Lactate Aggravates MASLD via PPARγ/CD36-Mediated Hepatocellular Fatty Acid Uptake

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent chronic liver disease worldwide, imposing a severe public health burden. Its core pathological hallmark is excessive hepatic lipid accumulation driven by systemic metabolic dysregulation. Concomitant hepatocellular injury impairs hepatic lactate clearance, leading to aberrant lactate buildup in the liver microenvironment. However, the causal role of lactate in exacerbating liver lipid metabolism dysfunction and driving the progression of MASLD remains unclear.

First, we performed a comprehensive bioinformatic analysis of publicly available transcriptomic datasets. Mining of the Gene Expression Omnibus (GEO) database showed that lactate dehydrogenase (LDH) expression was significantly upregulated in liver tissues from both metabolic dysfunction-associated fatty liver disease (MASLD) patients and MASLD mouse models. Next, network pharmacology approaches were employed to predict putative molecular targets that could mediate lactate's biological effects. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these candidate targets were predominantly enriched in pathways governing fatty acid metabolism and long-chain fatty acid transport. Molecular docking and molecular dynamics simulations further suggested possible interactions and supported the prioritization of cluster of differentiation 36 (CD36) as candidate lipid metabolism regulators potentially involved in lactate-mediated effects. Finally, liver-specific Ldha knockdown mice (AAV8-TBG-shRNA) and free fatty acid-induced steatotic AML12 hepatocytes were used to investigate the functional relevance of these findings in vivo and in vitro.

Network pharmacology analyses preliminarily identified the PPAR signaling pathway as a candidate pathway potentially linking lactate to MASLD. Experimental results showed that exogenous lactate administration was associated with significantly increased lipid accumulation in steatotic AML12 hepatocytes and the livers of MASLD mice, manifested as elevated triglyceride levels and enhanced lipid droplet formation, accompanied by upregulated expression of PPARγ and CD36. Conversely, inhibiting endogenous lactate production or silencing PPARγ or CD36 attenuated this lipid-accumulation phenotype and significantly reduced intracellular triglyceride levels.

In conclusion, these findings indicate that lactate exposure is associated with hepatic lipid accumulation and upregulation of the PPARγ/CD36 axis. Pharmacological inhibition or silencing of PPARγ or CD36 attenuates this phenotype, suggesting that this pathway may contribute to lactate-associated hepatic steatosis and potentially accelerate MASLD progression.