脂肪组织靶向11β-HSD1抑制剂治疗非酒精性脂肪肝的作用机制研究

As the increase of prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become an important disease. Visceral obesity, insulin resistance in fat tissue has been reported as the leading cause for NAFLD. It is reported that increased activity of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in fat tissue contributes to NAFLD in multiple roles: not only lead to visceral obesity, change of fat functions, and increased free fatty acids and cytokines to the liver, but also elevated levels of liver glucocorticoid (GC) through the portal system which further promotes the formation of NAFLD. Our previous studies have found that adipose tissue targeted 11β-HSD1 inhibitors can reduce the visceral obesity, at the same time, it can increase hepatic lipid oxidation and improve lipid metabolism. Therefore, inhibition of adipose tissue 11β-HSD1 activity may be a new target for treatment of NAFLD. This proposal provides an innovative way with adipose tissue targeted inhibition of 11β-HSD1 in NAFLD mouse model. We will study the effect of inhibition of the activity of 11β-HSD1 in adipose tissue to liver glucose, lipid metabolism and hepatic insulin resistance. This study will further elucidate the molecular mechanisms through which visceral obesity lead to NAFLD and provide a new strategy for the treatment of NAFLD.

随着生活水平的提高、肥胖的增加，非酒精性脂肪肝(NAFLD)已成为危害人类健康的重要疾病，而内脏性肥胖对NAFLD的发生和发展起关键作用。研究发现脂肪组织11β-羟化类固醇脱氢酶1(11β-HSD1)活性增强对NAFLD具有多重作用：不仅导致内脏性肥胖，引起脂肪功能改变，使游离脂肪酸、炎症因子释放到肝脏增加，引起NAFLD，还通过门脉系统使肝脏糖皮质激素(GC)水平升高，进一步促进脂肪肝形成。我们前期研究已发现脂肪组织靶向11β-HSD1抑制剂在减轻内脏肥胖同时，还能增加肝脏脂质氧化、改善脂代谢，因此，抑制脂肪组织11β-HSD1活性可能是治疗NAFLD的新靶点。本课题创新性地通过靶向抑制脂肪组织11β-HSD1的NAFLD小鼠模型，研究脂肪组织11β-HSD1活性变化对肝脏糖、脂代谢及肝胰岛素抵抗的影响，进一步阐明内脏肥胖引发NAFLD的分子机制，为治疗NAFLD提供新的策略。

随着生活水平的提高、肥胖的增加，非酒精性脂肪肝(NAFLD)已成为危害人类健康的重要疾病，而内脏性肥胖对NAFLD 的发生和发展起关键作用。研究发现脂肪组织11β-羟化类固醇脱氢酶1(11β-HSD1)活性增强对NAFLD 具有多重作用：不仅导致内脏性肥胖，引起脂肪功能改变，使游离脂肪酸、炎症因子释放到肝脏增加，引起NAFLD，还通过门脉系统使肝脏糖皮质激素(GC)水平升高，进一步促进脂肪肝形成。. 本课题以11β-HSD1作为靶点，研究了11β-HSD1特异性抑制剂BVT.2733对肥胖和炎症的影响。发现11β-HSD1 抑制剂可以减轻肥胖小鼠的体重，改善脂肪组织炎症；发现11β-HSD1抑制剂能够显著促进肥胖小鼠的棕色脂肪的功能基因表达。我们进一步的研究揭示在体外糖皮质激素能够显著抑制棕色脂肪功能，相反，BVT.2733能够抑制糖皮质激素的作用，从而促进棕色脂肪的功能。另一方面，我们通过研究MLCK和MYPT1在肠粘膜屏障功能中的调节作用，来研究肠黏膜屏障功能对非酒精性脂肪性肝的影响。这部分研究正在进行中。.