Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARα-mediated redistribution of ABCB4

Shoda, Junichi; Inada, Yoichi; Tsuji, Akiko; Kusama, Hiroshi; Ueda, Tetsuya; Ikegami, Tadashi; Suzuki, Hiroshi; Sugiyama, Yuichi; Cohen, David E.; Tanaka, Naomi

doi:10.1194/jlr.m400132-jlr200

Cited by 51 publications

(54 citation statements)

References 46 publications

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“…Fibrates induce MDR3 gene expression, canalicular redistribution of MDR3, and biliary phospholipid secretion by a PPARamediated pathway [16][17][18]. The relationship between MDR3 and PPARa expression in our study (Fig.…”

Section: Discussionmentioning

confidence: 89%

The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression

et al. 2009

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Aim Because dyslipidemia, such as hypercholesterolemia, is a characteristic of primary biliary cirrhosis (PBC), hepatic lipid metabolism may be disturbed in PBC patients. We examined the expression of lipid metabolism-associated genes in PBC liver. Methods All of the patients examined were in stage I or II PBC and without medication. RNA was isolated from liver specimens by needle biopsies of PBC patients and controls. The expression levels of various genes were measured by real-time RT-PCR. Multidrug resistance 3 (MDR3) expression was examined immunohistochemically. Statistical correlations between the gene expression levels and indices of blood testing were calculated. Results The expression levels of sterol regulatory element-binding protein (SREBP) 2 and LDL receptor were significantly lower, and those of apolipoprotein B, microsomal triglyceride transfer protein, ATP-binding cassette G5, and liver X receptor a (LXRa) were significantly higher in the PBC liver than in the normal control liver. The expression levels of bile acid synthesis-and excretionassociated genes did not change, and those of farnesoid X receptor, peroxisome proliferator-activated receptor a, and SREBP-1c were similar between the PBC and normal liver. MDR3 gene expression levels in the PBC liver were more than 4-fold higher than those in the control liver. Immunohistochemically, strong canalicular staining for MDR3 was observed in the PBC liver. LXRa expression was positively correlated with MDR3 levels. Serum levels of c-glutamyl transpeptidase (GGT) and IgM were negatively correlated with MDR3 levels. Conclusions Hepatocellular cholesterol metabolism was at least partially disturbed, even in the early stage of PBC. The most characteristic finding was a distinct elevation of MDR3 expression, and the MDR3 levels were negatively correlated with GGT and IgM levels.

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Section: Discussionmentioning

confidence: 89%

The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression

et al. 2009

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“…PPAR␣ Knockdown in HepG2 Cells by siRNA-siRNA oligonucleotides targeted to human PPAR␣ were described previously (30). Scrambled control RNA oligonucleotides were purchased from Santa Cruz Biotechnology (sc-37007).…”

Section: Methodsmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor α Positively Regulates Complement C3 Expression but Inhibits Tumor Necrosis Factor α-mediated Activation of C3 Gene in Mammalian Hepatic-derived Cells

Mogilenko

Кудрявцев

Shavva

et al. 2013

Journal of Biological Chemistry

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Background: Expression and secretion of complement C3 is positively regulated in hepatocytes during acute inflammation. Results: Activation of PPAR␣ stimulates C3 expression but interferes with up-regulation of C3 gene by TNF␣-NF-B axis. Conclusion:Interplays between PPAR␣ and TNF␣ may be involved in control of C3 gene expression and protein secretion during acute inflammation. Significance: Novel mechanism of PPAR␣-dependent regulation of C3 gene in the liver has been shown.

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“…Liver and kidney total homogenates and crude liver membranes were prepared as previously described (11,41). Transporter protein and antioxidant stress gene product levels in rat livers and kidneys were determined using monoclonal antibodies raised against Mrp2 (M 2III-6, Alexis Biochemicals, Lausen, Switzerland) and P-glycoproteins (C219, Abcam, Cambridge, UK) and polyclonal antibodies raised against Mrp3, Mrp4, bile salt export protein (Bsep), ␥-glutamyl cystein synthase (␥-GCS), and heme oxygenase (HO)-1 using recently detailed methodology (20,36,43).…”

Section: Methodsmentioning

confidence: 99%

Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers

Okada

Shoda

Kano

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers. Am J Physiol Gastrointest Liver Physiol 292: G1450 -G1463, 2007. First published October 12, 2006; doi:10.1152/ajpgi.00302.2006, a herbal medicine, has been recognized in Japan and China as a "magic bullet" for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT. Administration of ICKT or genipin to rats for 7 days increased bile flow and biliary excretion of bilirubin conjugates. Mrp2 protein and mRNA levels and Mrp2 membrane densities in the bile canaliculi and renal proximal tubules were significantly increased in ICKT-or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased hepatic levels of heme oxygenase-1 and GSH by a nuclear factor-E2-related factor (Nrf2)-dependent mechanism. Similar effects of ICKT on MRP2 expression levels were observed in humanized livers of chimeric mice. In conclusion, these findings provide the rationale for therapeutic options of ICKT and its ingredients that should potentiate bilirubin disposal in vivo by enhancing Mrp2/MRP2-mediated secretory capacities in both livers and kidneys as well as Nrf2-mediated antioxidative actions in the treatment of cholestatic liver diseases associated with jaundice.

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Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARα-mediated redistribution of ABCB4

Cited by 51 publications

References 46 publications

The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression

The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression

Peroxisome Proliferator-activated Receptor α Positively Regulates Complement C3 Expression but Inhibits Tumor Necrosis Factor α-mediated Activation of C3 Gene in Mammalian Hepatic-derived Cells

Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers

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