# Deletion of RhoGDI Protects Against Hepatic Steatosis via Improved Mitochondrial Metabolism in Mice

## TL;DR

Deleting RhoGDI in mice protects against fatty liver disease by improving mitochondrial function and reducing liver fat accumulation.

## Contribution

This study identifies RhoGDI as a key regulator of metabolic liver disease and shows that its deletion improves mitochondrial metabolism and reduces hepatic steatosis.

## Key findings

- Hepatocyte-specific deletion of Arhgdia (RhoGDI) reduced hepatic lipid accumulation and fibrosis in mice.
- RhoGDI deficiency suppressed the steroid hormone biosynthesis pathway and improved mitochondrial β-oxidation.
- A natural compound targeting RhoGDI alleviated liver steatosis and inflammation in a MASLD model.

## Abstract

The global incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising alongside epidemics of diabetes and obesity. Rho GDP-dissociation inhibitor (RhoGDI) is now recognized to play dual regulatory roles in disease. A deeper understanding of its mechanistic contributions in MASLD could offer critical insights for developing novel therapies against this growing health burden. Immunohistochemical staining was used to examine RhoGDI expression in liver tissues from patients with MASLD. Hepatocyte-specific deletion of Arhgdia (the gene encodes RhoGDI) was generated in mice, and they subjected to NASH diets to induce hepatic steatosis. Transcriptomic sequencing was carried out to identify altered pathways in the Arhgdia-deficient mice, followed by functional investigations of downstream signaling and mitochondrial performance. Finally, the therapeutic potential of a candidate compound was evaluated in the MASLD model. The expression level of RhoGDI was significantly upregulated, and hepatocyte-specific deletion of Arhgdia (the gene encodes RhoGDI) attenuated hepatic lipid accumulation and fibrotic progression. The RNA sequencing analysis revealed that RhoGDI deficiency suppressed the hepatic steroid hormone biosynthesis pathway. It was demonstrated that RhoGDI plays a crucial role in maintaining mitochondrial function, since hepatocyte-specific knockout of Arhgdia significantly reversed mitochondrial dysfunction in mice. Furthermore, a natural compound was found to alleviate hepatic steatosis and inflammation in MASLD mice by targeting RhoGDI. This finding demonstrates that Arhgdia deletion confers protection against the progression of MASLD by reducing hepatic lipid accumulation and enhances mitochondrial β-oxidation in hepatocytes establishing RhoGDI as a critical regulator of MASLD pathogenesis and highlighting its potential as a therapeutic target for metabolic liver diseases.