Journal Article

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

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

2024

Overview

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. Genetic and pharmacological inhibition of the overproduction of oxalate in the liver alleviates metabolic dysfunction-associated steatohepatitis in male mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/443/319 / 692/4020/4021/1607 / 692/4020/4021/1607/2751 / 692/4020/4021/288 / Animals / Biomedical and Life Sciences / Chemokines / Chemotaxis / Dehydrogenases / Enzymes / Fatty acids / Fatty liver / Fatty Liver - etiology / Fatty Liver - metabolism / Fibrosis / Hepatocytes / Hepatocytes - metabolism / Humans / L-Lactate dehydrogenase / Life Sciences / Lipids / Liver - metabolism / Liver diseases / Male / Meta-analysis / Metabolism / Mice / Mice, Inbred C57BL / Monocytes / Oxalates - metabolism / Oxalic acid / Pathogenesis / Peroxisome proliferator-activated receptors / PPAR alpha - metabolism / Proteins / Steatosis / Transaminases - metabolism