Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

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.

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Publication Details

Journal
Nature Metabolism
Published
2024-09-27
DOI
https://doi.org/10.1038/s42255-024-01134-4
Citations
20
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
7.73

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article

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

Tarek Magdy, Sumit Kumar Anand, Paul Thevenot, Eduardo Salido et al.
20 citations
Nature Metabolism
Liver Disease Diagnosis and Treatment
7.73
article

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

Tarek Magdy, Sumit Kumar Anand, Paul Thevenot, Eduardo Salido, A. Wayne Orr, Mónica Díaz‐Gavilán, Yanxing Chen, Sumati Rohilla, Christopher G. Kevil, Chowdhury S. Abdullah, Iqbal Mahmud, M. Peyton McKinney, Ida Surakka, Ari Cohen, Christopher B. Pattillo, Alia Ghrayeb, Arif Yurdagul, Oren Rom, Minerva T. Garcia-Barrio, Wanqing Liu, Fabio Arias, José A. Gómez-Vidal, Dhananjay Kumar, Philip L. Lorenzi, Elizabeth D Cockerham, Md. Shenuarin Bhuiyan, Kelley Núñez, Brenna H. Pearson, Andrew D. Yurochko, Sandeep Das, Gretchen Galliano, Joseph Eniafe, Nirav Dhanesha, Babak Razani, Bo Wei, Yuhao Liu, Alexandra C Finney, Erin H. Seeley, Eyal Gottlieb, Zhipeng Liu, Jifeng Zhang, Lin Tan, Ying Zhao, Nilesh Pandey, Koral S. E. Richard
article en
20 citations

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.

Nature MetabolismVol. 6(10)
The University of Texas MD Anderson Cancer Center (US), University of Pittsburgh (US), Wayne State University (US), Purdue University West Lafayette (US), University of Michigan (US), Ochsner Medical Center (US), Hospital Universitario de Canarias (ES), Centro de Investigación Biomédica en Red (ES), University of Pittsburgh Medical Center (US), Rede de Química e Tecnologia (PT), Louisiana State University Health Sciences Center Shreveport (US), The University of Texas at Austin (US)
American Heart Association, Cancer Prevention and Research Institute of Texas, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 2%
Liver Disease Diagnosis and Treatment
7.73
DOIOpen Access PDFOpenAlex
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