罗格列酮对老年胰岛素抵抗大鼠肝脏脂肪酸代谢及胰岛素敏感性的影响

目的 研究罗格列酮对老年胰岛素抵抗(insulin resistance,IR)大鼠肝脏脂肪酸代谢及胰岛素敏感性的影响.方法 22～24月龄雄性Wistar大鼠随机分为老年对照组(OC组)和高脂喂养组.OC组喂饲基础饲料,高脂喂养组喂饲高脂饲料.喂养至第4周末行高胰岛素-正葡萄糖钳夹实验评价高脂喂养组IR状态.判断造模成功后将高脂喂养组随机分为高脂(HF)组和罗格列酮干预(RSG)组.两组除继续喂以高脂饲料外,RSG组予罗格列酮3 mg·kg-1·d-1灌胃,HF组予等体积生理盐水灌胃,继续喂养4 w.实验第8周末,再次行钳夹实验评价各组大鼠胰岛素敏感性;肝脏甘油三酯经氯仿/甲醇抽提后用全自动生化分析仪测定.结果 分组喂养4时,钳夹实验发现高脂喂养组葡萄糖输注率(glucose infusion rates,GIR)低于OC组(P＜0.05),说明高脂喂养组IR模型诱导成功.继续喂养4 w后,HF组GIR进一步下降(P＜0.01),而RSG组GIR与HF组比较明显提高(P＜0.05).与OC组相比,HF组空腹血糖(FBG)、胰岛素(FINS)、游离脂肪酸(FFA)、血清甘油三酯(TG)和总胆固醇(TC)水平升高,而RSG组这些指标较HF组下降(P＜0.01或P＜0.05).肝脏TG含量在HF组高于OC组,RSG组低于HF组;肝脏TG含量与GIR呈负相关,与空腹血糖呈正相关.结论 高脂饮食导致老年大鼠肝脏脂质积聚及IR;罗格列酮干预可改善老年IR大鼠血浆脂代谢异常,降低肝脏脂质含量,提高胰岛素敏感性.     

罗格列酮对老年胰岛素抵抗大鼠肝脏腺苷酸活化蛋白激酶α表达及活性的影响

目的 探讨罗格列酮(RGZ)对老年胰岛素抵抗(IR)大鼠肝脏脂肪酸代谢和腺苷酸活化蛋白激酶(AMPK)α表达及活性的影响. 方法 22～24月龄雄性Wistar大鼠随机分为老年对照(OC)组和高脂喂养组.4周后高脂喂养组IR状态形成,再随机分为高脂(HF)组和RGZ干预(RGZ)组,RGZ组予RGZ 3mg·kg~(-1)·d~(-1)灌胃,继续喂养4周.测定肝脏TG和AMPKα1、AMPKα2 mRNA表达,以及AMPKα1、AMPKα2、p-AMPKα蛋白表达. 结果 (1)HF组FPG、FIns、FFA、TC和TG高于OC组;而RGZ干预后这些指标均下降;葡萄糖输注率HF组低于OC组,RGZ组高于HF组(P<0.05或P<0.01).(2)肝脏TG HF组高于OC组,RGZ组低于HF组(P<0.01).(3)肝脏AMPKα1、AMPKα2mRNA表达和蛋白表达三组问无统计学差异(P>0.05);肝脏P-AMPKα蛋白表达HF组低于OC组,RGZ组高于HF组(P<0.05或P<0.01). 结论 高脂饮食导致老年大鼠肝脏脂肪酸代谢异常及IR;RGZ干预后AMPKα活性增加和肝脏脂质堆积减少,IR改善.     

