Hepatic LGALS4 Alleviates Diet-Induced Steatosis by Promoting AMPK-Dependent Fatty Acid Oxidation.

AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by impaired hepatic lipid handling, and despite recent therapeutic advances, additional mechanistically distinct therapeutic strategies remain needed. We sought to identify endogenous hepatic regulators induced by energetic challenge that could be leveraged to counteract pathological lipid accumulation.

MATERIALS AND

METHODS

Integrative transcriptomic analyses were performed across multiple physiological energetic challenges, including cold exposure, β3-adrenergic activation, fasting and exercise, to identify conserved hepatic energy-responsive genes. The functional role of Galectin-4 (LGALS4) was investigated using hepatocyte-specific gain- and loss-of-function approaches in high-fat diet (HFD)-fed mice and primary hepatocytes. Mitochondrial function was assessed via Seahorse metabolic flux analysis.

RESULTS

LGALS4 emerged as a conserved hepatic factor induced by energetic challenge but suppressed during chronic nutrient excess and in human MASLD liver samples. Hepatocyte-specific overexpression of Lgals4 markedly attenuated HFD-induced hepatic steatosis and reduced hepatic triglyceride accumulation, with limited effects on systemic glucose tolerance or insulin sensitivity. Conversely, Lgals4 knockdown exacerbated lipid accumulation and impaired fatty acid oxidation (FAO) gene expression in hepatocytes. Mechanistically, LGALS4 increased AMPK and ACC phosphorylation and upregulated the PGC1α-PPARα fatty acid oxidation programme, leading to enhanced mitochondrial oxidative capacity and reduced lipid accumulation in hepatocytes. These effects were largely abolished by AMPK inhibition, supporting an AMPK-dependent mechanism.

CONCLUSIONS

LGALS4 is an energy-responsive hepatic regulator that protects against steatosis by promoting AMPK-dependent fatty acid oxidation. These findings identify LGALS4 as a potential metabolically selective target for MASLD treatment.