Nonalcoholic Steatohepatitis is Associated with a State of Betaine-Insufficiency

PUNEET PURI; FARIDODDIN MIRSHASHI; GUSTAVO CASTAÑO; ARUN SANYAL; SILVIA SOOKOIAN; ROMINA SCIAN; CARLOS J. PIROLA

San Diego, CA

Congreso; Digestive Disease Week; 2016

American Gastroenterology Association

ABSTRACT BODY:Abstract Body: Background: Nonalcoholic fatty liver disease (NAFLD) develops from a complex process, including changes in the liver methylome. S-adenosylmethionine (SAM) is the major methyl donor in the cell, and the liver is the major site for SAM- synthesis and degradation; SAM is involved in the regulation of the methylome-dynamics during DNA methylation. Methyl groups are usually delivered by dietary methyl donors, which include methionine, cholineand betaine. Betaine (N,N,N-trimethylglicine) is a critical player in the pathway of methylogenesis. Results from a recent genome-wide association study coupled with high-throughput metabolic profiling showed variants in the geneDMGDH, which encodes for the mitochondrial dimethylglycine dehydrogenase, significantly associated with circulating levels of betaine and betaine-related metabolites.Methods: We performed a two-stage case-control study, including patients with NAFLD-proven through liver biopsy recruited from two-different hospital setting from North and South America, to explore circulating levels of betaine andits association with NAFLD-histological spectrum. We also explored the association between a missense p.Ser646Pro variant in DMGDH and NAFLD severity (n =390 subjects, including 138 controls and 252 patients).Results: In the discovery phase (n = 48), betaine levels were associated with the disease severity (p = 0.0030), including liver inflammation (Spearman R: -0.51, p = 0.001), ballooning degeneration (R: -0.50, p = 0.01) and fibrosisstage (R: -0.54, p = 0.0008). Betaine levels were significantly decreased in nonalcoholic steatohepatitis (NASH) in comparison with nonalcoholic fatty liver (NAFL), area under the curve 0.824 (95% CI: 0.623?0.941). Further replication(n = 51) showed that betaine levels were associated with advanced NAFLD (p = 0.0085); patients with NASH compared with those with NAFL had a 1.26-fold decrease in betaine levels. The rs1805074 was significantly associated with the disease severity (p = 0.011). Furthermore, the rs1805074 was significantly associated with circulating levels of dimethylglicine in both the additive (Spearman R: -0.353, p = 0.0148) and dominant (Spearman R: -.034, p = 0.0189) models of inheritance.Conclusion: NAFLD severity is associated with a state of betaine-insufficiency.