2型糖尿病大鼠胰岛素抵抗与视黄醇结合蛋白4的相关性

目的 观察高糖高脂膳食加小剂量链脲佐菌素腹腔注射诱导的2型糖尿病(T2DM)大鼠的血清视黄醇结合蛋白4(RBP4)的变化,探讨胰岛素抵抗(IR)与RBP4的关系.方法 将30只健康SD雄性大鼠随机分为正常对照组15只,模型组15只,喂养8w后,模型组予小剂量链脲佐菌素腹腔注射,建立T2DM大鼠IR模型,造模成功后继续喂养4w.实验结束时检测两组大鼠空腹血糖(FBG)、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、空腹胰岛素水平(FINS)和血清RBP4水平,计算胰岛素敏感指数(ISI)和胰岛素抵抗指数(HOMA-IR).结果 ①模型组大鼠体重在前8 w呈更明显的持续增加,第9周模型组大鼠体重开始下降,至第12周末明显低于正常对照组;②模型组大鼠血清RBP4、FBG、FINS、TG、TC、LDL-C、HOMA-IR高于正常对照组,ISI则显著降低;③模型组大鼠血清RBP4与FBG、FINS、TG、TC、LDL-C、HOMA-IR呈正相关,与ISI呈负相关;HOMA-IR是血清RBP4的独立的影响因素.结论 RBP4参与了T2DM的IR发生发展.     

有氧运动联合KGM对高脂膳食大鼠胰岛素抵抗形成中肝脏Adiponectin/PPARα通路的影响

目的探讨胰岛素抵抗(IR)形成及其运动和KGM干预的机制。方法将6周龄50只雄性SD大鼠随机分为五组:对照组(C组)、高脂饮食组(HF组)、高脂饮食+运动组(HE组)、高脂饮食+葡甘聚糖组(HK组)、高脂饮食+运动训练+葡甘聚糖组(HEK级)。同时将HE、HK、HEK分别进行11 w无负重游泳训练。11 w后测定大鼠空腹血糖(FPG)、空腹胰岛素(FINS)、肝脏胆固醇(TC)、甘油三酯(TG)、脂联素(APN)、APN受体2(AdipoR2)、过氧化物增殖物激活受体α(PPARα)的蛋白含量。结果①HF组大鼠与C组相比,FPG、FINS含量以及胰岛素抵抗指数(HOMAIR)显著升高。②有氧运动和(或)KGM可以降低高脂膳食大鼠FPG水平、FINS以及HOMA-IR,并能显著降低肝脏中TG和TC含量。③与C组相比,HF组大鼠肝脏APN、PPARa含量显著降低,而HF组肝脏AdipoR2含量却升高,而通过双因素方差分析可知,有氧运动和(或)KGM可以显著增加肝脏APN含量和PPARα含量,降低肝脏AdipoR2含量。结论①11 w的高脂饮食可以诱导大鼠IR的形成,而高脂膳食引起的血脂代谢紊乱可能是引起IR产生的重要原因。②有氧运动或补充KGM可能通过改善高脂膳食大鼠肝脏Adiponectin/PPARα信号通路来调节血脂代谢,从而有效预防高脂膳食大鼠IR的形成。同时,有氧运动联合补充KGM对改善高脂大鼠肝脏Adiponectin/PPARα具有交互作用。     

大黄酸上调糖尿病大鼠脂肪组织PPAR-γ及GluT-4表达并改善胰岛素敏感性

目的探讨大黄酸改善糖尿病大鼠脂肪组织胰岛素敏感性及降血糖的作用机制。方法雄性Wistar大鼠随机分为对照组（NC，n=15）及糖尿病造模组（DM，n=40），DM组成模后随机分为糖尿病模型组（DM—C，n=15）和糖尿病大黄酸治疗组（DM—T，n=15）。DM—T组予大黄酸100mg·kg^-1·d^-1灌胃11周。实验末检测各组大鼠FBG、FIns、TG、TC、胰岛素敏感指数（ISI）、过氧化物酶体增殖物激活受体7（PPAR-γ）及葡萄糖转运蛋白4（GluT-4）在脂肪组织的表达水平。结果17周末DM—C组较NC组FBG、TG明显升高，ISI明显降低，脂肪组织PPAR-γ及GluT-4蛋白表达明显降低；DM—T组较DM—C组FBG明显降低；ISI明显升高；脂肪组织PPAR-γ蛋白表达明显升高，积分光密度有统计学差异；GluT-4蛋白表达明显升高，积分密度（ID）有统计学差异。结论大黄酸可上调糖尿病大鼠脂肪组织PPAR-γ及GluT-4蛋白表达，降血糖并改善胰岛素敏感性。     

