Imperial College London
Alternate

ProfessorStuartCook

Faculty of Medicine, Institute of Clinical Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 1346stuart.cook

 
 
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Location

 

RF 16Sydney StreetRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{Tripathi:2022:10.1016/j.jhep.2022.06.033,
author = {Tripathi, M and Singh, BK and Zhou, J and Tikno, K and Widjaja, A and Sandireddy, R and Arul, K and Ghani, SABA and Bee, GGB and Wong, KA and Pei, HJ and Shekeran, SG and Sinha, RA and Singh, MK and Cook, SA and Suzuki, A and Lim, TR and Cheah, C-C and Wang, J and Xiao, R-P and Zhang, X and Chow, PKH and Yen, PM},
doi = {10.1016/j.jhep.2022.06.033},
journal = {Journal of Hepatology},
pages = {1246--1255},
title = {Vitamin B and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation},
url = {http://dx.doi.org/10.1016/j.jhep.2022.06.033},
volume = {77},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Background & AimsSeveral recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH.MethodsWe examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B12 (B12) and folate (Fol) to reverse NASH features in mice and cell culture.ResultsSerum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B12/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated β -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH.ConclusionsHHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B12/folate also may represent a novel first-line therapy for NASH.Lay summaryThe incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B12 and folate could have therapeutic potential for the preventio
AU  - Tripathi,M
AU  - Singh,BK
AU  - Zhou,J
AU  - Tikno,K
AU  - Widjaja,A
AU  - Sandireddy,R
AU  - Arul,K
AU  - Ghani,SABA
AU  - Bee,GGB
AU  - Wong,KA
AU  - Pei,HJ
AU  - Shekeran,SG
AU  - Sinha,RA
AU  - Singh,MK
AU  - Cook,SA
AU  - Suzuki,A
AU  - Lim,TR
AU  - Cheah,C-C
AU  - Wang,J
AU  - Xiao,R-P
AU  - Zhang,X
AU  - Chow,PKH
AU  - Yen,PM
DO  - 10.1016/j.jhep.2022.06.033
EP  - 1255
PY  - 2022///
SN  - 0168-8278
SP  - 1246
TI  - Vitamin B and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation
T2  - Journal of Hepatology
UR  - http://dx.doi.org/10.1016/j.jhep.2022.06.033
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000898606500004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://www.journal-of-hepatology.eu/article/S0168-8278(22)02932-4/fulltext
UR  - http://hdl.handle.net/10044/1/107614
VL  - 77
ER  -
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