Lipidated Amino Acids in Cardiometabolic Diseases

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PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) affects 25% of the global population at a substantial burden to the health care system. 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 non-alcoholic steatohepatitis (NASH). Thus, there is an urgent clinical 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 in 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. Yet, little is known about the metabolic regulation of NAAs, particularly in cardiometabolic diseases. Our preliminary data uncovered that the liver is a major hub for NAA metabolism. Unbiased transcriptomics revealed suppression of known NAA biosynthetic genes (GLYAT, ADH7 and PM20D1) and upregulation of degradative genes (PAM, PTGS1 and PTGS2) in livers from humans and mice with NASH, concomitant with marked reduction of NAAs, as determined by metabolomics. Hepatic NAAs inversely correlated with NASH and inflammatory indices. Importantly, chronic administration of N-oleoyl leucine (C18:1-Leu), as proof-of-concept, protected against diet-induced NASH, independent of changes in systemic energy metabolism. This was associated with induction of hepatic peroxisome proliferator-activated receptor α (PPARα)/fatty acid oxidation (FAO), suppression of C-C motif chemokine ligand 2 (CCL2) and reduced hepatic macrophages and fibrosis. In atherosclerotic mice, C18:1-Leu reduced lesional macrophages and atherosclerosis, while concurrently lowering hepatic steatosis and CCL2. Thus, our findings support the potential of NAAs for the simultaneous treatment of NASH and atherosclerosis. This project will address the central hypothesis that lipid overload and ensuing inflammation inhibit hepatic NAA formation, while NAAs stimulate hepatic PPARα and suppress CCL2, simultaneously reducing NASH and atherosclerosis. Aim 1 will determine the mechanisms driving suppression of NAAs in NASH and atherosclerosis using in vitro and in vivo models of loss- and gain-of- function of NAA metabolic genes and will define genetic variants in these genes linking both diseases in GWAS and human liver samples. Aim 2 will define NAAs as a potential therapy for NASH, thereby atherosclerosis, and its dependence on PPARα-mediated hepatic FAO and suppression of CCL2 using new liver-specific and dietary mouse models combined with in vitro approaches. This work will characterize a newly identified metabolic pathway linking NASH and atherosclerosis and provide mechanistic data to accelerate the development of NAAs as a simultaneous treatment for these diseases, thus addressing a significant unmet clinical need.