# Intestinal Activation of LXRα Counteracts Metabolic-Associated Steatohepatitis Features in Mice

## TL;DR

Activating LXRα in the intestines of mice helps reduce liver disease features like fat buildup, inflammation, and fibrosis.

## Contribution

This study shows intestinal LXRα activation protects against MASLD by enhancing HDL and SRB1.

## Key findings

- Intestinal LXRα activation improved triglyceride levels, RCT, and reduced steatosis and inflammation.
- Increased HDL and hepatic SRB1 expression were linked to the protective effects observed.
- SRB1 depletion in vitro reduced the benefits of HDL on liver cells.

## Abstract

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)α on MASH. Methods: An intestinal-specific LXRα activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXRα improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors γ and small mothers against decapentaplegic homolog protein (SMAD)2/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXRα and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD.