非酒精性脂肪性肝病的发病机制和动物模型课件.pptx

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1、LuXiaozhao,Pathogenesis of NAFLD:Animal Models,非酒精性脂肪性肝病（nonalcoholic fatty liver disease，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，NASH 2-3%，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（hepatocellular steatosis）（单纯性脂肪肝）脂肪性肝炎（nonalcoholic steatohepat

2、itis，NASH）肝纤维化（fibrosis）肝硬化（cirrhosis）,NAFLD的自然病程,胰岛素抵抗（Insulin resistance）糖耐量异常糖尿病（Glucose intolerance or diabetes）中心性肥胖（Central obesity）高血压（Hypertension）血脂异常（Dyslipidaemia）肝细胞癌（hepatocellular carcinoma）,NAFLD伴随相关疾病,The first hit脂质积累，脂肪变性（Steatosis）,NAFLD发病机制一：The 2-hit hypothesis,The second hitinf

3、lammatorycytokinesadipokines,mitochondrial dysfunctionoxidative stress,NAFLD发病机制一：The 2-hit hypothesis,The key role of free fatty acids(FFA),NAFLD发病机制一：The 2-hit hypothesis,The third hit（a central feature of NAFLD pathogenesis）inadequate hepatocyte proliferation,NAFLD发病机制一：The 2-hit hypothesis,NAFLD

4、肝脏中FFAs来源：lipolysis of adipose tissue（60%）dietary sources（15%）de novo lipogenesis（25%）NAFLD肝脏中FFAs的去向：-oxidation triglycerides（lipid droplets）VLDL,NAFLD发病机制二：Lipid accumulation/steatosis,NAFLD发病机制二：Lipid accumulation/steatosis,NAFLD发病机制三：Insulin resistance,NAFLD发病机制三：Insulin resistance,Insulin resis

5、tance,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,Insulin resistance,NAFLD发病机制四：Inflammation/steatohepatitis,Inflammatory cytokines and FFA,HFD induced steatosis(murine models),NF-kB,FFAs,TNF-IL-6IL-1,NAFLD,Ins

6、ulin resistance,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，Leptin resistance,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,Oxidative stress and mitochondrial dysfunction,NAFLD,FFAs overload,ROS,oxidative st

7、ress,Activation of inflammatory pathways,Mitochondrial damage,NAFLD发病机制四：Inflammation/steatohepatitis,ER stress and bacterial overgrowth,ER stress,Hyperinsulinaemia hyperlipidaemia,IRinflammation apoptosis Mitochondrial dysfunction,Small intestinal bacterial overgrowth,lipopolysaccharides,inflammation,