Role of oxidative stress in the development of mild portal endotoxemia-induced chronic hepatic inflammation and impairment of pancreatic insulin secretion

• Main Authors: Yu-Ting Chen, 陳育廷
• Other Authors: 謝博軒
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/11640773136953732044

碩士 === 國防醫學院 === 生理學研究所 === 96 === Portal endotoxemia has been considered as a key pathogenic factor in chronic hepatic inflammation, which have shown to highly associate with metabolic syndrome and type 2 diabetes. Our previous study demonstrated that low-dose intraportal endotoxin infusion could induce chronic hepatic inflammation and impair endocrine pancreatic function. This study was to further test the role of oxidative stress in the pathogenesis of the portal endotoxemia-induced damages in liver and pancreas. from normal rats and fructose-induced insulin resistant rats with fatty liver. Chronic portal infusion was performed under the status of normal and fatty liver condition with portal catheterization connected to lipopolysaccharide (LPS, 0.42 ng/kg/min) or saline-filled osmotic mini-pump for 4 weeks. The rats with intraportal LPS infusion were further divided into two subgroups combined with or without α-Lipoic acid treatment (60 mg/kg/day, P.O.). Our results showed that mild portal endotoxemia created by low-dose intraportal LPS infusion induced subacute hepatic and pancreatic inflammation indicated by the increases in tissue contents of TNF-alpha, IL-6 and superoxide both in normal and fructose-fed rats. Portal LPS infusion significantly attenuated glucose-stimulated insulin secretion shown in hyperglycermic clamp study, but increased plasma amylase, CRP, superoxide levels and WBC count in normal rats. α-Lipoic acid administration significantly alleviated the portal endotoxemia -induced pathological changes in liver and pancreas by histological examination. α-Lipoic acid also reduced plasma amylase, CRP and superoxide production in normal rats with portal LPS infusion. Fructose-induced attenuation in insulin-stimulated glucose uptake was further deteriorated in those with portal LPS infusion and was partially reversed in those LPS-treated rats with α-Lipoic acid administration. Fructose-induced increases in plasma amylase, CRP, superoxide, and WBC counts were further deteriorated in those with LPS treatment. α- Lipoic acid significantly attenuated the detrimental effects of portal endotoxemia on the above-mentioned parameters in fructose-fed rats. These results showed that α-Lipoic acid effectively attenuated portal endotoxemia-induced hepatic inflammation and pancreatic insulin secretion, implicating that augmentation of oxidative stress is crucial for the detrimental effects of chronic portal endotoxemia on liver and pancreas in normal rats and fructose-fed rats, an animal model of metabolic syndrome with fatty liver.