A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

Nishioka, Tomoji; Hyogo, Hideyuki; Numata, Yoshihiro; Yamaguchi, Atsushi; Kobuke, Toshiya; Komichi, Daisuke; Nonaka, Michihiro; Inoue, Motoki; Nabeshima, Yoshitaka; Ogi, Mami; Iwamoto, Keiko; Ishitobi, Tomokazu; Ajima, Takeyoshi; Chayama, Kazuaki; Tazuma, Susumu

doi:10.5551/jat.12.211

Cited by 17 publications

(11 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This choleretic action of fibrates mainly bezafibrate was further attributed to enhancement in canalicular membrane fluidity (opposing EE and CPZ cholestatic mechanism discussed above) and transporter activity mediating bile acid-independent bile secretion [29]. …”

Section: Discussionmentioning

confidence: 99%

Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

2013

View full text Add to dashboard Cite

Background. Activation of PPARα modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of PPARα agonists, fenofibrate, bezafibrate, and gemfibrozil, on acute cholestasis induced by ethinylestradiol (EE) plus chlorpromazine (CPZ) in rats. Method. 100 male albino rats (150–200 gm) were divided randomly into 10 equal groups. Control group received 1% methylcellulose vehicle; disease group received CPZ plus EE for 5 consecutive days; four groups received either ursodeoxycholic acid, fenofibrate, bezafibrate, or gemfibrozil for 7 days; 2 days before EE + CPZ, three other groups received one of the three fibrates after GW6471, a selective PPARα antagonist in addition to EE + CPZ. The final group received GW6471 alone. Results. The three fibrates showed marked reduction (P < 0.05) in serum levels of ALP, GGT, ALT, AST, total bile acids, bilirubin, TNFα, and IL-1β and in hepatic malondialdehyde level as well as a significant increase in bile flow rate (P < 0.05) in addition to improvements in histopathological parameters compared to diseased group. In groups which received GW6471, these effects were completely abolished with fenofibrate and partially blocked with bezafibrate and gemfibrozil. Conclusion. Short-term administration of fibrates to EE/CPZ-induced intrahepatic cholestatic rats exerted beneficial effects on hepatocellular damage and apoptosis. Fenofibrate anticholestatic effect was solely PPARα dependent while other mechanisms played part in bezafibrate and gemfibrozil actions.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

2013

View full text Add to dashboard Cite

show abstract

“…It has also been established by various groups that fibrates induce the expression of Abcb4 in mice [36,37]. This most likely involves activation of the nuclear hormone Ppar-α because Abcb4 expression was inert to fibrate treatment in Ppar-α −/− mice [38].…”

Section: Regulation Of Abcb4 Expressionmentioning

confidence: 97%

Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein)

Elferink

Paulusma

2006

Pflugers Arch - Eur J Physiol

250

197

View full text Add to dashboard Cite

Like several other ATP-binding cassette (ABC) transporters, ABCB4 is a lipid translocator. It translocates phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane of the hepatocyte. Its function is quite crucial as evidenced by a severe liver disease, progressive familial intrahepatic cholestasis type 3, which develops in persons with ABCB4 deficiency. Translocation of PC makes the phospholipid available for extraction into the canalicular lumen by bile salts. The primary function of biliary phospholipid excretion is to protect the membranes of cells facing the biliary tree against these bile salts: the uptake of PC in bile salt micelles reduces the detergent activity of these micelles. In this review, we will discuss the functional aspects of ABCB4 and the regulation of its expression. Furthermore, we will describe the clinical and biochemical consequences of complete and partial deficiency of ABCB4 function.

show abstract

“…By contrast, the PPAR α -dependent regulation of MRP2 expression sustained some controversy in the recent years. Although bezafibrate exposure caused significant increase in MRP2 mRNA in human hepatic HepaRG cells [22] as well as in liver cells from treated mice [46], it was unclear whether such effects were PPAR α -dependent [22]. Other in vivo investigations using ciprofibrate also revealed conflicting results.…”

Section: Discussionmentioning

confidence: 99%

PPARα: A Master Regulator of Bilirubin Homeostasis

et al. 2014

View full text Add to dashboard Cite

Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed.

show abstract

A Nuclear Receptor-mediated Choleretic Action of Fibrates is Associated with Enhanced Canalicular Membrane Fluidity and Transporter Activity Mediating Bile Acid-independent Bile Secretion

Cited by 17 publications

References 34 publications

Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein)

PPARα: A Master Regulator of Bilirubin Homeostasis

Contact Info

Product

Resources

About