高脂饲养大鼠脂代谢调控基因的表达与胰岛素抵抗的关系及机制

目的探讨高脂饲养SD大鼠脂代谢基因表达的改变与胰岛素抵抗（IR）的关系。方法8周龄雄性SD大鼠随机分为3组：正常饲养组（NC,10只）、高脂饲养组（HF,10只）、高脂饲养＋吡格列酮15mg·kg^-1·d^-1进行灌胃组（HP,12只）。饲养20周时测定血清、肝脏及肌肉组织中TG含量,3组均行正常血糖高胰岛素钳夹试验,并用实时定量PCR方法分析脂肪、肝脏和肌肉中脂代谢调控基因mRNA表达的变化。结果饲养20周时,与NC组比较,HF组血清TG增加45．0％（P〈0．01）,肝脏和肌肉TG含量增加2．28倍和9．31倍（P〈0．01）;HF组葡萄糖的输注率（GIR）下降61％（P〈0．01）,存在明显的IR;脂肪组织脂肪酸合成酶、激素敏感酯酶表达分别增高21．3％、28．2％（P〈0．05）;肝脏乙酰辅酶A羧化酶表达增高48．3％（P〈0．05）、肉毒碱脂酰转移酶1（CPT-1）表达呈增高趋势（P〉0．05）;肌肉乙酰辅酶A羧化酶表达增加101．1％、CPT-1表达减少71．0％（P〈0．01）。HP组与HF组比较,血TG、肝脏TG、肌肉TG分别下降66．0％、64．5％及59．6％,GIR增加1．54倍,脂代谢基因的表达也发生了明显的改变。结论高脂饲养可引起sD大鼠肝脏和肌肉组织脂肪异位沉积及IR,吡格列酮干预可以改善,可能与脂代谢调控基因的改变有关。     

高饱合脂肪酸饮食下调大鼠肝脏和脂肪胰岛素信号通路的基因表达

目的检测高饱和脂肪酸饮食诱导胰岛素抵抗大鼠肝脏和脂肪胰岛素信号表达改变,探讨高脂肪酸饮食诱导胰岛素抵抗的发病机制。方法将大鼠分为普通饲料对照组(N组)和饱和脂肪酸组(S组);酶免法测定血中胰岛素水平,IGTT实验确定胰岛素抵抗形成,计算胰岛素抵抗指数(IRS)实时PCR检测肝脏和脂肪组织IRS-1,PI3K,Akt,GLUT4基因表达改变。结果相同条件喂养,饱和脂肪酸饮食和普通饲料对大鼠体重和空腹血糖无明显差异;饱和脂肪酸组大鼠血浆胰岛素水平上升,IRS和葡萄糖曲线下面积高于对照组(P<0.05);饱和脂肪酸组大鼠肝脏组织和腹部脂肪组织IRS-1,PI3K,Akt,GLUT4基因表达较对照组明显下降(P<0.05)。结论高饱和脂肪酸饮食引起大鼠血糖正常,胰岛素含量上升,但是肝脏和脂肪胰岛素信号通路基因表达下调,是高饱和脂肪酸饮食诱导大鼠胰岛素抵抗的重要发病机制。     

