TY - JOUR
T1 - MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention
AU - Qiu, Bin
AU - Lawan, Ahmed
AU - Xirouchaki, Chrysovalantou E.
AU - Yi, Jae-Sung
AU - Robert, Marie
AU - Zhang, Lei
AU - Brown, Wendy
AU - Fernández-Hernando, Carlos
AU - Yang, Xiaoyong
AU - Tiganis, Tony
AU - Bennett, Anton M.
N1 - Funding Information:
This work was supported by NIH grant R01 DK34989 to A.M.B., a National Health and Medical Research Council (NHMRC) of Australia grant to (2008572). C.F.-H. was supported by R35HL135820. A.L. was supported by a grant from the University of Alabama (#251359). We thank the Silvio O. Conte Digestive Diseases Research Core Center (5P30 DK034989) for the isolation of primary hepatocytes, histological and fluorescence microscopy instrumentation. We thank Yale Flow Cytometry (NCI Cancer Center Support Grant #NIH P30 CA016359) for their assistance with flow cytometry service. We thank Yanhong Deng and Maria Ciarleglio for their statistical analyses support. Schematic Fig. , S7a and S9 were created using BioRender.
Funding Information:
This work was supported by NIH grant R01 DK34989 to A.M.B., a National Health and Medical Research Council (NHMRC) of Australia grant to (2008572). C.F.-H. was supported by R35HL135820. A.L. was supported by a grant from the University of Alabama (#251359). We thank the Silvio O. Conte Digestive Diseases Research Core Center (5P30 DK034989) for the isolation of primary hepatocytes, histological and fluorescence microscopy instrumentation. We thank Yale Flow Cytometry (NCI Cancer Center Support Grant #NIH P30 CA016359) for their assistance with flow cytometry service. We thank Yanhong Deng and Maria Ciarleglio for their statistical analyses support. Schematic Fig. 1b , S7a and S9 were created using BioRender.
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85169761719&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-41145-5
DO - 10.1038/s41467-023-41145-5
M3 - Article
C2 - 37669951
AN - SCOPUS:85169761719
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5405
ER -