Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates non-alcoholic fatty liver disease by activating farnesoid X receptor
Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates non-alcoholic fatty liver disease by activating farnesoid X receptor
BACKGROUND AND AIMS: Hydrogen sulfide (H
2 S) plays a protective role in NAFLD. However, whether cystathionine γ lyase (CSE), a dominant H
2 S generating enzyme in hepatocytes, has a role in the pathogenesis of NAFLD is currently unclear.
APPROACH AND RESULTS: We showed that CSE protein expression is dramatically downregulated, especially in fibrotic areas, in livers from patients with NAFLD. In high-fat diet (HFD)-induced NAFLD mice or an oleic acid-induced hepatocyte model, the CSE/H
2 S pathway is also downregulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte-specific CSE knockout mouse (CSE
LKO ). Feeding an HFD to CSE
LKO mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de novo synthesis pathway, increased hepatic insulin resistance, and higher hepatic gluconeogenic ability compared to CSE
Loxp control mice. By contrast, H
2 S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H
2 S was blocked by farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro-β-muricholic acid (FXR activation elevated) was reduced in CSE
LKO . CSE/H
2 S promoted a post-translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patients' livers supported the CSE/H
2 S modulation noted in the CSE
LKO mice.
CONCLUSIONS: FXR sulfhydration is a post-translational modification affected by hepatic endogenous CSE/H
2 S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of nonalcoholic steatohepatitis. The interaction between H
2 S and FXR may be amenable to therapeutic drug treatment in NAFLD.
1794-1810
Xu, Wenjing
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Cui, Changting
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Cui, Chunmei
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Chen, Zhenzhen
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Zhang, Haizeng
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Cui, Qinghua
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Xu, Guoheng
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Fan, Jianglin
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Han, Yu
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Tang, Liangjie
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Targher, Giovanni
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Byrne, Christopher
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Zheng, Ming-Hua
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Yang, Liming
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Cai, Jun
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Geng, Bin
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December 2022
Xu, Wenjing
6aa42b37-0509-45e6-98bf-9fc166e89353
Cui, Changting
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Cui, Chunmei
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Chen, Zhenzhen
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Zhang, Haizeng
33e5b5be-24b1-4a5c-aece-aff8325cd783
Cui, Qinghua
6b9c865f-73a4-45b1-a327-36133192ae78
Xu, Guoheng
4f3b2f4f-cc2f-4274-8433-d282bc5eb72f
Fan, Jianglin
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Han, Yu
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Tang, Liangjie
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Targher, Giovanni
3be4e34d-8f64-44cd-919f-db3bb02b288f
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c
Zheng, Ming-Hua
3cbcc56f-f8cb-49c6-923a-26bf02767158
Yang, Liming
a92d1388-93db-40a1-9b16-8df78931c493
Cai, Jun
ed1aa66d-32de-40e5-a3eb-447d83e637ce
Geng, Bin
14b9a528-cb20-475a-b590-e029a07cd6a2
Xu, Wenjing, Cui, Changting, Cui, Chunmei, Chen, Zhenzhen, Zhang, Haizeng, Cui, Qinghua, Xu, Guoheng, Fan, Jianglin, Han, Yu, Tang, Liangjie, Targher, Giovanni, Byrne, Christopher, Zheng, Ming-Hua, Yang, Liming, Cai, Jun and Geng, Bin
(2022)
Hepatocellular cystathionine γ lyase/hydrogen sulfide attenuates non-alcoholic fatty liver disease by activating farnesoid X receptor.
Hepatology, 76 (6), .
(doi:10.1002/hep.32577).
Abstract
BACKGROUND AND AIMS: Hydrogen sulfide (H
2 S) plays a protective role in NAFLD. However, whether cystathionine γ lyase (CSE), a dominant H
2 S generating enzyme in hepatocytes, has a role in the pathogenesis of NAFLD is currently unclear.
APPROACH AND RESULTS: We showed that CSE protein expression is dramatically downregulated, especially in fibrotic areas, in livers from patients with NAFLD. In high-fat diet (HFD)-induced NAFLD mice or an oleic acid-induced hepatocyte model, the CSE/H
2 S pathway is also downregulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte-specific CSE knockout mouse (CSE
LKO ). Feeding an HFD to CSE
LKO mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de novo synthesis pathway, increased hepatic insulin resistance, and higher hepatic gluconeogenic ability compared to CSE
Loxp control mice. By contrast, H
2 S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H
2 S was blocked by farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro-β-muricholic acid (FXR activation elevated) was reduced in CSE
LKO . CSE/H
2 S promoted a post-translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patients' livers supported the CSE/H
2 S modulation noted in the CSE
LKO mice.
CONCLUSIONS: FXR sulfhydration is a post-translational modification affected by hepatic endogenous CSE/H
2 S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of nonalcoholic steatohepatitis. The interaction between H
2 S and FXR may be amenable to therapeutic drug treatment in NAFLD.
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Hepatology - 2022 - Xu - Hepatocellular Cystathionine lyase Hydrogen sulfide Attenuates Non‐Alcoholic Fatty Liver Disease
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Accepted/In Press date: 19 May 2022
e-pub ahead of print date: 30 June 2022
Published date: December 2022
Additional Information:
Funding Information:
We would like to thank Professor Ming-Hua Zheng and Dr. Yu Han for providing liver biopsy samples from patients with and without NAFLD and Liming Yang for providing condition CSE knockout construction with alb-cre mice.
Publisher Copyright:
© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
Identifiers
Local EPrints ID: 457604
URI: http://eprints.soton.ac.uk/id/eprint/457604
ISSN: 0270-9139
PURE UUID: 01c16e3e-014c-4e33-baa1-474bde092e3c
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Date deposited: 14 Jun 2022 16:32
Last modified: 17 Mar 2024 02:49
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Contributors
Author:
Wenjing Xu
Author:
Changting Cui
Author:
Chunmei Cui
Author:
Zhenzhen Chen
Author:
Haizeng Zhang
Author:
Qinghua Cui
Author:
Guoheng Xu
Author:
Jianglin Fan
Author:
Yu Han
Author:
Liangjie Tang
Author:
Giovanni Targher
Author:
Ming-Hua Zheng
Author:
Liming Yang
Author:
Jun Cai
Author:
Bin Geng
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