利拉鲁肽对非酒精性脂肪肝大鼠肝脏组织中胰岛素JNK1信号通路的影响

目的探究利拉鲁肽对非酒精性脂肪肝(NAFLD)大鼠肝脏组织中胰岛素JNK1信号通路的影响。方法选取40只6周龄SPF级大鼠,采用高脂饮食喂养12周建立NAFLD大鼠模型。将NAFLD大鼠随机分为空白对照组(control)、模型组(model)、低剂量利拉鲁肽组(low lira)和高剂量利拉鲁肽组(high lira)。利拉鲁肽干预18 d后,测量大鼠体质量及肝指数变化;全自动生化分析仪测定大鼠血清丙氨酸氨基转移酶(ALT)、空腹血糖(FBG)、甘油三酯(TG)、总胆固醇(TC)和血清胰岛素(FINS)变化;酶联免疫吸附法测定大鼠肝组织中肿瘤坏死因子(TNF-α)、超氧化物歧化酶(SOD)、丙二醛(MAD)及游离脂肪酸(FFAs)含量; Western blot检测大鼠肝脏组织中胰岛素受体(IR)、磷酸化胰岛素受体底物1(p-IRS1)、C-Jun氨基端激酶1(JNK1)及磷酸化C-Jun氨基端激酶1(p-JNK1)表达情况; HE染色观察大鼠肝脏组织病理学变化。结果与对照组相比,模型组大鼠体质量,肝指数,血清ALT、TG、TC、FINS、TNF-α、MAD、FFAs含量,p-IRS1、JNK1、p-JNK1蛋白表达量显著升高,SOD含量显著降低,差异有统计学意义(P 0. 01);血清FBG含量和IR蛋白表达量无显著变化(P 0. 05);相比模型组,利拉鲁肽组大鼠体质量,肝指数,血清ALT、TG、TC、FINS、TNF-α、MAD、FFAs含量,p-IRS1、JNK1、p-JNK1蛋白表达量显著降低,且高剂量组显著低于低剂量组(P 0. 01); SOD含量显著升高,且高剂量组显著高于低剂量组(P 0. 01);血清FBG含量和IR蛋白表达量无显著变化(P 0. 05)。结论利拉鲁肽可以缓解大鼠脂肪肝的发展,其作用机制可能与抑制JNK1信号通路及JNK1磷酸化相关,且在一定范围内呈浓度依赖性。     

非酒精性脂肪性肝病大鼠肝脏肝细胞核因子-4α的表达

目的:探讨高脂饮食所致大鼠非酒精性脂肪性肝病(NAFLD)肝细胞核因子4α(HNF-4α)mRNA的表达及在NAFLD发病机制中的作用.方法:24只Wistar大鼠随机分为模型组和对照组(各12只),通过高脂饮食建立NAFLD大鼠模型,并在造模第8、12周末分批处死大鼠,同期设正常饮食组作为对照组.检测大鼠血清甘油三酯(TG)、肿瘤坏死因子-α(TNF-α)、丙氨酸转氨酶(ALT)及内毒素(ET)等指标,测空腹血糖(FBG)、空腹胰岛素(FINS),并计算胰岛素抵抗指数(IRI);采用逆转录-聚合酶链反应(RT-PCR)技术检测肝脏HNF-4α mRNA的表达;取肝标本做HE染色,观察其病理变化.结果:模型组大鼠肝脏HNF-4α mRNA表达量于第8周时开始降低,与同期对照组比较差异有统计学意义(P<0.05);同时血清TNF-α、IRI及ET与同期对照组相比明显升高(P<0.05),HNF-4α与TNF-α、IRI、ALT、TG及ET均呈负相关(P<0.05).结论:胰岛素抵抗(IR)可能是NAFLD发生、发展的基础,NAFLD大鼠肝脏HNF-4α可能通过一定机制参与了IR及炎症反应,进而影响了NAFLD的发生、发展.     

胰岛素抵抗大鼠骨骼肌中蛋白激酶B表达及葡萄糖转运蛋白4转位的改变

目的研究高脂饮食喂养的胰岛素抵抗(IR)大鼠骨骼肌中蛋白激酶B(PKB)表达和葡萄糖转运蛋白4(GluT4)转位的改变及饮食治疗、葛根素、罗格列酮干预的影响。方法将雄性SD大鼠50只随机分为正常饮食(A)组和高脂饮食(B)组,2个月后再将B组大鼠随机分为高脂饮食(C)组、正常饮食干预(D)组、葛根素干预(E)组和罗格列酮干预(F)组。干预1个月后检测骨骼肌中PKB的表达及转位至质膜的GluT4含量。结果C组大鼠产生了明显的IR,骨骼肌中PKB的表达较A组显著降低(P<0.01),转位到质膜上的GluT4含量显著减低(P<0.01);D、E、F组大鼠IR明显改善,骨骼肌中PKB的表达较C组大鼠显著增加(P<0.01),GluT4含量较C组大鼠显著升高(P<0.01)。结论高脂饮食喂养的SD大鼠骨骼肌产生明显的IR,骨骼肌中Ins诱导的PKB表达降低,Ins刺激的GluT4向质膜的转位减少。饮食治疗及葛根素、罗格列酮干预能增加骨骼肌中Ins刺激的PKB表达及GluT4向质膜的转位。     

