Article Synopsis
- Elevated serum homocysteine (Hcy) levels are associated with increased severity of non-alcoholic steatohepatitis (NASH), while vitamin B and folate levels are inversely related.
- Research indicates that hyperhomocysteinemia (HHcy) worsens NASH by increasing liver inflammation and fibrosis through the alteration of the protein Syntaxin 17, which disrupts autophagy.
- Supplementation with vitamin B and folate can reduce HHcy, improve liver function, and potentially serve as a new treatment option for managing NASH.
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Article Abstract
Background & Aims: Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B (B) 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 (B) 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/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.
Conclusions: HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B/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 and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis.
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| http://dx.doi.org/10.1016/j.jhep.2022.06.033 | DOI Listing |
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