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- Title
MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention.
- Authors
Qiu, Bin; Lawan, Ahmed; Xirouchaki, Chrysovalantou E.; Yi, Jae-Sung; Robert, Marie; Zhang, Lei; Brown, Wendy; Fernández-Hernando, Carlos; Yang, Xiaoyong; Tiganis, Tony; Bennett, Anton M.
- 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. Nonalcoholic steatohepatitis (NASH) is a devastating type of liver disease that is caused by hepatocellular death which triggers liver inflammation and fibrosis. Here, the authors show that MAP kinase phosphatase-1 promotes hepatocellular death thus, driving the development of NASH.
- Subjects
NON-alcoholic fatty liver disease; AMP-activated protein kinases; HEPATIC fibrosis; DUAL specificity phosphatase 1; HEPATITIS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41145-5