Gary-Bobo Magali, Elachouri Ghizlane, Gallas Jean François, Janiak Philip, Marini Pietro, Ravinet-Trillou Christine, Chabbert Michèle, Cruccioli Noël, Pfersdorff Christian, Roque Claude, Arnone Michèle, Croci Tiziano, Soubrié Philippe, Oury-Donat Florence, Maffrand Jean Pierre, Scatton Bernard, Lacheretz Frederic, Le Fur Gérard, Herbert Jean Marc, Bensaid Mohammed
Sanofi-Aventis Recherche & Développement, Discovery Research CNS Department, Montpellier, France.
Hepatology. 2007 Jul;46(1):122-9. doi: 10.1002/hep.21641.
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 [TNFalpha]), 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 TNFalpha currently associated with steatohepatitis. In parallel, treatment of obese (fa/fa) rats with rimonabant reduced the high plasma level of the proinflammatory cytokine TNFalpha and increased the reduced plasma level of the anti-inflammatory hormone adiponectin. Finally, rimonabant treatment also improved dyslipidemia 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.
本研究调查了大麻素1型受体（CB1）拮抗剂利莫那班（SR141716）对肥胖相关的肝脂肪变性以及代谢综合征相关特征的影响：炎症（肿瘤坏死因子α[TNFα]血浆水平升高）、血脂异常以及脂联素血浆水平降低。我们报告称，对肥胖（fa/fa）大鼠每日口服利莫那班（30 mg/kg），持续8周，可消除肝脂肪变性。这种治疗减少了肝脏肿大，降低了肝损伤酶标志物（丙氨酸转氨酶、γ-谷氨酰转移酶和碱性磷酸酶）血浆水平的升高，并降低了目前与脂肪性肝炎相关的肝脏局部高水平TNFα。同时，用利莫那班治疗肥胖（fa/fa）大鼠可降低促炎细胞因子TNFα的高血浆水平，并提高抗炎激素脂联素降低的血浆水平。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提高HDLc/LDLc比值改善了血脂异常。在本研究中发现的利莫那班的所有作用在配对喂养的肥胖动物中未观察到或仅轻微观察到，这突出了与饮食相比，利莫那班治疗的额外有益效果。这些结果表明利莫那班具有肝脏保护作用，并表明这种CB1受体拮抗剂在治疗肥胖相关肝病和代谢综合征相关特征方面可能具有临床应用价值。
