MAPK15 Protects Against The Development Of Metabolic Dysfunction-Associated Steatotic Liver Disease

Inzalaco, G.; Gargiulo, S.; Bonente, D.; Gherardini, L.; Franci, L.; Lorito, N.; Del Turco, S.; Tatoni, D.; Tamborrino, T.; Bertelli, E.; D'Aurizio, R.; Andreassi, M. G.; Basta, G.; Gastaldelli, A.; Morandi, A.; Barone, V.; Chiariello, M.

doi:10.1101/2024.12.23.630083

bioRxiv · 10.1101/2024.12.23.630083

MAPK15 Protects Against The Development Of Metabolic Dysfunction-Associated Steatotic Liver Disease

Inzalaco, G.·Gargiulo, S.·Bonente, D.·Gherardini, L.·Franci, L.·Lorito, N.·Del Turco, S.·Tatoni, D.·Tamborrino, T.·Bertelli, E.·D'Aurizio, R.·Andreassi, M. G.·Basta, G.·Gastaldelli, A.·Morandi, A.·Barone, V.·Chiariello, M.

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Abstract

Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. As liver injury progresses to metabolic dysfunction-associated steatohepatitis (MASH), MASLD can predispose individuals to cirrhosis and hepatocellular carcinoma. Here, we characterized the first knockout mouse model for mitogen-activated protein kinase 15 (MAPK15) and revealed its critical role in controlling lipid homeostasis in the liver. Indeed, Mapk15-/- mice exhibited a MASLD-like phenotype, and hepatocellular models allowed us 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 MASH-like phenotype. Ultimately, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, compared to unaffected individuals, ultimately supporting a protective role for MAPK15 against this disease. Overall, our data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintain physiological intracellular levels of lipids in this tissue.

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Inzalaco, G., Gargiulo, S., Bonente, D., Gherardini, L., Franci, L., Lorito, N., Del Turco, S., Tatoni, D., Tamborrino, T., Bertelli, E., D'Aurizio, R., Andreassi, M. G., Basta, G., Gastaldelli, A., Morandi, A., Barone, V., Chiariello, M.. 2024-12-23. MAPK15 Protects Against The Development Of Metabolic Dysfunction-Associated Steatotic Liver Disease. https://doi.org/10.1101/2024.12.23.630083

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