Annals of hepatologySep 1, 2025

Changes in one-carbon metabolism in fatty liver disease linked to metabolic problems may be influenced by semaglutide

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 2, 2026

Abstract

Alterations in one-carbon metabolism were observed in 100 patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Changes in folate, vitamin B6, betaine, serine, and glycine concentrations suggest disruptions in metabolic pathways related to one-carbon metabolism.
Increased levels of metabolites associated with the conversion of homocysteine and elevated glutamate were noted in MASLD patients.
Corresponding changes in the activity of key enzymes involved in these metabolic pathways were identified.
Similar metabolic alterations were found in a mouse model of diet-induced obesity and steatohepatitis treated with semaglutide.
Semaglutide treatment resulted in reductions in body weight, liver inflammation, and fibrosis in mice, reversing observed metabolic and gene expression changes.

Simplified

INTRODUCTION AND OBJECTIVES: Disruptions in one-carbon metabolism (OCM) have been linked to cardiometabolic diseases. We evaluated alterations in OCM metabolites and enzymes and the impact of semaglutide in MASLD.

MATERIALS AND METHODS: Using targeted metabolomics and bulk-transcriptomics, we analyzed components of OCM in plasma samples and liver biopsies from MASLD patients (n = 100 with F0-F4 fibrosis, 51 % type 2 diabetes) and healthy controls (n = 50). Untargeted metabolomics and transcriptomics were used to analyze plasma and liver specimens from mice with diet-induced obesity and steatohepatitis (DIO-MASH) treated with vehicle or semaglutide compared with chow for 12 weeks.

RESULTS: In patients with MASLD vs healthy controls, changes in the concentrations of folate and pyridoxal 5'-phosphate (vitamin B6), betaine, serine, and glycine suggested alteration to the activity of the transsulfuration pathway as well as the methionine and folate cycles. Increased concentrations of metabolites related to enhanced homocysteine conversion and elevated glutamate were also observed. These findings were supported by corresponding alterations in the activity of key enzymes. Similar patterns were identified in comparisons of patients with significant vs no/mild fibrosis and in DIO-MASH mice vs chow. Treatment with semaglutide led to reductions in body weight, hepatic inflammation, and fibrosis and largely reversed the metabolic and gene expression changes observed in DIO-MASH mice.

CONCLUSIONS: MASLD may be linked to alterations in key metabolites and enzymes involved in OCM. The changes in humans were replicated in a MASLD mouse model, and reversal was found after treatment with semaglutide.

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Declaration of interests Lise Lotte Gluud has received consulting fees and payment or honoraria for lectures, presentations or manuscript writing from: Boehringer Ingelheim, Novo Nordisk, Pfizer, Gilead, AstraZeneca, Norgine, Sobi, Becton Dickinson, and Alexion. Jenny Norlin, Sanne Veidal, Dorte Holst, Anne Bugge, Lea Mørch Harder, Gianluca Mazzoni, Birgitte Martine Viuff, Henning Hvid, Kristian Moss Bendtsen and Elisabeth Douglas Galsgaard are employed at Novo Nordisk A/S.

PubMed

Changes in one-carbon metabolism in fatty liver disease linked to metabolic problems may be influenced by semaglutide

Abstract

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Abstract

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