高脂饮食对老年大鼠肝脏脂肪酸代谢及胰岛素敏感性的影响

目的 探讨增龄和高脂饮食对大鼠肝脏脂肪酸代谢及胰岛素敏感性的影响,了解老年大鼠胰岛素抵抗(IR)的发病机制. 方法 将22～24月龄雄性Wistar大鼠随机分为老年对照组和高脂组;4～5月龄大鼠作为青年对照组.老年对照组和青年对照组给予基础饲料,高脂组给予高脂饲料,喂养8周.用高胰岛素-正葡萄糖钳夹实验评价各组大鼠胰岛素敏感性;肝脏三酰甘油经氯仿/甲醇抽提后用全自动生化分析仪测定. 结果 (1)老年对照组空腹血糖、胰岛素和游离脂肪酸均高于青年对照组,高脂组进一步升高,且血清三酰甘油和总胆同醇水平增高;(2)葡萄糖输注率老年对照组[(23.80±2.79)mU·kg-1·min-1]较青年对照组[(30.08±3.89)mU·kg-1·min-1]低,高脂组((18.83±2.18)mU·kg-1·min-1]最低,差异有统计学意义(P<0.01);高脂组8周末较4周末低;(3)肝脏三酰甘油老年对照组较青年对照组升高,分别为(16.6±4.8)μmol/g和(9.6±2.2)μmol/g,高脂组(24.7±6.6)μmol/g较老年对照组进一步升高(P<0.01);在老年组中,肝脏三酰甘油与葡萄糖输注率呈负相关.与空腹血糖呈正相关. 结论 与青年对照组比较,老年对照组更易出现脂肪酸代谢异常及IR;高脂饮食导致老年大鼠肝脏脂质积聚更加严重,进一步加重IR;肝脏脂质堆积可能参与了与增龄和高脂饮食相关IR的发生.     

The effect of LXRα, ChREBP and Elovl6 in liver and white adipose tissue on medium- and long-chain fatty acid diet-induced insulin resistance

Aims

We aimed to investigate the effects of LXRα, ChREBP and Elovl6 in the development of insulin resistance-induced by medium- and long-chain fatty acids.

Methods

Sprague Dawley rats were fed a standard chow diet (Control group) or a high-fat, high sucrose diet with different fat sources (coconut oil, lard, sunflower and fish oil) for 8 weeks. These oils were rich in medium-chain saturated fatty acids (MCFA group), long-chain saturated fatty acids (LCFA group), n-6 and n-3 long-chain polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA groups), respectively, which had different chain lengths and degrees of unsaturation. Hyperinsulinemic–euglycemic clamp with [6-³H] glucose infusion was performed in conscious rats to assess hepatic insulin sensitivity.

Results

LCFA and n-6 PUFA groups induced hepatic insulin resistance and increased liver X receptor α (LXRα), carbohydrate response element binding protein (ChREBP) and long-chain fatty acid elongase 6 (Elovl6) expression in liver and white adipose tissue (WAT). Furthermore, LCFA and n-6 PUFA groups suppressed Akt serine 473 phosphorylation in liver and WAT. By contrast, in liver and WAT, MCFA and n-3 PUFA groups decreased LXRα, ChREBP and Elovl6 expression and improved insulin signaling and insulin resistance, but Akt serine 473 phosphorylation was not restored by MCFA group in WAT.

Conclusions

This study demonstrated that the mechanism of the different effects of medium- and long-chain fatty acids on hepatic insulin resistance involves LXRα, ChREBP and Elovl6 alternations in liver and WAT. It points to a new strategy for ameliorating insulin resistance and diabetes through intervention on Elovl6 or its control genes.     

