosting mitophagy, a process that clears damaged mitochondria, offering a new target for treating fatty liver disease.

## Contribution

MRPL44 is newly identified as a regulator of lipid metabolism through BNIP3-mediated mitophagy in metabolic dysfunction-associated steatotic liver disease.

## Key findings

- MRPL44 overexpression reduces triglyceride accumulation and enhances fatty acid oxidation in HepG2 cells.
- Liver-specific MRPL44 overexpression in mice attenuates high-fat diet-induced hepatic lipid deposition.
- MRPL44 activates BNIP3-dependent mitophagy, promotes mitochondrial biogenesis, and reduces mitochondrial damage.

## Abstract

Mitophagy is a critical defense mechanism against metabolic dysfunction–associated steatotic liver disease. MRPL44, a mitochondrial ribosomal protein that regulates mitochondrial DNA-encoded gene expression, has not previously been linked to lipid metabolism.

This study employed an oleic acid/palmitic acid induced HepG2 cell models and a high-fat diet fed mouse models, combined with lentivirus-mediated MRPL44 overexpression and mitophagy assays, to investigate the regulatory role of MRPL44 in the progression of metabolic dysfunction–associated steatotic liver disease.

Our findings demonstrated that MRPL44 alleviates lipid metabolic disorders induced by high-fat diet through the mitophagy pathway. Specifically, in oleic acid/palmitic acid-stimulated HepG2 cells, overexpression of MRPL44 reduced intracellular triglyceride accumulation and enhanced fatty acid oxidation. Moreover, liver-specific overexpression of MRPL44 in mice attenuated high-fat diet induced hepatic lipid deposition. Mechanistically, MRPL44 activated the BNIP3-dependent mitophagy pathway, promoted mitochondrial biogenesis, and mitigated mitochondrial damage, ultimately reducing lipid accumulation in hepatocytes.

This study identifies MRPL44 as a novel regulator of lipid metabolism and a potential therapeutic target for metabolic dysfunction–associated steatotic liver disease.

Graphical abstract illustrating the effects of a high-fat diet (HFD) on a mouse, showing normal and MRPL44-altered liver states. Mitochondrial dysfunction increases, denoted by red arrows. Mitochondrial fission and fusion cycles are depicted alongside mitophagy processes involving LC3 and Bnip3 proteins. Changes in ATP, ROS, and lipid levels are indicated with arrows.