Akira Honda, Teruo Miyazaki, Junichi Iwamoto, Takeshi Hirayama, Yukio Morishita, Tadakuni Monma, Hajime Ueda, Seiya Mizuno, Fumihiro Sugiyama, Satoru Takahashi, Tadashi Ikegami

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.

Akira Honda, Kouwa Yamashita, Takashi Hara, Tadashi Ikegami, Teruo Miyazaki, Mutsumi Shirai, Guorong Xu, Mitsuteru Numazawa, Yasushi Matsuzaki

Akira Honda, Kouwa Yamashita, Hiroshi Miyazaki, Mutsumi Shirai, Tadashi Ikegami, Guorong Xu, Mitsuteru Numazawa, Takashi Hara, Yasushi Matsuzaki

Gut microbiota have profound effects on bile acid metabolism by promoting deconjugation, dehydrogenation, and dehydroxylation of primary bile acids in the distal small intestine and colon. High-fat diet-induced dysbiosis of gut microbiota and bile acid dysregulation may be involved in the pathology of steatosis in patients with non-alcoholic fatty liver disease. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic catechin in green tea, has been widely investigated for its inhibitory or preventive effects against fatty liver. The aim of the present study was to investigate the effects of EGCG on the abundance of gut microbiota and the composition of serum bile acids in high-fat diet-fed mice and determine the specific bacterial genera that can improve the serum bile acid dysregulation associated with EGCG anti-hepatic steatosis action. Male C57BL/6N mice were fed with the control diet, high-fat diet, or high-fat diet + EGCG at a concentration of 0.32% for 8 weeks. EGCG significantly inhibited the increases in weight, the area of fatty lesions, and the triglyceride content in the liver induced by the high-fat diet. Principal coordinate analysis revealed significant differences in microbial structure among the groups. At the genus level, EGCG induced changes in the microbiota composition in high-fat diet-fed mice, showing a significantly higher abundance of Adlercreutzia, Akkermansia, Allobaculum and a significantly lower abundance of Desulfovibrionaceae. EGCG significantly reversed the decreased population of serum primary cholic acid and β-muricholic acid as well as the increased population of taurine-conjugated cholic acid, β-muricholic acid and deoxycholic acid in high-fat diet-fed mice. Finally, the correlation analysis between bile acid profiles and gut microbiota demonstrated the contribution of Akkermansia and Desulfovibrionaceae in the improvement of bile acid dysregulation in high-fat diet-fed mice by treatment with EGCG. In conclusion, the present study suggests that EGCG could alter bile acid metabolism, especially taurine deconjugation, and suppress fatty liver disease by improving the intestinal luminal environment.