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- Carmona-Cuenca, Irene, et al.
(författare)
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Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity
- 2008
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 49:6, s. 965-76
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: The transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes through an oxidative stress process. Here, we have analyzed the role of different NADPH oxidase isoforms in the intracellular signalling induced by TGF-beta in hepatocytes, to later explore whether this mechanism is altered in liver tumor cells.METHODS: Primary cultures of rat and human hepatocytes, HepG2 and Hep3B cells were used in in vitro studies to analyze the TGF-beta response.RESULTS: TGF-beta-induced apoptosis in rat hepatocytes does not require Rac-dependent NADPH oxidases. TGF-beta upregulates the Rac-independent Nox4, which correlates with its pro-apoptotic activity. Regulation of Nox4 occurs at the transcriptional level and is counteracted by intracellular survival signals. siRNA targeted knock-down of Nox4 attenuates NADPH oxidase activity, caspase activation and cell death in rat hepatocytes. NOX4 upregulation by TGF-beta is also observed in human hepatocytes, coincident with apoptosis. In human hepatocellular carcinoma (HCC) cell lines, NOX4 upregulation by TGF-beta is only observed in cells that are sensitive to its cytotoxic effect, such as Hep3B cells. siRNA targeted knock-down of NOX4 in these cells impairs TGF-beta-induced apoptosis.CONCLUSIONS: Upregulation of NOX4 by TGF-beta is required for its pro-apoptotic activity in hepatocytes. Impairment of this TGF-beta-induced response might confer apoptosis resistance in HCC cells.
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- Ekstedt, Mattias, et al.
(författare)
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Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes : a histopathological follow-up study.
- 2007
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 47:1, s. 135-141
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins. Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up. Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.
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- Koroxenidou, Lena, et al.
(författare)
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Long-term 17 alpha-ethinyl estradiol treatment decreases cyclin E and cdk2 expression, reduces cdk2 kinase activity and inhibits S phase entry in regenerating rat liver
- 2005
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 43:3, s. 478-484
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: The synthetic estrogen 17 alpha-ethinyl estradiol (EE), a potent tumor promoter in rat liver, stimulates growth during short-term treatment but inhibits hepatocyte proliferation upon prolonged treatment. To identify the molecular targets of the mitoinhibitory effect of EE, the expression of proteins regulating G(1)- and S-progression were analyzed during the first cell cycle in EE-treated female Wistar rats. Methods: Long-term (60 days) EE treatment. Immunohistochemical staining for proliferation cell nuclear antigen (PCNA) to detect cells in S phase and quantification of mitosis. Western blot to monitor protein expression. Cdk2 kinase assay to examine histone H1 phosphorylation. Results: EE reduced the number of cells in S phase and mitosis by about 70%. Cyclin D-1 and D-3 were unaffected, while cdk4 was moderately decreased. Cyclin E and cdk2 were markedly decreased with concomitant marked reduction of cdk2 kinase activity. EE also decreased cyclin A and increased G(1) levels of p53 and p21. Conclusions: EE causes a cell cycle block before S-phase. The reduction of the cdk2 kinase activity, essential for G(1)/S-transition, might be involved in the cell cycle block. Also, EE treatment results in p53 activation and upregulation of the cdk inhibitor p21 that might contribute to the G(1) arrest.
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- Melum, Espen, et al.
(författare)
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Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma.
- 2007
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Ingår i: Journal of hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 47:6, s. 777-83
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. METHODS: Two hundred and eighty-two HCV patients listed for LTX in the Nordic countries in a 17-year period were included. For comparison a group of patients with non-viral chronic liver disease (n=1552) was used. RESULTS: Two hundred and fifty-three (90%) patients received a first liver allograft. HCC was found in 38% of the explanted livers. Survival at 1, 3 and 5years was 82%, 69% and 61% vs. 85%, 80% and 76% for the comparison group (p<0.0001), this survival difference was also evident when excluding patients with HCC (p=0.007). HCV patients with HCC had 1, 3 and 5year survival of 73%, 52% and 46% compared with 88%, 80% and 71% for the HCV patients without HCC (p=0.0005). In an intention-to-treat analysis (from time of acceptance to the waiting list) HCV was also associated with an impaired survival. CONCLUSIONS: HCV cirrhosis, which is now also an important indication for LTX in the Nordic countries, and significantly impairs survival following LTX. Concomitant HCC and donor age are the two most important factors contributing to an impaired survival.
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- Werner, Mårten, et al.
(författare)
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Hepatic and extrahepatic malignancies in autoimmune hepatitis. A long-term follow-up in 473 Swedish patients
- 2009
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 50:2, s. 388-393
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Autoimmune Hepatitis (AIH) is a liver disease which may lead to liver cirrhosis. Cirrhosis is a well-known risk factor for hepatocellular cancer. Lymphoma is a disease, where immune modulating drugs as well as the autoimmune disease itself may contribute to the elevated risk. The aim was to investigate the risks of malignancies in a large cohort of AIH patients. Methods: Four hundred and seventy-three patients with AIH were matched to the Swedish national cancer register as well as to the death cause register. Results: We found an overall higher risk of malignancies in the cohort of A I H patients from the date of diagnosis with a SIR of 1.51 (95% CI 1.10-2.03). SIR in the subpopulation of well defined catchment areas and complete case finding was 23.28 (95% CI 7.5-54.34) for HCC. Lymphomas were found a SIR of 13.09 (95% CI 4.22-30.56). Conclusions: There was an overall increased risk of malignancies in a cohort of AIH patients, which manly was caused by hepatobiliary cancers. However, the true risk of HCC in an AIH cirrhotic cohort has yet to be investigated. A significantly higher risk of lymphomas was also found, but no clear cut association to the use of immune modulators.
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