Retinoic Acid Metabolites and Isomers have Differential Effects on Lipid Metabolism

All‐trans retinoic acid ( at RA) and 13‐ cis RA, and their metabolites 4‐oxo‐ at RA and 4‐oxo‐13‐ cis RA are found in circulation in humans as endogenous compound and following clinical doses of at RA and 13‐ cis RA. Of these four compounds, only at RA is believed to be biologically important due to its high affinity towards RARs and activation of PPARδ. 13‐ cis RA and 4‐oxo‐ at RA also activate RARs but less is known about the 4‐oxo‐13‐ cis RA. The activation of PPARs by 13‐ cis RA and 4‐oxo‐metabolites has not been studied. The aim of this study was to determine whether at RA, 4‐oxo‐ at RA, 13‐ cis RA and 4‐oxo‐13‐ cis RA have biological effects via RAR and other non‐RAR mediated pathways in human hepatocytes, HepG2 cells and adipocytes. At 1 μM concentration at RA, 4‐oxo‐ at RA, 13‐ cis RA and 4‐oxo‐13‐ cis RA each significantly increased the mRNA levels of RARβ demonstrating that all four compounds activate RARs. at RA treatment increased expression of PPARδ targeted genes PGC1α, PGC1β and NRF1 and fatty acid oxidation, but had no effect on fatty acid and triglyceride synthesis genes SREBP1, MTTP, DGAT2 and PPARγ. In contrast, 13‐ cis RA, 4‐oxo‐ at RA, and 4‐oxo‐13‐ cis RA had no effect on PPARδ targeted genes PGC1α, PGC1β and NRF1 and fatty acid oxidation, but significantly increased the expression of SREBP1, MTTP, DGAT2 and PPARγ. This suggests that 13‐ cis RA, 4‐oxo‐ at RA, and 4‐oxo‐13‐ cis RA increase triglyceride synthesis and secretion. In addition, 4‐oxo‐ at RA antagonized the induction of PGC1α, PGC1β and NRF1 and fatty acid oxidation by at RA demonstrating an independent activity of the 4‐oxo‐ at RA when compared to at RA. Collectively, these results indicate that at RA promotes lipid catabolism via PPARδ, and 13‐ cis RA and 4‐oxo‐RAs increase triglyceride synthesis, possibly via SREBP1 and PPARγ. Our findings regarding 13‐ cis RA and its main circulatory metabolite 4‐oxo‐13‐ cis RA explain the clinical data of increased incidence of hypertriglyceridemia and hypercholesterolemia following 13‐ cis RA dosing. In addition, our data supports the mouse findings that at RA increases fatty acid oxidation in vivo. This study demonstrates that the 13‐ cis RA isomer and 4‐oxo‐metabolites of RA found in circulation regulate lipid metabolism independent of at RA and RAR activation, and may play an important role in vivo in modulating lipid homeostasis in human tissues. Support or Funding Information NIH R01 GM111772, R01 GM081569, R01 GM081569‐S1 and P30 DK035816