Novel insights into bexarotene's role in preventing cholestasis: mechanisms and implications

Cholestasis is defined as an impairment in the flow of bile, resulting in the accumulation of its components. Despite ursodeoxycholic acid (UDCA) being the only FDA-approved drug for cholestasis, it has little value in treating or preventing cholestasis; hence, new medications are required to treat these illnesses. The farnesoid X receptor (FXR) maintains bile acid (BA) homeostasis. It exists as heterodimers with retinoid X receptor (RXR) and responds to ligands that bind to any one of the partners and are activated synergistically in the presence of both. The hepatoprotective effect of bexarotene (Bex) against cholestasis liver injury induced by α-naphthyl isothiocyanate (ANIT) was evaluated in male Wistar albino rats. Our study demonstrates that compared to the ANIT group, Bex improves liver function tests, liver histology, and considerably reduces inflammatory mediators. Additionally, antioxidant levels increased significantly. Besides that, Bex upregulates the gene expression of FXR, bile salt export pump, hepatocyte nuclear factor 1α, and small heterodimer partner. Moreover, it enhances antioxidative nuclear factor erythroid 2-related factor gene expression and the expression of the NAD(P)H quinone oxidoreductase 1, and heme-oxygenase 1 protein targets in the rats' livers, reinforcing its hepatoprotective potential. Furthermore, Bex increases protein expressions of FXR, The bile salt export pump, and sirtuin 1 levels in the rats' livers. This study demonstrates that Bex protects against ANIT-induced cholestasis. This protective strategy involves controlling BA metabolism, inhibiting inflammatory mediators, and reducing oxidative stress.