Alpha-(13′-hydroxy)-6-hydroxychroman, the main product of alpha-tocopherol metabolism in human hepatocytes, regulates CYP4F2 and PPAR-γ expression

The enzymatic metabolism of vitamin E in liver cells generates long chain metabolites (LCMs) with proposed regulatory activity on inflammatory and atherogenic genes. In this study the LCM formation kinetics was characterized in HepG2 and HepaRG human hepatic cells, supplemented with RRR-α-tocopherol (α-TOH). α-13’OH was the main product of α-TOH metabolism, while α-13’COOH metabolite and the short chain metabolite α-CEHC, were detected only in traces, thus demonstrating the poor efficiency of vitamin E catabolism in these cells. However, this metabolism was significantly simulated when the hepatic cells were challenged with (lipo)toxic agents, such as ethanol or palmitate. Under such conditions a significant gene repression effect was observed for PPARγ nuclear receptor and the CYP-450 isoenzyme 4F2, which therefore appear to play a minor role in this metabolism. The upregulation of other CYPs such as 3A4 and 2E1 during these challenges, supports the previously proposed role of PXR as key responsive element in the hepatic metabolism of vitamin E. Worth of note, LCMs, similarly to their semi-synthesis natural precursor garcinoic acid, were found to be more potent than α-TOH to stimulate CYP4F2 and PPAR-γ protein expression, an original finding that may lead to speculate the importance of vitamin E metabolism in the gene regulation and lipid homeostasis of liver cells.