The metabolic disorders that predispose patients to NASH (non-alcoholic steatohepatitis) include insulin resistance and obesity. Repeated hypoxic events, such as occur in obstructive sleep apnoea syndrome, have been designated as a risk factor in the progression of liver disease in such patients, but the mechanism is unclear, in particular the role of hypoxia. Therefore we studied the influence of hypoxia on the development and progression of steatohepatitis in an experimental mouse model. Mice with a hepatocellular-specific deficiency in the Pten (phosphatase and tensin homologue deleted on chromosome 10) gene, a tumour suppressor, were exposed to a 10% O2 (hypoxic) or 21% O2 (control) atmosphere for 7 days. Haematocrit, AST (aspartate aminotransferase), glucose, triacylglycerols (triglycerides) and insulin tolerance were measured in blood. Histological lesions were quantified. Expression of genes involved in lipogenesis and mitochondrial β-oxidation, as well as FOXO1 (forkhead box O1), hepcidin and CYP2E1 (cytochrome P450 2E1), were analysed by quantitative PCR. In the animals exposed to hypoxia, the haematocrit increased (60±3% compared with 50±2% in controls; P<0.01) and the ratio of liver weight/body weight increased (5.4±0.2% compared with 4.7±0.3% in the controls; P<0.01). Furthermore, in animals exposed to hypoxia, steatosis was more pronounced (P<0.01), and the NAS [NAFLD (non-alcoholic fatty liver disease) activity score] (8.3±2.4 compared with 2.3±10.7 in controls; P<0.01), serum AST, triacylglycerols and glucose were higher. Insulin sensitivity decreased in mice exposed to hypoxia relative to controls. The expression of the lipogenic genes SREBP-1c (sterol-regulatory-element-binding protein-1c), PPAR-γ (peroxisome-proliferator-activated receptor-γ), ACC1 (acetyl-CoA carboxylase 1) and ACC2 (acetyl-CoA carboxylase 2) increased significantly in mice exposed to hypoxia, whereas mitochondria β-oxidation genes [PPAR-α (peroxisome-proliferator-activated receptor-α) and CPT-1 (carnitine palmitoyltransferase-1)] decreased significantly. In conclusion, the findings of the present study demonstrate that hypoxia alone aggravates and accelerates the progression of NASH by up-regulating the expression of lipogenic genes, by down-regulating genes involved in lipid metabolism and by decreasing insulin sensitivity.
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December 14 2009
Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN
Anne-Christine Piguet;
*Institute of Clinical Pharmacology and Visceral Research, University of Bern, CH-3010 Bern, Switzerland
Correspondence: Dr Anne-Christine Piguet (email [email protected]).
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Deborah Stroka;
Deborah Stroka
*Institute of Clinical Pharmacology and Visceral Research, University of Bern, CH-3010 Bern, Switzerland
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Arthur Zimmermann;
Arthur Zimmermann
†Institute of Pathology, University of Berne, CH-3010 Berne, Switzerland
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Jean-François Dufour
Jean-François Dufour
*Institute of Clinical Pharmacology and Visceral Research, University of Bern, CH-3010 Bern, Switzerland
‡Department of Visceral Surgery and Medicine, University of Berne, CH-3010 Berne, Switzerland
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Publisher: Portland Press Ltd
Received:
June 05 2009
Revision Received:
September 24 2009
Accepted:
October 15 2009
Accepted Manuscript online:
October 15 2009
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 118 (6): 401–410.
Article history
Received:
June 05 2009
Revision Received:
September 24 2009
Accepted:
October 15 2009
Accepted Manuscript online:
October 15 2009
Citation
Anne-Christine Piguet, Deborah Stroka, Arthur Zimmermann, Jean-François Dufour; Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN. Clin Sci (Lond) 1 March 2010; 118 (6): 401–410. doi: https://doi.org/10.1042/CS20090313
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