1、LuXiaozhao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%。我国我国 仅次于病毒性肝炎的第二大慢性肝病。 肝细胞脂肪变性(hepatocellular steatosis)(单纯性脂肪肝)脂肪性肝炎(nonalcoholic steatohepatitis,NASH)肝纤维化(fibrosis)肝硬化(cirrhosi
2、s)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)The first hit脂质积累,脂肪变性(Steatosis) The second hitinflammatorycytokinesadipokines, mitochondrial dysfunctionoxidative stress The key role of free
3、fatty acids (FFA)The third hit(a central feature of NAFLD pathogenesis) inadequate hepatocyte proliferationNAFLD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) VLDLInsulin resistanceLipolysis增加SREBP-1
4、c上调FFAs合成增加脂肪来源的FFAs增多-oxidation减少FFAs分解减少NAFLDNAFLDFFAsTNF-aNF-kBJNK1SOCSCYP2E1DAG抑制insulin受体活性抑制IRS磷酸化级联Insulin resistanceInflammatory cytokines and FFAHFD induced steatosis(murine models)NF-kBFFAsTNF-IL-6IL-1NAFLDInsulin resistanceAdipokinesLeptin:抑制抑制食欲,增加能量分解代谢,抑制脂肪合成食欲,增加能量分解代谢,抑制脂肪合成增加炎症增加炎症促
5、进纤维化促进纤维化肥胖和肥胖和NAFLD患者血清中水平上调,患者血清中水平上调,Leptin resistanceAdiponectin:抗炎抗炎增加胰岛素敏感性增加胰岛素敏感性肥胖肥胖和和NAFLD患者中患者中水平下调水平下调Oxidative stress and mitochondrial dysfunctionNAFLDFFAs overloadROSoxidative stressActivation of inflammatory pathwaysMitochondrial damageER stress and bacterial overgrowthER stressHyperinsulinaemia hyperlipidaemiaIRinflammation apoptosis Mitochondrial dysfunctionSmall intestinal bacterial overgrowthlipopolysaccharidesinflammation