Targeting lipidated amino acid deficiency mitigates fibrosis via a PPARα/CCL2 axis in metabolic dysfunction-associated steatohepatitis models

Metabolic dysfunction-associated steatohepatitis (MASH) is rising globally despite recent therapeutic advances, highlighting the need to identify new targetable pathways. While dysregulated lipid and amino acid metabolism are established features of MASH, the interplay between these two metabolic pathways remains unexplored. Here, metabolomics of livers from humans and mice with MASH uncovered depletion of lipidated amino acids, where these two distinctive pathways converge. Notably, hepatic levels of N-oleoyl-leucine (C18:1-Leu) were inversely correlated with the severity of MASH-fibrosis. The C18:1-Leu-regulating enzyme, peptidase M20 domain containing 1 (PM20D1), was suppressed in MASH due to attenuated de novo transcription, and stable-isotope tracing confirmed impaired hepatic biosynthesis of C18:1-Leu in MASH. Hepatocyte-specific PM20D1 ablation lowered hepatic C18:1-Leu and exacerbated MASH, whereas hepatocyte-specific PM20D1 overexpression restored C18:1-Leu and ameliorated both MASH progression and established disease. Exogenous administration of C18:1-Leu similarly ameliorated MASH-fibrosis. In silico modeling, transcriptomics, metabolic flux analyses and hepatocyte-specific in vivo manipulations revealed that C18:1-Leu binds and activates peroxisome proliferator-activated receptor alpha to suppress C-C motif chemokine ligand 2, concurrently enhancing fatty acid β-oxidation and attenuating monocyte recruitment to reduce MASH-fibrosis. These findings highlight C18:1-Leu deficiency as a driver and a therapeutic target in MASH-fibrosis, warranting further clinical evaluation.

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Journal
Journal of Clinical Investigation
Published
2026-09-24
DOI
https://doi.org/10.1172/jci204511
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
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article

Targeting lipidated amino acid deficiency mitigates fibrosis via a PPARα/CCL2 axis in metabolic dysfunction-associated steatohepatitis models

Gurranna Male, Sumit Kumar Anand, Paul Thevenot, Y. Eugene Chen et al.
Journal of Clinical Investigation
Liver Disease Diagnosis and Treatment
article

Targeting lipidated amino acid deficiency mitigates fibrosis via a PPARα/CCL2 axis in metabolic dysfunction-associated steatohepatitis models

Gurranna Male, Sumit Kumar Anand, Paul Thevenot, Y. Eugene Chen, Sumati Rohilla, Alia Ghrayeb, Oren Rom, Rajan Pandit, Wanqing Liu, Fabio Arias, Fei Chang, Brenna H. Pearson, Andrew D. Yurochko, Duxin Sun, Joseph Eniafe, Jibin Ding, Babak Razani, Eyal Gottlieb, Jemiah Maxie, Yu Liu, Jifeng Zhang, Nilesh Pandey, Bishuang Cai, Koral S. E. Richard, Sandeep Das, Reethika Gade, M. Peyton McKinney, Kelley Nunez, Francisco J. Schopfer, Ying Zhao, Xin Huang, Cyrine Ben Dhaou, Nirav Dhanesha, Lu Wang, Lin Tan, Arif Yurdagul Jr., Zhipeng Liu, Bo Wen, Alexandra C. Finney, Suman Mohajan, Minerva T. Garcia-Barrio, Harpreet Kaur, Dhananjay Kumar, A. Wayne Orr, Xiaolu Zhang, Jennifer Lee, Ari J. Cohen
article en

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is rising globally despite recent therapeutic advances, highlighting the need to identify new targetable pathways. While dysregulated lipid and amino acid metabolism are established features of MASH, the interplay between these two metabolic pathways remains unexplored. Here, metabolomics of livers from humans and mice with MASH uncovered depletion of lipidated amino acids, where these two distinctive pathways converge. Notably, hepatic levels of N-oleoyl-leucine (C18:1-Leu) were inversely correlated with the severity of MASH-fibrosis. The C18:1-Leu-regulating enzyme, peptidase M20 domain containing 1 (PM20D1), was suppressed in MASH due to attenuated de novo transcription, and stable-isotope tracing confirmed impaired hepatic biosynthesis of C18:1-Leu in MASH. Hepatocyte-specific PM20D1 ablation lowered hepatic C18:1-Leu and exacerbated MASH, whereas hepatocyte-specific PM20D1 overexpression restored C18:1-Leu and ameliorated both MASH progression and established disease. Exogenous administration of C18:1-Leu similarly ameliorated MASH-fibrosis. In silico modeling, transcriptomics, metabolic flux analyses and hepatocyte-specific in vivo manipulations revealed that C18:1-Leu binds and activates peroxisome proliferator-activated receptor alpha to suppress C-C motif chemokine ligand 2, concurrently enhancing fatty acid β-oxidation and attenuating monocyte recruitment to reduce MASH-fibrosis. These findings highlight C18:1-Leu deficiency as a driver and a therapeutic target in MASH-fibrosis, warranting further clinical evaluation.

Journal of Clinical Investigation
The University of Texas MD Anderson Cancer Center (US), University of California, Los Angeles (US), University of Pittsburgh (US), Wayne State University (US), Purdue University West Lafayette (US), Louisiana State University in Shreveport (US), University of Michigan (US), Ochsner Medical Center (US), University of Pittsburgh Medical Center (US), Louisiana State University Health Sciences Center Shreveport (US)
Openalex Percentile: Top 11%
Liver Disease Diagnosis and Treatment
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