Faculty, Staff and Student Publications
Publication Date
10-1-2024
Journal
Nature Metabolism
Abstract
The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.
Keywords
Animals, Mice, Oxalates, Humans, Liver, Fatty Liver, Male, Transaminases, PPAR alpha, Hepatocytes, Mice, Inbred C57BL, Non-alcoholic steatohepatitis, Liver, Liver diseases, Metabolism
DOI
10.1038/s42255-024-01134-4
PMID
39333384
PMCID
PMC11495999
PubMedCentral® Posted Date
9-27-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons