非酒精性脂肪性肝病的发病机制和动物模型课件

LuXiaozhao PathogenesisofNAFLD AnimalModels 非酒精性脂肪性肝病 nonalcoholicfattyliverdisease NAFLD 一系列除外酒精和其他明确损肝因素所致的 以肝实质细胞脂肪堆积为主要特征的疾病 西方国家人群发病率 成人20 30 肥胖人群90 其中 NASH2 3 肥胖人群37 儿童3 肥胖儿童57 我国仅次于病毒性肝炎的第二大慢性肝病 NAFLD流行病学 肝细胞脂肪变性 hepatocellularsteatosis 单纯性脂肪肝 脂肪性肝炎 nonalcoholicsteatohepatitis NASH 肝纤维化 fibrosis 肝硬化 cirrhosis NAFLD的自然病程 胰岛素抵抗 Insulinresistance 糖耐量异常 糖尿病 Glucoseintoleranceordiabetes 中心性肥胖 Centralobesity 高血压 Hypertension 血脂异常 Dyslipidaemia 肝细胞癌 hepatocellularcarcinoma NAFLD伴随 相关疾病 The firsthit 脂质积累 脂肪变性 Steatosis NAFLD发病机制一 The 2 hithypothesis The secondhit inflammatorycytokinesadipokines mitochondrialdysfunctionoxidativestress NAFLD发病机制一 The 2 hithypothesis NAFLD肝脏中FFAs来源 lipolysisofadiposetissue 60 dietarysources 15 denovolipogenesis 25 NAFLD肝脏中FFAs的去向 oxidationtriglycerides lipiddroplets VLDL NAFLD发病机制二 Lipidaccumulation steatosis NAFLD发病机制二 Lipidaccumulation steatosis NAFLD发病机制三 Insulinresistance NAFLD发病机制三 Insulinresistance Insulinresistance Lipolysis增加 SREBP 1c上调 FFAs合成增加 脂肪来源的FFAs增多 oxidation减少 FFAs分解减少 NAFLD NAFLD FFAsTNF aNF kBJNK1SOCSCYP2E1DAG 抑制insulin受体活性抑制IRS磷酸化级联 Insulinresistance NAFLD发病机制四 Inflammation steatohepatitis InflammatorycytokinesandFFA HFDinducedsteatosis murinemodels NF kB FFAs TNF IL 6IL 1 NAFLD Insulinresistance NAFLD发病机制四 Inflammation steatohepatitis Adipokines Leptin 抑制食欲 增加能量分解代谢 抑制脂肪合成增加炎症促进纤维化肥胖和NAFLD患者血清中水平上调 Leptinresistance Adiponectin 抗炎增加胰岛素敏感性肥胖和NAFLD患者中水平下调 NAFLD发病机制四 Inflammation steatohepatitis Oxidativestressandmitochondrialdysfunction NAFLD FFAsoverload ROS oxidativestress Activationofinflammatorypathways Mitochondrialdamage NAFLD发病机制四 Inflammation steatohepatitis ERstressandbacterialovergrowth ERstress Hyperinsulinaemiahyperlipidaemia IRinflammationapoptosisMi