Abstract Body: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over one third of the global population, and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is strongly associated with atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality in these patients. Despite major advances in therapies targeting MASH and ASCVD independently, the metabolic pathways that mechanistically link hepatic dysfunction to vascular disease remain poorly defined, limiting the development of integrated cardiometabolic treatments.
Using a novel mouse model of concurrent MASH and atherosclerosis, unbiased metabolic profiling identified hepatic lactate accumulation as a metabolic signature strongly associated with both hepatic injury and atherosclerotic burden. Although the liver is a central organ for systemic lactate clearance via lactate dehydrogenase A (LDHA), the contribution of dysregulated hepatic lactate metabolism to vascular disease progression has not been systematically explored.
In vitro, elevated lactate promoted hepatocellular lipid accumulation, suppressed peroxisome proliferator-activated receptor α (PPARα) target genes governing fatty acid β-oxidation, and induced expression of the pro-inflammatory chemokine C-C motif chemokine ligand 2 (CCL2), a key mediator of monocyte recruitment and vascular inflammation. In vivo, hepatocyte-specific deletion of LDHA enhanced hepatic fatty acid oxidation pathways and improved systemic metabolic parameters. Importantly, pharmacologic reduction of LDHA activity using a novel first-in-class inhibitor/degrader (FAB-599) reduced hepatic lactate levels and significantly attenuated both steatohepatitis and atherosclerotic lesion development.
Together, these findings identify hepatic lactate overproduction as a liver-derived metabolic driver of vascular inflammation and atherosclerosis. Our results support a model in which impaired hepatic lactate metabolism promotes ASCVD through suppression of PPARα-dependent fatty acid oxidation and induction of inflammatory signaling and establish hepatic LDHA as a therapeutic target for coordinated treatment of MASH and atherosclerotic cardiovascular disease.