The University of Southampton
University of Southampton Institutional Repository

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
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.

0270-9139
1794-1810
Xu, Wenjing
6aa42b37-0509-45e6-98bf-9fc166e89353
Cui, Changting
cfc36fd2-291f-4d07-b976-f5c671e5703d
Cui, Chunmei
7b42281a-fc2f-44c4-8762-bc38e8c15636
Chen, Zhenzhen
ece574aa-0e79-447b-8199-9c1e0e3513cc
Zhang, Haizeng
33e5b5be-24b1-4a5c-aece-aff8325cd783
Cui, Qinghua
6b9c865f-73a4-45b1-a327-36133192ae78
Xu, Guoheng
4f3b2f4f-cc2f-4274-8433-d282bc5eb72f
Fan, Jianglin
fa7e225d-282a-42f1-aa54-a0e188bae9ef
Han, Yu
a60a3316-9751-4c03-bdf8-2a1f419d277c
Tang, Liangjie
2e11b15e-ec04-4949-8072-11ef2f97c796
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
6aa42b37-0509-45e6-98bf-9fc166e89353
Cui, Changting
cfc36fd2-291f-4d07-b976-f5c671e5703d
Cui, Chunmei
7b42281a-fc2f-44c4-8762-bc38e8c15636
Chen, Zhenzhen
ece574aa-0e79-447b-8199-9c1e0e3513cc
Zhang, Haizeng
33e5b5be-24b1-4a5c-aece-aff8325cd783
Cui, Qinghua
6b9c865f-73a4-45b1-a327-36133192ae78
Xu, Guoheng
4f3b2f4f-cc2f-4274-8433-d282bc5eb72f
Fan, Jianglin
fa7e225d-282a-42f1-aa54-a0e188bae9ef
Han, Yu
a60a3316-9751-4c03-bdf8-2a1f419d277c
Tang, Liangjie
2e11b15e-ec04-4949-8072-11ef2f97c796
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), 1794-1810. (doi:10.1002/hep.32577).

Record type: Article

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.

Text
CSE-H2S FXR maintext-Hepa R1-clean - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (845kB)
Text
supplementary data R1 - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (3MB)
Text
CSE-FXR R1 figures - Accepted Manuscript
Available under License Creative Commons Attribution.
Download (7MB)
Image
Graphic Abstract - Accepted Manuscript
Restricted to Repository staff only
Request a copy
Text
Hepatology - 2022 - Xu - Hepatocellular Cystathionine lyase Hydrogen sulfide Attenuates Non‐Alcoholic Fatty Liver Disease - Version of Record
Available under License Creative Commons Attribution.
Download (8MB)

Show all 5 downloads.

More information

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
ORCID for Christopher Byrne: ORCID iD orcid.org/0000-0001-6322-7753

Catalogue record

Date deposited: 14 Jun 2022 16:32
Last modified: 17 Mar 2024 02:49

Export record

Altmetrics

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×