MAPK15 controls intracellular lipid uptake and protects mammalian liver from steatotic disease

Background: Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. Methods: To explore the role of mitogen-activated protein kinase 15 (MAPK15) in mammalian lipid homeostasis, we created and characterized the first knockout mouse model for this gene. Hepatocellular in vitro models were also used to further investigate molecular mechanisms underlying MAPK15-dependent regulation of lipid metabolism in the liver. Results: We observed that Mapk15-/- mice exhibited liver steatosis in the context of a MASLD-like phenotype while hepatocellular in vitro models allowed to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a steatohepatitis-like phenotype. Importantly, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, suggesting a compensatory role in disease progression. In this context, overexpression of this kinase efficiently opposed lipid accumulation in a MASLD hepatocellular model, opening to the possibility of counteracting hepatic steatosis in humans by pharmacologically or genetically activating this MAP kinase. Conclusions: Presented data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintaining physiological intracellular levels of lipids in this tissue.