3B). UDCA treatment did not affect serum 4β-HC or 24S-HC concentrations but MAPK Inhibitor Library cost increased the 27-HC concentration significantly. Treatment with bezafibrate clearly increased serum 4β-HC levels, whereas it significantly reduced the 24S-HC and 27-HC levels. Differentiated HepaRG cells exhibit a gene expression pattern similar to primary human hepatocytes and human liver tissues and maintain significant levels of hepatic cell functions, including CYP and transporter activities.26 Rifampicin and carbamazepine are classical inducers of CYP3A4 by way of the activation of PXR,27 whereas GW4064 is one of the most potent agonists of FXR.28 As shown in Fig. 4A, bezafibrate, as well as rifampicin
and carbamazepine, induced both CYP3A4 mRNA expression
and activity in a dose-dependent manner. The DPX2 cell-based luciferase reporter gene assay demonstrated that in comparison with rifampicin, bezafibrate was a weak but significant activator of human PXR as well as carbamazepine (Fig. 4B). It is noteworthy that GW4064 activated human PXR at concentrations higher than 3 μM. Among the nuclear receptors and related coactivators (Fig. 5A), PXR expression was induced by bezafibrate to a greater degree than that by rifampicin, which suggests that PXR is a target gene of PPARs, as reported.29 In contrast, the small heterodimer partner (SHP; NR0B2), a target of FXR, and LXRα were down-regulated by bezafibrate, as well as rifampicin and carbamazepine. FXR and peroxisome proliferator-activated Panobinostat research buy receptor-γ coactivator-1α (PGC1α) expressions were significantly down-regulated by rifampicin and carbamazepine but not by bezafibrate. The MDR1 (ABCB1) and MRP2 (ABCC2) transporters (Fig. 5B) were up-regulated
by bezafibrate, similar to rifampicin, whereas MDR3, ABCG5, and ABCG8 were up-regulated by bezafibrate but not by rifampicin. In addition, Na+/taurocholate cotransporting polypeptide (NTCP) was down-regulated by Amino acid bezafibrate but did not change significantly by rifampicin. It is notable that significant messenger RNA (mRNA) expression of BSEP was observed in HepaRG cells treated with GW4064, whereas only a trace amount of BSEP expression was detected in control cells and those treated with other compounds. Enzymes involved in cholesterol, bile acid, and fatty acid syntheses and LDL receptor expression are summarized in Fig. 5C. CYP7A1, CYP7B1, and CYP27A1 were down-regulated and CYP8B1, fatty acid synthase (FAS), and LDL receptor (LDLR) were up-regulated by bezafibrate, which was the same as the effects of rifampicin. HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, was down-regulated by rifampicin but was slightly up-regulated by bezafibrate. Our results clearly showed that the combination therapy of bezafibrate and UDCA significantly improved cholestasis in early-stage PBC patients who were refractory to UDCA monotherapy.
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