Assessing the roles of various retinoid‐metabolizing CYP enzymes in liver disease

Abstract

Development of liver disease (LD) is associated with progressive depletion of hepatic stellate cell (HSC) retinoid‐storing lipid droplets. It is not clear whether this loss is the result of increased hepatic mobilization of retinol or increased retinoid catabolism by hepatic cytochrome P450 (CYP) enzymes. Wild type (WT) mice were treated with CCl4 as a model of experimentally induced hepatic fibrosis (EIHF). We did not observe any alterations in the expression of genes encoding proteins involved in retinoid transport in the livers of WT mice in response to CCl4. However, we did find that EIHF is accompanied by an approximate 4‐fold elevation in CYP26A1 and CYP2S1 mRNA levels. Because retinol uptake and storage in the liver involves both hepatocytes and HSCs, we were interested in understanding how each cell type may contribute to the progression of LD. We isolated hepatocytes and HSCs from the livers of WT mice and generated CYP expression profiles for each cell type. HSCs have approximately 50‐fold higher levels of CYP2S1 mRNA relative to hepatocytes, whereas CYP26A1 is highly expressed in hepatocytes. The high expression of CYP2S1 in HSCs and its induction in EIHF provides evidence for a role of this cytochrome in the progression of LD. Thus, the loss of HSC lipid droplets in LD may arise from increased CYP‐mediated retinoid catabolism and not increased retinol mobilization from the liver.Grant Funding SourceR01 DK079221