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为了探讨NF-κB诱导激酶(NIK)诱导非酒精性脂肪肝(NAFLD)的分子机制,选用ob/ob雄性小鼠作为NAFLD模型,在ob/ob小鼠肝脏表达NIK失活突变体(NIKKA),抑制内源性NIK活性.在正常小鼠肝脏过表达NIK,升高肝脏NIK活性.测定小鼠肝脏甘油三酯(TG)水平和原代肝细胞脂肪酸β-氧化速度;RT-PCR试验方法测定脂肪酸β-氧化关键基因CPT-1α mRNA水平;Western Blot和Luciferase检测过氧化物酶体增生物激活受体α(PPARα)蛋白的水平和活性.结果显示:NIKKA下调ob/ob小鼠肝脏TG水平,过表达NIK显著增加正常小鼠肝脏中TG水平;NIK抑制肝脏游离脂肪酸β-氧化,并抑制氧化关键酶肉毒碱棕榈酰转移酶-1α(CPT-1α)的表达;NIK激活NF-κB1 (p50/p65)、NF-κB2 (p52/RelB),后两者竞争性抑制PPARα,降低其对CPT-1α的转录.NIK通过下调PPARα的转录活性,抑制肝脏脂肪酸氧化,进而促进NAFLD的发展.“,”In order to explore the molecular mechanism of NF-κB inducing kinase (NF-κB inducing kinase,NIK)in the development of nonalcoholic fatty liver disease (Nonalcoholic fatty liver disease,NAFLD),ob/ob male mice were selected as NAFLD model.Dominant negative mutation of NIK (NIKKA) was expressed in ob/ob mice liver to inhibit endogenous NIK activity and NIK was overexpressed in normal mice liver to enhance hepatic NIK activity.The level of liver triglyceride (Triglyceride,TG) and β-oxidation rate of primary hepatocytes were measured.The mRNA level of carnitine palmitoyl transferase-1α (Carnitine palmitoyl transferase-1α,CPT-1α),as key gene in fatty acid β-oxidation,was detected by RT-PCR.Western Blot and Luciferase were applied to detect the level and activity of PPARα (peroxisome proliferator-activated receptor α,PPARα).The results indicated that NIKKA down regulated liver TG level in ob/ob mice (P ＜0.05),while overexpressed NIK prominently increased the TG level in normal mice (P ＜ 0.05).NIK inhibited liver fatty acid β-oxidation (P ＜ 0.05)and the expression of CPT-1α as oxidation key enzyme (P ＜ 0.05).NIK activated NF-κB1 (p50/p65) and NF-κB2 (p52/RelB) which inhibited PPARα by competitive inhibition (P ＜ 0.05) as well as lowering the transcription of CPT-1α.NIK inhibited liver fatty acid oxidation through down regulating the transcriptional activity of PPARα,so as to promote the development of NAFLD.