高脂饲养大鼠脂肪组织抵抗素、脂联素及其受体的表达

目的阐明抵抗素、脂联素及其受体在胰岛素抵抗发生中的作用。方法30只Wistar雄性大鼠随机分为对照组和高脂组。用逆转录聚合酶链反应和Southem blot方法分析抵抗素、脂联素和脂联素受体表达的改变。结果高脂组大鼠体重明显增加，空腹血糖、低密度脂蛋白胆固醇、总游离脂肪酸、胰岛素和HOMA胰岛素抵抗指数明显高于对照组，高密度脂蛋白胆固醇明显低于对照组，糖耐量和胰岛素耐量明显下降（P均〈0．01）。高脂组脂肪组织抵抗素和脂联素的表达均明显下降（P〈0．01）；脂联素受体1的表达呈下降趋势，但与对照组相比无统计学意义（P〉0．05）。结论抵抗素和脂联素表达的下降在高脂饮食导致的胰岛素抵抗的发生中起着重要作用，脂联素受体1水平的降低可能是脂联素敏感性降低的重要原因之一。     

Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance

Insulin resistance in skeletal muscle and liver may play a primary role in the development of type 2 diabetes mellitus, and the mechanism by which insulin resistance occurs may be related to alterations in fat metabolism. Transgenic mice with muscle- and liver-specific overexpression of lipoprotein lipase were studied during a 2-h hyperinsulinemic-euglycemic clamp to determine the effect of tissue-specific increase in fat on insulin action and signaling. Muscle-lipoprotein lipase mice had a 3-fold increase in muscle triglyceride content and were insulin resistant because of decreases in insulin-stimulated glucose uptake in skeletal muscle and insulin activation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity. In contrast, liver-lipoprotein lipase mice had a 2-fold increase in liver triglyceride content and were insulin resistant because of impaired ability of insulin to suppress endogenous glucose production associated with defects in insulin activation of insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity. These defects in insulin action and signaling were associated with increases in intracellular fatty acid-derived metabolites (i.e., diacylglycerol, fatty acyl CoA, ceramides). Our findings suggest a direct and causative relationship between the accumulation of intracellular fatty acid-derived metabolites and insulin resistance mediated via alterations in the insulin signaling pathway, independent of circulating adipocyte-derived hormones.     

高血压合并脂肪肝与胰岛素抵抗的相关分析

目的：探讨高血压合并脂肪肝与胰岛素抵抗（IR）的相关性。方法：根据超声影像学的诊断结果将住院治疗的高血压患者分为高血压合并脂肪肝组（98例）和高血压未合并脂肪肝组（104例），研究两组的体重指数（BMD、血压（BP）、血糖、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、肝酶和血浆胰岛索，胰岛素抵抗指数（IRI）水平。结果：高血压合并脂肪肝组较高血压未合并脂肪肝组的血糖、胰岛素水平、甘油三酯和胰岛素抵抗指数均明显增高（P〈0．05）。Logistic回归结果表明空腹血糖（FBG）、肥胖、丙氨酸氨基转氨酶（ALT）、葡萄糖负荷试验后3h胰岛素水平、甘油三醋（TG）是脂肪肝形成的独立危险因素（OR=1．980～3．245，P〈0．05）。结论：高血压和脂肪肝均是胰岛素抵抗的重要表现，高血压合并的脂肪肝其发病机制与胰岛素抵抗有关。     

Intracellular fatty acid metabolism in skeletal muscle and insulin resistance

Triglyceride accumulation in skeletal muscle is increased in subjects with insulin resistance. Increased intracellular lipolysis from stored triglyceride may induce insulin resistance in skeletal muscle by activating the glucose-fatty acid cycle. However, inconsistent with this hypothesis, intracellular lipolysis from skeletal muscle is decreased in high fat-fed, insulin resistant rats. Therefore, it is suggested that an increase in triglyceride accumulation is the result of decreased mitochondrial fatty acid oxidation in the cells. As evidence, fenofibrate (a PPARalpha activator), rosiglitazone (a PPARgamma activator) and alpha-lipoic acid completely prevented the development of diabetes in obese diabetes-prone rats. All three drugs increased fatty acid oxidation and decreased triglyceride accumulation in skeletal muscle. Administration of ALA activated AMPK and increased fatty acid oxidation. It is suggested that decreased fatty acid oxidation in skeletal muscle is one of the major factors leading to an accumulation of lipid metabolites and insulin resistance.     

