Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN
Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN
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DOI：
10.1042/cs20090313
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发表时间：
2010-03-01
期刊：
影响因子：
6
通讯作者：
Dufour, Jean-Francois
中科院分区：
文献类型：
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作者：
Piguet, Anne-Christine;Stroka, Deborah;Dufour, Jean-Francois
使患者容易患NASH（非酒精性脂肪性肝炎）的代谢性疾病包括胰岛素抵抗和肥胖。反复缺氧事件，如阻塞性睡眠呼吸暂停综合征中发生的缺氧事件，已被指定为此类患者肝脏疾病进展的危险因素，但其机制尚不清楚，特别是缺氧的作用。因此，我们在实验小鼠模型中研究了缺氧对脂肪性肝炎发生和发展的影响。将具有Pten（染色体10上缺失的磷酸酶和张力蛋白同源物）基因（肿瘤抑制剂）中的肝细胞特异性缺陷的小鼠暴露于10%O2（缺氧）或21%O2（对照）气氛中7天。测量血液中的红细胞压积、AST（天冬氨酸转氨酶）、葡萄糖、三酰甘油（甘油三酯）和胰岛素耐受性。定量组织学病变。通过定量PCR分析参与脂肪生成和线粒体β-氧化的基因以及FOXO 1（叉头框O 1）、hepcidin和CYP 2 EI（细胞色素P450 2 EI）的表达。在暴露于缺氧的动物中，红细胞压积增加（60 +/-3%，而对照组为50 +/-2%; P < 0.01），肝脏重量/体重比增加（5.4 +/-0.2%，而对照组为4.7 +/-0.3%; P < 0.01）。此外，在暴露于缺氧的动物中，脂肪变性更明显（P < 0.01），NAS [NAFLD（非酒精性脂肪性肝病）活动评分]（8.3 +/- 2.4与对照组的2.3 +/- 10.7; P < 0.01），血清AST，三酰甘油和葡萄糖更高。与对照组相比，暴露于缺氧的小鼠胰岛素敏感性降低。脂肪生成基因SREBP-1c的表达（固醇调节元件结合蛋白-1c），PPAR-gamma（过氧化物酶体增殖物激活受体-γ），ACC 1（乙酰辅酶A羧化酶1）和ACC 2（乙酰辅酶A羧化酶2）在暴露于缺氧的小鼠中显著增加，而线粒体β-氧化基因[PPAR-alpha（过氧化物酶体增殖物激活受体-α）和CPT-I（肉毒碱棕榈酰转移酶-1）]显著降低。总之，本研究的结果表明，缺氧单独通过上调生脂基因的表达、下调参与脂质代谢的基因和降低胰岛素敏感性来加剧和加速NASH的进展。
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 % 02 (hypoxic) or 21 % 02 (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 beta-oxidation, as well as FOXO1 (forkhead box O1), hepcidin and CYP2EI (cytochrome P450 2EI), 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-gamma (peroxisome-proliferator-activated receptor-gamma), ACC1 (acetyl-CoA carboxylase 1) and ACC2 (acetyl-CoA carboxylase 2) increased significantly in mice exposed to hypoxia, whereas mitochondria beta-oxidation genes [PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and CPT-I (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.