Department of General Surgery, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha 410013, China.
Department of General Surgery, Xiangya Hospital, Central South University, No. 87 Xiangya Road, Changsha 410008, China.
Biomed Res Int. 2018 Feb 18;2018:8071093. doi: 10.1155/2018/8071093. eCollection 2018.
Abnormal metabolism of cholesterol may be a contributing factor in nonalcoholic steatohepatitis (NASH) pathogenesis. Accumulating evidence has shown that liver X receptor (LXR) is closely related to intrahepatic inflammation and fibrosis. In this study, we evaluated the effects of a novel liver-specific LXR inverse agonist, SR9243, on antifibrosis in NASH mice. A high-cholesterol diet was employed to induce NASH in BALB/c mice by either carbon tetrachloride (CCL4) administration or bile-duct ligation (BDL). Once NASH was induced, mice were treated with SR9243 for one month by intraperitoneal (i.p.) injection. Liver tissues were collected to determine the degree of fibrosis and intrahepatic inflammation via pathological examination and QPCR; serum was collected to analyze the plasma lipid levels and liver function by clinical biochemistry. The mice developed hepatic steatosis, severe hepatic inflammation, and fibrosis by BDL or CCL4. Treatment with SR9243 significantly reduced the severity of hepatic inflammation and ameliorated hepatic fibrosis; simultaneously, body weight, serum glucose, and plasma lipid levels were controlled effectively. Our data demonstrate that SR9243 exerts an antifibrotic and anti-inflammatory effect in NASH mice; hence these findings highly suggest that LXR inverse agonist could be therapeutically important in NASH treatment.
胆固醇代谢异常可能是非酒精性脂肪性肝炎（NASH）发病机制中的一个促成因素。越来越多的证据表明，肝 X 受体（LXR）与肝内炎症和纤维化密切相关。在这项研究中，我们评估了新型肝特异性 LXR 反向激动剂 SR9243 在 NASH 小鼠抗纤维化中的作用。采用高胆固醇饮食，通过四氯化碳（CCl4）给药或胆管结扎（BDL）在 BALB/c 小鼠中诱导 NASH。一旦诱导出 NASH，通过腹腔内（i.p.）注射用 SR9243 对小鼠进行为期一个月的治疗。收集肝组织，通过病理检查和 QPCR 确定纤维化和肝内炎症的程度；收集血清，通过临床生化分析血浆脂质水平和肝功能。BDL 或 CCl4 导致小鼠发生肝脂肪变性、严重肝炎症和纤维化。SR9243 治疗可显著减轻肝炎症的严重程度，并改善肝纤维化；同时，有效控制体重、血清葡萄糖和血浆脂质水平。我们的数据表明，SR9243 在 NASH 小鼠中具有抗纤维化和抗炎作用；因此，这些发现强烈表明 LXR 反向激动剂在 NASH 治疗中可能具有重要的治疗意义。
