Sphingosine kinase 1 mediates sexual dimorphism in fibrosis in a mouse model of NASH.
Fibrosis
NAFLD
NASH
Sphingolipid
Sphingosine kinase
Sphingosine-1-phosphate
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
05
01
2022
revised:
04
05
2022
accepted:
25
05
2022
pubmed:
8
6
2022
medline:
8
7
2022
entrez:
7
6
2022
Statut:
ppublish
Résumé
Men with non-alcoholic fatty liver disease (NAFLD) are more likely to progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of this dimorphism is unclear. We have previously shown that mice with global deletion of SphK1, the enzyme that produces the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P), were protected from development of NASH. The aim of this study was to elucidate the role of hepatocyte-specific SphK1 in development of NASH and to compare its contribution to hepatosteatosis in male and female mice. We assessed mouse livers in early-stage fibrosis induced by high fat feeding, using single harmonic generation microscopy, LC-MS/MS analysis of hydroxyproline levels, and expression of fibrosis markers. We identified an antifibrotic intercellular signaling mechanism by culturing primary mouse hepatocytes alongside, and in co-culture with, LX2 hepatic stellate cells. We generated hepatocyte-specific SphK1 knockout mice (SphK1-hKO). Unlike the global knockout, SphK1-hKO male mice were not protected from diet-induced steatosis, inflammation, or fibrogenesis. In contrast, female SphK1-hKO mice were protected from inflammation. Surprisingly, however, in these female mice, there was a ∼10-fold increase in the fibrosis markers Col1α1 and 2-3 fold induction of alpha smooth muscle actin and the pro-fibrotic chemokine CCL5. Because increased fibrosis in female SphK1-hKO mice occurred despite an attenuated inflammatory response, we investigated the crosstalk between hepatocytes and hepatic stellate cells, central players in fibrosis. We found that estrogen stimulated release of S1P from female hepatocytes preventing TGFβ-induced expression of Col1α1 in HSCs via S1PR3. The results revealed a novel pathway of estrogen-mediated cross-talk between hepatocytes and HSCs that may contribute to sex differences in NAFLD through an anti-fibrogenic function of the S1P/S1PR3 axis. This pathway is susceptible to pharmacologic manipulation, which may lead to novel therapeutic strategies.
Identifiants
pubmed: 35671973
pii: S2212-8778(22)00092-8
doi: 10.1016/j.molmet.2022.101523
pmc: PMC9194589
pii:
doi:
Substances chimiques
Estrogens
0
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
Sphk1 protein, mouse
EC 2.7.1.-
sphingosine kinase
EC 2.7.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
101523Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL151243
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103339
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM043880
Pays : United States
Organisme : BLRD VA
ID : I01 BX000200
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016059
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117233
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.
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