PMID- 35820507 OWN - NLM STAT- MEDLINE DCOM- 20221019 LR - 20230623 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 77 IP - 5 DP - 2022 Nov TI - Vitamin B(12) and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation. PG - 1246-1255 LID - S0168-8278(22)02932-4 [pii] LID - 10.1016/j.jhep.2022.06.033 [doi] AB - BACKGROUND & AIMS: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B(12) (B(12)) 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. METHODS: We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B(12) (B(12)) and folate (Fol) to reverse NASH features in mice and cell culture. RESULTS: Serum 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 B(12)/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated beta -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH. CONCLUSIONS: HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B(12)/folate also may represent a novel first-line therapy for NASH. LAY SUMMARY: The 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 B(12) and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis. CI - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Tripathi, Madhulika AU - Tripathi M AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. Electronic address: madhulika.tripathi@duke-nus.edu.sg. FAU - Singh, Brijesh Kumar AU - Singh BK AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Zhou, Jin AU - Zhou J AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Tikno, Keziah AU - Tikno K AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Widjaja, Anissa AU - Widjaja A AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Sandireddy, Reddemma AU - Sandireddy R AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Arul, Kabilesh AU - Arul K AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Abdul Ghani, Siti Aishah Binte AU - Abdul Ghani SAB AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Bee, George Goh Boon AU - Bee GGB AD - Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608. FAU - Wong, Kiraely Adam AU - Wong KA AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Pei, Ho Jia AU - Pei HJ AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Shekeran, Shamini Guna AU - Shekeran SG AD - National Heart Center, 5 Hospital Drive, Singapore 169609. FAU - Sinha, Rohit Anthony AU - Sinha RA AD - Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh 226014, Lucknow, India. FAU - Singh, Manvendra K AU - Singh MK AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857. FAU - Cook, Stuart Alexander AU - Cook SA AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857; Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh 226014, Lucknow, India. FAU - Suzuki, Ayako AU - Suzuki A AD - Duke Gastroenterology Clinic, 40 Duke Medicine Circle, Suite 03107, DUMC 3913 Durham, NC 27710, USA. FAU - Lim, Teegan Reina AU - Lim TR AD - Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608. FAU - Cheah, Chang-Chuen AU - Cheah CC AD - Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore 169608. FAU - Wang, Jue AU - Wang J AD - Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, China 100871. FAU - Xiao, Rui-Ping AU - Xiao RP AD - Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, China 100871. FAU - Zhang, Xiuqing AU - Zhang X AD - Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, China 100871. FAU - Chow, Pierce Kah Hoe AU - Chow PKH AD - Department of Surgery, Singapore General Hospital and Dept. of Surgical Oncology, National Cancer Centre, Singapore 169608. FAU - Yen, Paul Michael AU - Yen PM AD - Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857; Duke Molecular Physiology Institute, 300 N Duke St, Durham, NC 27701, USA; Endocrinology, Metabolism, and Nutrition, 30 Duke Medicine Circle Clinic 1A, Durham, NC 27710, USA. Electronic address: paul.yen@duke-nus.edu.sg. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220709 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Fatty Acids) RN - 0 (Qa-SNARE Proteins) RN - 0 (Vitamins) RN - 0LVT1QZ0BA (Homocysteine) RN - 935E97BOY8 (Folic Acid) RN - AE28F7PNPL (Methionine) RN - P6YC3EG204 (Vitamin B 12) SB - IM CIN - J Hepatol. 2023 Jan;78(1):e34-e35. PMID: 36031159 CIN - J Hepatol. 2023 Jan;78(1):e35-e36. PMID: 36257371 CIN - J Hepatol. 2023 May;78(5):e172-e174. PMID: 36460167 CIN - J Hepatol. 2023 May;78(5):e174-e175. PMID: 36736736 MH - Animals MH - Fatty Acids MH - Fibrosis MH - Folic Acid MH - Homocysteine MH - Humans MH - *Hyperhomocysteinemia MH - Inflammation MH - Methionine MH - Mice MH - *Non-alcoholic Fatty Liver Disease/etiology/prevention & control MH - Qa-SNARE Proteins MH - Vitamin B 12 MH - Vitamins OTO - NOTNLM OT - Autophagy OT - B(12) OT - Fibrosis OT - Folate OT - Homocysteine OT - Non-alcoholic steatohepatitis (NASH) OT - Protein homocysteinylation OT - Syntaxin-17 OT - Vitamin therapy COIS- Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. EDAT- 2022/07/13 06:00 MHDA- 2022/10/20 06:00 CRDT- 2022/07/12 19:24 PHST- 2021/12/04 00:00 [received] PHST- 2022/06/22 00:00 [revised] PHST- 2022/06/28 00:00 [accepted] PHST- 2022/07/13 06:00 [pubmed] PHST- 2022/10/20 06:00 [medline] PHST- 2022/07/12 19:24 [entrez] AID - S0168-8278(22)02932-4 [pii] AID - 10.1016/j.jhep.2022.06.033 [doi] PST - ppublish SO - J Hepatol. 2022 Nov;77(5):1246-1255. doi: 10.1016/j.jhep.2022.06.033. Epub 2022 Jul 9.