Vitamin A, not naturally produced by the body, undergoes a series of metabolic steps to become retinyl esters, which are then stored and activated in the liver. Before being stored as retinyl ester in HSCs (hepatic stellate cells), though, the liver receives retinol bound to chylomicrons from the intestine and transported through the blood. It is known that retinol is first released in hepatocytes, but there is not a consensus on what reactions occur in hepatocytes and in HSCs. Mechanistically, the final product of retinol is retinoic acid (RA), the natural ligand for the retinoic acid receptors (RARα, β, and γ) that drive the transcription of target genes. In order to test what processes happen in HSCs and hepatocytes, gene expression of the RARs was tested in response to RA, and AC261066 (AC), a RARb2 agonist, using gel electrophoresis. It was reported that RARβ is essential to maintain lipid homeostasis, so this was tested in both stellate cells and hepatocytes using oleic and palmitic acids with dye-fold change, then quantified. In addition, fibrosis-related genes were tested in stellate cells, because it is known that they produce scar tissue in the liver. Overall, RA did not affect the expression of the RARs in the HSCs and hepatocytes. For the lipid accumulation experiments, RA and AC were both extremely effective in reducing fat levels, especially in the hepatocytes. In conclusion, hepatocytes are more affected by RA and AC, especially in regards to lipid accumulation, though further testing at different concentrations and time points needs to be done.

Reference

[1] J. L. Napoli, “Physiological insights into all-trans-retinoic acid biosynthesis,” Biochim. Biophys. Acta, vol. 1821, no. 1, pp. 152–167, Jan. 2012.

[2] M. A. Blaner, “Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders,” Pharmacol. Ther., vol. 197, pp. 153–178, May 2019.

[3] R. Ross and J. A. Harrison, “Vitamin A: Nutritional aspects of retinoid metabolism and function,” Annu. Rev. Nutr., vol. 20, pp. 63–88, 2000.

[4] J. L. Napoli, “Retinoic acid biosynthesis and metabolism,” FASEB J., vol. 10, no. 9, pp. 993–1001, Jul. 1996.

[5] P. Chambon, “A decade of molecular biology of retinoic acid receptors,” FASEB J., vol. 10, no. 9, pp. 940–954, Jul. 1996.

[6] C. D. O'Byrne and M. A. Blaner, “Retinol and retinyl esters: Biochemistry and physiology,” J. Lipid Res., vol. 54, no. 7, pp. 1731–1743, Jul. 2013.

[7] S. L. Friedman, “Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver,” Physiol. Rev., vol. 88, no. 1, pp. 125–172, Jan. 2008.

[8] S. L. Friedman, “Mechanisms of hepatic fibrogenesis,” Gastroenterology, vol. 134, no. 6, pp. 1655–1669, May 2008.

[9] M. A. Blaner, W. S. O'Byrne, N. Wongsiriroj, J. Kluwe, D. M. D'Ambrosio, H. Jiang, et al., “Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage,” Biochim. Biophys. Acta, vol. 1791, no. 6, pp. 467–473, Jun. 2009.

[10] N. Berry, A. Noy, and M. A. Blaner, “Retinoid metabolism and signaling in liver disease,” Biochim. Biophys. Acta - Molecular and Cell Biology of Lipids, vol. 1821, no. 1, pp. 168–176, Jan. 2012.

[11] M. Schug, P. Berry, R. Shaw, A. Travis, and N. Noy, “Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors,” Cell, vol. 129, no. 4, pp. 723–733, May 2007.

[12] Y. He, M. A. Blaner, R. Noy, and D. Chen, “Retinoic acid receptor β regulates hepatic lipid metabolism and protects against diet-induced hepatic steatosis,” Hepatology, vol. 63, no. 3, pp. 782–795, Mar. 2016.