Retinoids are essential endogenous compounds involved in regulation of critical biologic processes, including maintenance of metabolic homeostasis in the liver. Much of the knowledge of altered retinoid homeostasis in human disease states is derived from changes in indirect markers such as mRNA expression of retinoid-related genes and circulating concentrations of retinol or its binding protein RBP4. We hypothesized that in the human liver, concentrations of the active retinoid all-trans-retinoic acid (atRA) correlate with the concentrations of retinyl palmitate (RP), the storage form of atRA, retinol, the inactive vitamin A, and the mRNA expression of retinoid-related genes. On the basis of existing knowledge of altered vitamin A homeostasis in metabolic syndrome, we also predicted that in human livers with nonalcoholic fatty liver disease (NAFLD) retinoid concentrations would be decreased. Using novel liquid chromatography-tandem mass spectrometry methods, the hepatic vitamin A metabolome was quantified in normal human livers (n = 50) and 22 livers from donors with NAFLD. The hepatic concentrations of RP, atRA, 13-cisRA, and 4-oxo-atRA were significantly decreased in NAFLD samples in comparison with normal liver samples, whereas retinol levels remained unchanged. The concentrations of atRA were positively correlated with RP and 13-cisRA but not with retinol or the relative mRNA expression of LRAT, ALDH1A1, CYP26A1, RARα, and RARβ An active metabolite of atRA, 4-oxo-atRA was, for the first time, detected in human tissues at comparable concentration with RA isomers, suggesting this retinoid may contribute to retinoid signaling in humans. SIGNIFICANCE STATEMENT: This study shows that in NAFLD liver vitamin A homeostasis is disrupted potentially contributing to disease progression. The results show that interpretation of retinoid homeostasis on the basis of indirect markers such as retinol concentrations or mRNA data is probably misleading when evaluating human disease processes, and analysis of the broader retinoid metabolome is needed to characterize disease effects on retinoid signaling.
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.