Vitamin B₁₂ and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation

Area of Science:

• Hepatology and Metabolic Diseases
• Molecular Biology and Biochemistry
• Nutritional Science

Background:

• Non-alcoholic steatohepatitis (NASH) is a growing health concern with limited therapeutic options.
• Clinical studies suggest correlations between serum homocysteine (Hcy) and NASH severity, but HHcy's pathogenic role remains unclear.

Purpose of the Study:

• To investigate the pathogenic role of hyperhomocysteinemia (HHcy) in non-alcoholic steatohepatitis (NASH) progression.
• To explore the potential of vitamin B12 (B12) and folate (Fol) as therapeutic agents for NASH.

Main Methods:

• Examined HHcy effects on NASH in mouse models, primates, and human patients.
• Utilized vitamin B12 and folate supplementation to reverse NASH features in vitro and in vivo.
• Analyzed protein homocysteinylation, ubiquitination, autophagy markers, and hepatic histology.

Main Results:

• Elevated hepatic Hcy levels induced and worsened NASH, correlating with inflammation and fibrosis.
• HHcy led to homocysteinylation and ubiquitination of hepatic proteins, including Syntaxin 17 (Stx17), impairing autophagy.
• Vitamin B12/folate supplementation reduced HHcy, restored Stx17 and autophagy, improved fatty acid metabolism, and ameliorated liver histology in established NASH.

Conclusions:

• HHcy plays a critical role in NASH pathogenesis through Stx17 homocysteinylation and subsequent autophagy dysfunction.
• Vitamin B12 and folate supplementation demonstrate significant therapeutic potential for NASH treatment and prevention.