Oxidant stress is a significant feature of primary biliary cirrhosis

Aboutwerat, Ali; Pemberton, Philip W.; Smith, Alwyn; Burrows, P.C.; Mcmahon, Raymond; Jain, Sanjiv; Warnes, Thomas W.

doi:10.1016/s0925-4439(02)00225-9

Cited by 143 publications

(111 citation statements)

References 45 publications

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“…27 Because the involvement of oxidative stress has been suggested in the pathogenesis of cellular senescence in PBC, 8,28,29 we examined the influence of oxidative stress in the expression of bmi1 and cellular senescence using cultured mBECs. We took advantage of mBECs, because nonneoplastic human BECs are not always conveniently available and the features of senescent mBECs are reportedly similar to those of senescent human BECs.…”

Section: Discussionmentioning

confidence: 99%

Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis

Sasaki

Ikeda

Sato

et al. 2006

The American Journal of Pathology

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Cellular senescence of biliary epithelial cells with p16INK4a and p21 WAF1/Cip expression in damaged small bile ducts may be critical for progressive bile duct loss in primary biliary cirrhosis. We investigated the involvement of bmi1, a polycomb group gene repressing p16INK4a expression, in the pathogenesis of biliary cellular senescence. Bmi1 expression was examined immunohistochemically in livers taken from the patients with primary biliary cirrhosis (n ‫؍‬ 18) and other diseased (n ‫؍‬ 19) and normal livers (n ‫؍‬ 16). We examined the effect of oxidative stress and a short interference RNA (siRNA) targeting bmi1 on cellular senescence in cultured mouse biliary epithelial cells. Bmi1 was widely expressed in the nuclei of biliary epithelial cells in the control livers. In contrast, bmi1 expression was significantly decreased in damaged small bile ducts in 43% of livers with primary biliary cirrhosis of stage 1/2, coordinating with the increased p16 INK4a expression. In cultured biliary epithelial cells, oxidative stress by H 2 O 2 treatment significantly decreased bmi1 expression, followed by increased P16INK4a expression. A knockdown of bmi1 induced increased p16INK4a expression, decreased cell proliferation, and increased cellular senescence. In conclusion, the decreased bmi1 expression caused by oxidative stress may be involved in the pathogenesis of cellular senescence of biliary epithelial cells in primary biliary cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis

Sasaki

Ikeda

Sato

et al. 2006

The American Journal of Pathology

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“…Shifts in cellular redox status reflect perturbations in the relative ratios of oxidative and toxic products (eg, bile acids, superoxide, hydroxyl radical, lipid peroxides) and antioxidants during cholestatic liver disease. Although the precise mechanism is not completely known, it is generally accepted that oxidative stress is involved in the progression of hepatic damage during human cholestasis (Parola et al 1996;Aboutwerat et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Nuclear factor-E2-related factor 2 expression in liver is critical for induction of NAD(P)H:quinone oxidoreductase 1 during cholestasis

Aleksunes¹,

Slitt²,

Maher³

et al. 2006

Cell Stress Chaper

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Bile duct ligation (BDL) causes hepatocellular oxidative stress and injury. The transcription factor nuclear factor-E2-related factor (Nrf2) induces expression of numerous genes including NAD(P)H:quinone oxidoreductase 1 (Nqo1) during periods of oxidative stress. Therefore, we hypothesized that BDL increases liver expression of mouse antioxidant genes in an Nrf2-dependent manner. BDL or sham surgeries were performed on male C57BL/6, Nrf2-null, and wild-type mice. Livers were collected at 1, 3, and 7 days after surgery for analysis of messenger ribonucleic acid (mRNA) levels of Nrf2-responsive genes as well as Nqo1 protein and activity. BDL increased mRNA expression of multiple Nrf2 genes in mouse liver, compared to sham-operated controls. Follow-up studies investigating protein expression, enzyme activity, and Nrf2 dependency were limited to Nqo1. Nqo1 protein expression and activity in mouse livers was increased 2-to 3-, and 4-to 5-fold at 3 and 7 days after BDL, respectively. Studies also showed that BDL increases Nqo1 mRNA, protein expression, and enzyme activity in livers from wild-type mice, but not in Nrf2-null mice. In conclusion, expression of Nrf2-dependent genes is increased during cholestasis. These studies also demonstrate that Nqo1 expression and activity in mouse liver are induced via an Nrf2-dependent mechanism.

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“…In early PBC, lipid peroxidation markers, including plasma and urinary 8-isoprostane and plasma malondialdehyde, are increased, whereas plasma antioxidants, such as total glutathione, are decreased (27). Although these changes lead to eventual bile duct pathology, their effects on the vascular wall have not been documented.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation

Chang

et al. 2004

Journal of Lipid Research

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Hypercholesterolemic human LDL contains oxidized subfractions that have atherogenic properties. Paradoxically, atherosclerosis incidence is low in patients with primary biliary cirrhosis (PBC), a disease characterized by marked increases in plasma LDL, including the LDL subfraction lipoprotein-X (Lp-X). To investigate the mechanisms underlying this paradox, we first examined the propensity to oxidation of unfractionated LDL isolated from PBC patients. After prolonged incubation with copper, PBC-LDL failed to increase the oxidation index or electrophoretic mobility noted in control LDL. An admixture of PBC-LDL or Lp-X with control LDL prevented oxidation of the latter in a dose-dependent manner. PBC-LDL was also noncompetitive against copper-oxidized LDL (oxLDL) for binding with a murine monoclonal anti-oxLDL antibody in a competitive ELISA. OxLDL exerts its proapoptotic and antiangiogenic effects in part by inhibiting fibroblast growth factor 2 (FGF2) expression. Preincubation of oxLDL with PBC-LDL, but not control LDL, attenuated the inhibitory effects of oxLDL on FGF2 expression in cultured bovine aortic endothelial cells (ECs). The antioxidant and prosurvival properties of PBC-LDL diminished after the patients underwent orthotopic liver transplantation. These results suggest that Lp-X reduces LDL atherogenicity by preventing LDL oxidation to protect EC integrity in the presence of hypercholesterolemia. They also suggest that altering LDL composition may be as important as reducing LDL concentration in preventing or treating atherosclerosis. -Chang, P-Y., S-C. Lu, T-C. Su, S-F. Chou, W-H. Huang, J. D. Morrisett, C-H. Chen, C-S. Liau, and Y-T. Lee. Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation.

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Oxidant stress is a significant feature of primary biliary cirrhosis

Cited by 143 publications

References 45 publications

Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis

Decreased Expression of Bmi1 Is Closely Associated with Cellular Senescence in Small Bile Ducts in Primary Biliary Cirrhosis

Nuclear factor-E2-related factor 2 expression in liver is critical for induction of NAD(P)H:quinone oxidoreductase 1 during cholestasis

Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation

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