Amelioration of non-alcoholic fatty liver disease with NPC1L1-targeted IgY or n-3 polyunsaturated fatty acids in mice

Patients with non-alcoholic fatty liver disease (NAFLD) have an increased risk for progression to hepatocellular carcinoma in addition to comorbidities such as cardiovascular and serious metabolic diseases; however, the current therapeutic options are limited. Based on our previous report that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can significantly ameliorate high fat diet (HFD)-induced NAFLD, we explored the therapeutic efficacy of n-3 PUFAs and N-IgY, which is a chicken egg yolk-derived IgY specific for the Niemann-Pick C1-Like 1 (NPC1L1) cholesterol transporter, on NAFLD in mice. We generated N-IgY and confirmed its efficient cholesterol transport-blocking activity in HepG2 and Caco-2 cells, which was comparable to the effect of ezetimibe (EZM). C57BL/6 wild type and fat-1 transgenic mice, capable of producing n-3 PUFAs, were fed a high fat diet (HFD) alone or supplemented with N-IgY. Endogenously synthesized n-3 PUFAs combined with N-IgY led to significant decreases in hepatic steatosis, fibrosis, and inflammation (p < 0.01). The combination of N-IgY and n-3 PUFAs resulted in significant upregulation of genes involved in cholesterol uptake (LDLR), reverse cholesterol transport (ABCG5/ABCG8), and bile acid metabolism (CYP7A1). Moreover, fat-1 transgenic mice treated with N-IgY showed significant downregulation of genes involved in cholesterol-induced hepatic stellate cell activation (Tgfb1, Tlr4, Col1a1, Col1a2, and Timp2). Collectively, these data suggest that n-3 PUFAs and N-IgY, alone or in combination, represent a promising treatment strategy to prevent HFD-induced fatty liver through the activation cholesterol catabolism to bile acids and by decreasing cholesterol-induced fibrosis.     

Early growth restriction, membrane phospholipid fatty acid composition, and insulin sensitivity

An animal model of protein restriction during pregnancy and lactation with subsequent dietary fatty acid manipulation was used to investigate the association between poor early growth, defective unsaturated fatty acid handling, and later disease. Both control and early growth-restricted animals fed a diet rich in saturated fatty acids showed a doubling of the plasma insulin levels as well as a reduced degree of unsaturation in liver and skeletal muscle membrane phospholipids compared with animals fed diets rich in unsaturated fatty acids. The skeletal muscle of early growth-restricted animals weaned onto a saturated fat diet had reduced proportions of 22:6n-3 and increased proportions of 18:1n-9. This reduction in 22:6n-3 is similar to that observed in Pima Indians, a population with a high prevalence of type 2 diabetes.     

Exenatide 对高脂诱导胰岛素抵抗大鼠胰岛素敏感性及糖脂代谢的影响

目的 探讨Exenatide对高脂诱导胰岛素抵抗大鼠胰岛β细胞功能、胰岛素敏感性及糖脂代谢的影响. 方法 高脂诱导胰岛素抵抗大鼠给予Exenatide 6周后,采用静脉葡萄糖耐量(IVGTT)和胰岛素耐量(ITT)试验以及扩展胰岛素钳夹技术测定胰岛素敏感性和糖脂代谢,并观察血浆脂联素水平的变化.结果 高脂大鼠(HF)经Exenatide处理后,Lee′s指数、空腹血浆游离脂肪酸(FFA)、甘油三酯、胆固醇明显降低(均P＜0.01);IVGTT和ITT明显改善,胰岛素分泌水平增高,高剂量组(HFH)较低剂量组(HFL)上述指标改善更为明显.同时,HFH组血浆脂联素水平也明显升高(P＜0.01).在钳夹稳态时,HF组与对照组(NC)相比,血浆FFA、胰岛素水平均明显升高(均P＜0.01),葡萄糖输注率(GIR)、葡萄糖清除率(GRd)明显降低(均P＜0.01),且胰岛素对肝糖输出(HGP)的抑制作用明显障碍(仅抑制26%).经Exenatide(2 μg/kg)处理以后,血浆FFA、胰岛素水平则明显降低(均P＜0.01),GRd、GIR明显升高(均P＜0.01),胰岛素对HGP的抑制作用明显增强(抑制72%).结论 对高脂喂养大鼠用Exenatide预处理可能通过促进β细胞胰岛素分泌和上调血浆脂联素水平,改善糖脂代谢而使机体胰岛素敏感性增加.