Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats
Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats
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DOI：
10.1002/hep.21641
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发表时间：
2007-07-01
期刊：
影响因子：
13.5
通讯作者：
Bensaid, Mohammed
中科院分区：
文献类型：
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作者：
Gary-Bobo, Magali;Elachouri, Ghizlane;Bensaid, Mohammed
本研究调查了大麻素受体1（CB 1）拮抗剂利莫那班（SR 141716）对肥胖相关性肝脂肪变性和代谢综合征相关特征的影响：炎症（肿瘤坏死因子α [TNF α]血浆水平升高）、血脂异常和脂联素血浆水平降低。我们报告，口服治疗肥胖（FA/FA）大鼠与利莫那班（30毫克/公斤），每天8周废除肝脂肪变性。该治疗减轻了肝肿大，降低了肝损伤酶标志物（丙氨酸氨基转移酶、γ-谷氨酰转移酶和碱性磷酸酶）的血浆水平升高，并降低了目前与脂肪性肝炎相关的局部肝TNF α的高水平。同时，用利莫那班治疗肥胖（fa/fa）大鼠降低了促炎细胞因子TNF α的高血浆水平，并增加了抗炎激素脂联素的血浆水平。最后，利莫那班治疗还通过降低甘油三酯、游离脂肪酸和总胆固醇的血浆水平以及增加HDL c/LDL c比值来改善血脂异常。本研究中发现的利莫那班的所有作用在成对喂养的肥胖动物中没有观察到或仅轻微观察到，突出了与饮食相比利莫那班治疗的额外有益作用。这些结果表明，利莫那班发挥了保肝作用，并表明这种CB 1受体拮抗剂可能在治疗肥胖相关的肝脏疾病和代谢综合征的相关特征的临床应用。
This study investigated the effects of rimonabant (SR141716), an antagonist of the cannabinoid receptor type 1 (CB1), on obesity-associated hepatic steatosis and related features of metabolic syndrome: inflammation (elevated plasma levels of tumor necrosis factor alpha [TNF alpha]), dyslipidemia, and reduced plasma levels of adiponectin. We report that oral treatment of obese (fa/fa) rats with rimonabant (30 mg/kg) daily for 8 weeks abolished hepatic steatosis. This treatment reduced hepatomegaly, reduced elevation of plasma levels of enzyme markers of hepatic damage (alanine aminotransferase, gamma glutamyltransferase, and alkaline phosphatase) and decreased the high level of local hepatic TNF alpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNF alpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyshpidemia by both decreasing plasma levels of triglycerides, free fatty acids, and total cholesterol and increasing the HDLc/LDLc ratio. All the effects of rimonabant found in this study were not or only slightly observed in pair-fed obese animals, highlighting the additional beneficial effects of treatment with rimonabant compared to diet. These results demonstrate that rimonabant plays a hepatoprotective role and suggest that this CB1 receptor antagonist potentially has clinical applications in the treatment of obesity-associated liver diseases and related features of metabolic syndrome.