Fenofibrate improves hepatic and renal excretion of bile acids in estrogen-induced cholestasis

HILLOTTE G.L.; RAZORI M.V.; MARTÍN P.L.; MEDEOT A.C.; BASIGLIO, C.L.; ROMA M.G.

CABA

Congreso; Reunión Anual de la Sociedad Argentina de Fisiología 2023; 2023

Sociedad Argentina de Fisiología

Introduction: Estrogens are causal agents of pregnancy- and oral contraceptive-induced cholestasis in susceptible women. 17α-ethinylestradiol (EE) is a prototypical estrogen used to mimic this disease in rats. EE impairs bile formation by inhibiting expression of bile salt (BS) heparocellular transporters. Fenofibrate (FF) is a potent PPARα agonist used to treat some human cholestatic hepatopathies, since it can upregulate several of these transporters.Objetives: To ascertain whether FF improves elimination of accumulated bile salts (BS) in EE-induced cholestasis, by counteracting the drop in the expression of BS hepatic transporters and/or by stimulating alternative renal BS excretion.Methods: Male Wistar rats were randomly divided into the following groups: i) Control (C), ii) EE (5 mg/kg/day, i.d., 5 days), iii) FF (200 mg/kg/day, p.o., 7 days), and iv) EE+FF. Next, serum alkaline phosphatase (ALP), a surrogate marker of hepatic retention of BS in cholestasis, and the maximal cumulative biliary output of the model BS taurocholate (TCBO) were assessed. The expression of Bsep (main apical BS transporter) and Mrp3 (main basolateral BS efflux pump) were evaluated by Western blot and real-time PCR, respectively. The alternative renal route of BS excretion was evaluated by determining total BS concentration in plasma and urine.Results: (*p<0.05 vs. control; #p<0.05 vs. EE). FF normalized serum ALP (U/L), which had been elevated (+64%*) by EE, and improved TCBO (mmol/ g liver wt) (C: 486 ± 40; EE: 214 ± 31*, EE+FF: 403 ± 34#). This improvement in BS biliary output was associated with an increase (+42%#) in Bsep expression, compared to that in the EE group (31%* lower than C). FF also increased expression of Mrp3 (+336%#) in EE-treated rats, thus potentiating the inducing effect that EE had per se (131%*). The marked increase in Mrp3 was associated with higher BS blood (+652%#) and urine (+302%#) levels in the EE+FF group. Conclusions: FF has anticholestatic effects in EE-induced cholestasis by improving BS elimination through both biliary and urinary routes, via induction of the apical and basolateral efflux transporters Bsep and Mrp3, respectively.