Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes

Abstract

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

Retinoids in the Pathogenesis and Treatment of Liver Diseases

“…The Ferdouse et al study [ 146 ] did show, in agreement with a recent RNA-sequencing study of livers from alcohol-treated mice by Melis et al [ 147 ], that 3–4 weeks of chronic alcohol treatment leads to robust and broad hepatic mRNA increases in numerous CYPs (including Cyp2c29, Cyp3a11, Cyp26a1, and Cyp26b1) that are capable of degrading retinoids [ 125 ]. These data strongly suggest that in addition to CYP2E1, alcohol-induced CYP450s, including the RA hydroxylases CYP26A1 and CYP26B1, are likely involved in alcohol-mediated reductions in hepatic retinoids.…”

“…Nevertheless, the conclusions from these studies were in agreement that alcohol promotes hepatic RA catabolism [ 133 , 146 , 147 ]. However, this phenomenon does not appear to occur in some extra-hepatic tissues, as Kane et al [ 133 ] also demonstrated that chronic alcohol exposure increases RA levels in the testes, and, consistent with another report [ 149 ], the brain.…”

“…That notion, however, was challenged in a study by Clugston et al [ 139 ] that demonstrated that Cyp2e1 −/− mice were only protected from alcohol-mediated reductions in hepatic retinol, not retinyl esters [ 139 ]. The Clugston et al study [ 139 ], and a similar study by Ferdouse et al using alcohol-treated Cyp2e1 −/− mice [ 146 ], did not determine if loss of CYP2E1 could mitigate alcohol-driven reductions in hepatic RA.…”

“…Furthermore, there is debate as to whether alcohol leads to reductions to hepatic RA [ 123 , 148 ]. Three studies using highly sensitive tandem mass spectrometry (LC-MS/MS) approaches to measure hepatic RA in male mice show that chronic alcohol feeding resulted in either no changes [ 133 , 147 ] or reductions in hepatic RA levels [ 146 ]. The discrepancies in these findings may be partly explained by data from Kane et al [ 133 ], who performed the most comprehensive examination of both acute and chronic effects of alcohol on hepatic and extra-hepatic RA.…”

“…Therefore, the data from Kane et al [ 133 ] suggest that the timing of the hepatic RA measurements is likely critically important in the determination of the effects of alcohol on hepatic RA levels. In the same regard, differences in the length of reported alcohol exposure and dose across these studies (4 weeks of 6.5% v / v in Kane et al [ 133 ], vs. 3 weeks of 5% v / v in Melis et al [ 147 ], vs. 2 weeks of 6.4% v / v in Ferdouse et al [ 146 ]), should also be considered when comparing these findings.…”