Abstract 152: Metabolism And Therapeutic Potential Of Lipidated Amino Acids In Nonalcoholic Steatohepatitis And Atherosclerosis

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the global population. Despite significant advances in our understanding of the underlying causes and considerable efforts in drug development, no pharmacological therapy currently exists for this disease. Accelerated atherosclerosis, independent of traditional risk factors, is the major cause of death in patients with NAFLD, particularly in those with the more severe nonalcoholic steatohepatitis (NASH). Thus, there is an urgent need to identify new pathways for simultaneous targeting of NASH and atherosclerosis. Imbalanced lipid metabolism and dysregulated amino acid metabolism are emerging as common features of both NASH and atherosclerosis, although their crosstalk has not received much attention. Lipidated amino acids or N-acyl amino acids (NAAs) have emerged as endogenous signaling molecules in which an amide bond links an amino acid to the acyl moiety of a long-chain fatty acid. Utilizing unbiased transcriptomics, we uncovered suppression of known NAA biosynthetic genes and upregulation of degradative genes in livers from humans and mice with NASH, concomitant with marked reduction of NAAs, as determined by metabolomics. Similar findings were noted in lipid loaded primary hepatocytes and hepatic cell lines. Hepatic NAAs, particularly N-oleoyl leucine (C18:1-Leu), inversely correlated with NASH and inflammatory indices. Importantly, C18:1-Leu administered to mice with established NASH reduced transaminases, steatohepatitis, hepatic macrophages and fibrosis. RNA-seq revealed induction of hepatic peroxisome proliferator-activated receptor α (PPARα)/fatty acid oxidation (FAO) and suppression of chemokine signaling pathways aligned with reduced liver and plasma C-C motif chemokine ligand 2 (CCL2). Luciferase and qPCR analyses showed that C18:1-Leu induces PPARα transcriptional activity, while stimulating FAO, as determined by Seahorse. In atherosclerotic mice, C18:1-Leu reduced lesional macrophages and atherosclerosis while lowering hepatic steatosis and CCL2. Our findings uncovered a newly identified metabolic pathway linking NASH and atherosclerosis and a novel potential therapy for the simultaneous treatment of these two prominent diseases.