Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

ABSTRACT Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20‐like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating β‐oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl‐coenzyme A carboxylase protein abundance were reduced in MST3‐deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH ( i.e ., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs . lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.—Cansby, E., Kulkarni, N. M., Magnusson, E., Kurhe, Y., Amrutkar, M., Nerstedt, A., Ståhlman, M., Sihlbom, C., Marschall, H.‐U., Borén, J., Blüher, M., Mahlapuu, M. Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans. FASEB J. 33, 9974–9989 (2019). www.fasebj.org