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

Journal article
Authors Emmelie Cansby
Nagaraj M. Kulkarni
Elin Magnusson
Yeshwant Kurhe
Manoj Amrutkar
Annika Nerstedt
Marcus Ståhlman
Carina Sihlbom
Hanns-Ulrich Marschall
Jan Borén
Matthias Blüher
Margit Mahlapuu
Published in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume 33
Issue 9
Pages 9974-9989
ISSN 1530-6860
Publication year 2019
Published at Wallenberg Laboratory
Core Facilities, Proteomics
Department of Chemistry and Molecular Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 9974-9989
Language en
Subject categories Gastroenterology and Hepatology


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.

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