MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention

Bin Qiu, Ahmed Lawan, Chrysovalantou E. Xirouchaki, Jae-Sung Yi, Marie Robert, Lei Zhang, Wendy Brown, Carlos Fernández-Hernando, Xiaoyong Yang, Tony Tiganis and Anton M. Bennett ()
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Bin Qiu: Yale University School of Medicine, Department of Pharmacology
Ahmed Lawan: University of Alabama, Department of Biological Sciences
Chrysovalantou E. Xirouchaki: Monash University
Jae-Sung Yi: Yale University School of Medicine, Department of Pharmacology
Marie Robert: Yale University School of Medicine, Department of Pathology
Lei Zhang: Yale University School of Medicine, Department of Pharmacology
Wendy Brown: Alfred Hospital, Melbourne
Carlos Fernández-Hernando: Yale University School of Medicine, Yale Center of Molecular and Systems Metabolism
Xiaoyong Yang: Yale University School of Medicine, Yale Center of Molecular and Systems Metabolism
Tony Tiganis: Monash University
Anton M. Bennett: Yale University School of Medicine, Department of Pharmacology

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.

Date: 2023
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DOI: 10.1038/s41467-023-41145-5

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