iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7-Dependent Pathway.
Activation, Metabolic
Animals
Carrier Proteins
/ biosynthesis
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Disease Progression
Fatty Liver
/ etiology
Inflammation
/ metabolism
Insulin Resistance
/ physiology
Intracellular Signaling Peptides and Proteins
/ biosynthesis
Liver
/ metabolism
MAP Kinase Kinase Kinases
/ metabolism
Macrophages
/ metabolism
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease
/ etiology
Signal Transduction
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
26
05
2020
received:
24
12
2019
accepted:
27
05
2020
pubmed:
28
6
2020
medline:
13
10
2021
entrez:
28
6
2020
Statut:
ppublish
Résumé
Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD-associated metabolic disorder. Inactive rhomboid-like protein 2 (iRhom2) is regarded as a key regulator in inflammation. However, the precise mechanisms by which iRhom2-regulated inflammation promotes NAFLD progression remain to be elucidated. Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2-deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high-fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen-activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c-Jun N-terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3β-associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2-regulated liver steatosis. iRhom2 may represent a therapeutic target for the treatment of HFD-induced hepatic steatosis and insulin resistance.
Sections du résumé
BACKGROUND AND AIMS
Nonalcoholic fatty liver disease (NAFLD) has been widely recognized as a precursor to metabolic complications. Elevated inflammation levels are predictive of NAFLD-associated metabolic disorder. Inactive rhomboid-like protein 2 (iRhom2) is regarded as a key regulator in inflammation. However, the precise mechanisms by which iRhom2-regulated inflammation promotes NAFLD progression remain to be elucidated.
APPROACH AND RESULTS
Here, we report that insulin resistance, hepatic steatosis, and specific macrophage inflammatory activation are significantly alleviated in iRhom2-deficient (knockout [KO]) mice, but aggravated in iRhom2 overexpressing mice. We further show that, mechanistically, in response to a high-fat diet (HFD), iRhom2 KO mice and mice with iRhom2 deficiency in myeloid cells only showed less severe hepatic steatosis and insulin resistance than controls. Inversely, transplantation of bone marrow cells from healthy mice to iRhom2 KO mice expedited the severity of insulin resistance and hepatic dyslipidemia. Of note, in response to HFD, hepatic iRhom2 binds to mitogen-activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and nuclear factor kappa B cascade activation, thereby promoting the activation of c-Jun N-terminal kinase/insulin receptor substrate 1 signaling, but disturbing AKT/glycogen synthase kinase 3β-associated insulin signaling. The iRhom2/MAP3K7 axis is essential for iRhom2-regulated liver steatosis.
CONCLUSIONS
iRhom2 may represent a therapeutic target for the treatment of HFD-induced hepatic steatosis and insulin resistance.
Substances chimiques
Carrier Proteins
0
Intracellular Signaling Peptides and Proteins
0
RHBDF2 protein, human
0
iRhom2 protein, mouse
0
MAP Kinase Kinase Kinases
EC 2.7.11.25
MAP kinase kinase kinase 7
EC 2.7.11.25
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1346-1364Informations de copyright
© 2020 American Association for the Study of Liver Diseases.
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