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

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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.

Authors

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