Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid

Abstract

Bezafibrate is a widely used hypolipidemic agent and is known as a ligand of the peroxisome proliferator-activated receptors (PPARs). Recently this agent has come to be recognized as a potential anticholestatic medicine for the treatment of primary biliary cirrhosis (PBC) that does not respond sufficiently to ursodeoxycholic acid (UDCA) monotherapy. The aim of this study was to explore the anticholestatic mechanisms of bezafibrate by analyzing serum lipid biomarkers in PBC patients and by cell-based enzymatic and gene expression assays. Nineteen patients with early-stage PBC and an incomplete biochemical response to UDCA (600 mg/day) monotherapy were treated with the same dose of UDCA plus bezafibrate (400 mg/day) for 3 months. In addition to the significant improvement of serum biliary enzymes, immunoglobulin M (IgM), cholesterol, and triglyceride concentrations in patients treated with bezafibrate, reduction of 7α-hydroxy-4-cholesten-3-one (C4), a marker of bile acid synthesis, and increase of 4β-hydroxycholesterol, a marker of CYP3A4/5 activity, were observed. In vitro experiments using human hepatoma cell lines demonstrated that bezafibrate controlled the target genes of PPARα, as well as those of the pregnane X receptor (PXR); down-regulating CYP7A1, CYP27A1, and sinusoidal Na+/taurocholate cotransporting polypeptide (NTCP), and up-regulating CYP3A4, canalicular multidrug resistance protein 3 (MDR3), MDR1, and multidrug resistance-associated protein 2 (MRP2). Conclusion : Bezafibrate is a dual PPARs/PXR agonist with potent anticholestatic efficacy in early-stage PBC patients with an incomplete biochemical response to UDCA monotherapy.

Biochemical and Histological Effectiveness of Long-term Use of Fenofibrate for Asymptomatic Primary Biliary Cholangitis

“…For example, Hazzan et al and Lens et al demonstrated that the addition of bezafibrate to UDCA significantly and safely improves the biochemical profiles of European patients with PBC [33,34] . The proposed mechanism of action of fibric acid derivatives in the setting of PBC involves the regulation of cell proliferation and the expression of various lipids and proteins via the activation of PPAR-α [8,10] . Through PPAR-α activation, fibrates inhibit NF-κβ activation, resulting in decreased expression levels of IL-1 and IL-6, thereby potentially reducing the inflammatory and immune responses [9,10] .…”

“…The proposed mechanism of action of fibric acid derivatives in the setting of PBC involves the regulation of cell proliferation and the expression of various lipids and proteins via the activation of PPAR-α [8,10] . Through PPAR-α activation, fibrates inhibit NF-κβ activation, resulting in decreased expression levels of IL-1 and IL-6, thereby potentially reducing the inflammatory and immune responses [9,10] . In addition to regulating proteins and lipids, the benefits of fibrates in cases of PBC may result from cross-talk between PPAR-α and the bile acid-activated nuclear receptor farnesoid-X-receptor (FXR) [35] .…”

“…Pineda-Torra et al demonstrated that bile acid-activated FXR enhances PPAR-α transcription in human hepatic stellate cells [35] . Furthermore, fibrates may facilitate the expression of multidrug resistance gene 3 (MDR), a transport element of the ATP-dependent bile secretion system found in biliary membranes [10,[36][37][38] . An increased expression of MDR-3-encoded proteins would lead to the enhanced secretion of biliary phospholipids and improved inactivation of hydrophobic bile acids via micellization, thus protecting hepatocytes and the biliary epithelium.…”

The Role of Canalicular ABC Transporters in Cholestasis

“…In addition, PPARa decreased bile acid synthesis (CYP7A1) and induced bile acid detoxification (SULT2A1, UGT2B4, UGT1A3) in animal models (Patel et al, 2000;Jung et al, 2002;Barbier et al, 2003;Fang et al, 2005). The PPAR agonist bezafibrate showed beneficial effects in PBC patients in pilot trials, although these results need to be confirmed by larger randomized-controlled clinical trials (Honda et al, 2013).…”

Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver

“…Fibrates are agonists of the nuclear receptor PPAR-alpha, with antiinflammatory and choleretic properties. Several small studies have shown significant improvement in liver biochemistries and serum IgM in patients with PBC and incomplete response to UDCA who are treated with fibrates (161)(162)(163)(164)(165)(166)(167)(168)(169)(170) . One meta-analysis of 6 randomized studies including 151 Japanese patients, concluded there was not enough evidence to support or refute an effect of bezafibrate on the morbi-mortality of patients with PBC (171) .…”