高脂饮食诱导肥胖与肥胖抵抗型非酒精性脂肪肝大鼠模型的建立

目的:利用高脂饲料复制肥胖与肥胖抵抗型非酒精性脂肪肝SD大鼠模型。方法:体质量100±10g的雄性SD大鼠140只,按照体重随机抽取120只用于模型建立,喂食高脂、高能饲料。连续8周后,将体质量大于正常对照组平均体质量+1.96倍标准差的模型大鼠作为肥胖型非酒精性脂肪肝组(NO组),体质量小于正常对照组平均体质量+1.0倍标准差的作为肥胖抵抗型非酒精性脂肪肝组(NOR组)。8周内动态观察大鼠的一般情况、体质量变化,8周末每组随机取8只处死,比较血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、胆固醇(TC)、甘油三脂(TG)水平变化及肝指数、脂体比,观察肝脏形态学改变。剩余20只作为正常对照组,喂食普通饲料。结果:NO与NOR组大鼠体重增长差距逐渐增大,至8w末,NO组体重显著高于NOR组及正常对照组(P0.01),脂肪重量和脂体比均显著升高,NO组脂肪重量显著高于NOR组(P0.05,0.01),但脂体比间未见显著差异;NO与NOR组TG、ALT显著升高(P0.05),其中NO组大鼠血清TG、TC显著高于NOR组(P0.05);两组肝重量和肝指数均显著升高,NO组肝重量显著高于NOR组(P0.05,0.01),但肝指数间未见显著差异,两组肝细胞内均弥散大量脂肪空泡。结论:利用高脂饲料成功建立肥胖与肥胖抵抗型非酒精性脂肪肝SD大鼠模型,与人类发病特征相似,为肥胖与非酒精性脂肪的研究提供更有针对性的动物模型。     

肠道菌群在肥胖发病中的作用

近十年来,肠道菌群在人类许多疾病发病机制中的潜在作用引起了人们的广泛关注。已被证实肠道菌群与肥胖和肥胖相关的代谢性疾病的发生发展密切相关。与肥胖相关的肠道微生物可调控宿主的能量代谢、胰岛素抵抗和脂肪组织堆积,这些在肥胖发生中都起着至关重要的作用。本综述重点介绍了代谢紊乱中肠道菌群组成的变化以及肠道菌群在肥胖发病机制中的作用,包括能量代谢、中枢食欲、免疫系统和宿主昼夜节律。在不久的将来,该领域的研究将为治疗肥胖及其并发症开辟新的途径。     

胰岛素抵抗与脂肪肝关系的研究

胰岛素抵抗(IR)是许多疾病的独立危险因素。胰岛素抵抗与脂肪代谢紊乱非常密切,研究发现它在脂肪肝的发生、发展过程中起了很大的作用。近年来,越来越多的人已经意识到脂肪肝与胰岛素抵抗之间的密切关系。在胰岛素抵抗与脂肪肝的研究中关于瘦素及瘦素抵抗在胰岛素抵抗及脂肪肝的关系中的作用是研究比较多的,本文主要介绍了胰岛素抵抗、脂肪肝的发生机制及瘦素、瘦素抵抗在其中的催化作用。     

代谢性内毒素血症在果糖诱发的NAFLD等代谢疾病中的作用研究

目的:探讨果糖饮食诱发大鼠发生非酒精性脂肪性肝病(NAFLD)等代谢疾病中,代谢性内毒素血症发挥的作用及机制。方法:30只SD雄性大鼠随机分为三组:正常对照组(NC组)、高果糖组(HFD组,8%高果糖水喂养)、内毒素组(LPS组,300μg·kg~(-1)·d~(-1)皮下注射)。8周糖耐量实验后,测定血浆内毒素(LPS)、胰岛素、血脂系列,计算胰岛素抵抗指数(HOMA-IR),检测促炎因子(TNF-α、IL-6)表达,观测肝组织病理学变化,Western blot检测肝组织胰岛素信号转导关键蛋白、内毒素受体表达。结果:与NC组比较,HFD组与LPS组大鼠血浆LPS、血脂(TG、TC、FFA、HDL)、促炎因子(TNF-α、IL-6),FPG(Fasting plasm glucose)、FINS(Fasting insulin)、HOME-IR(homeostasis model assessment of IR)的水平有统计学意义(P0.05,P0.01),胰岛素受体底物P-IRS1Tyr632/IRS1比值下降、内毒素受体TLR-4表达升高(P0.05,P0.01),HFD组与LPS组上述指标变化无统计学差异。结论:高果糖饮食及皮下注射LPS诱发大鼠发生NAFLD等代谢疾病时,普遍伴有内毒素血症;LPS通过炎症机制引发胰岛素抵抗,促进NAFLD等代谢疾病的发生发展。     

肥胖儿童非酒精性脂肪肝病与血清铁蛋白相关性研究

目的：探讨血清铁蛋白和肥胖儿童非酒精性脂肪肝（NAFLD）之间的关系,为早期发现肥胖儿童NAFLD提供临床科学依据。方法：选取2016年5月—2018年12月在丽水市中心医院诊断为肥胖的儿童315例,男233例、女82例,平均年龄(11.4±2.6)岁,体质指数（BMI）（24.5±4.6）kg/m2。依据B超结果将315例儿童分为单纯性肥胖184例、肥胖伴NAFLD 131例。按照标准方法测量儿童体重、身高、腰围,同时选取同时期体检同年龄段的健康儿童35例作为对照组。检测血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、血清铁蛋白（SF）等指标。结果：在315例肥胖儿童中,其中116人检出脂肪肝（男性91例、女性25例）,脂肪肝检出率为36.9%,男性和女性肥胖儿童青少年脂肪肝检出率分别是39.1%、30.4%,两组之间差异有统计学意义（P＜0.05）。年龄及BMI在对照组、单纯肥胖组和肥胖伴NAFLD组之间差异无统计学意义（P＞0.05）。腰围在肥胖伴NAFLD组和单纯肥胖组均大于对照组（P＜0.05）;TG、HDL、SF在3组间比较有差异（P＜0.05）;TG在肥胖伴NAFLD组结果要高于对照组;HDL在肥胖伴NAFLD组和单纯肥胖组低于对照组;SF在肥胖伴NAFLD组高于单纯肥胖组和对照组。轻、中、重度3组脂肪肝儿童SF比较发现重度NAFLD＞中度NAFLD＞轻度NAFLD。经多因素Logistic回归分析,甘油三酯（TG）、血清铁蛋白（SF）和性别均是儿童非酒精性脂肪肝的危险因素。结论：血清铁蛋白、血脂、腰围等指标可以作为监测肥胖儿童伴发NAFLD的有效指标。     

Hedgehog信号通路在代谢相关脂肪性肝病发生与发展中的作用

随着肥胖和2型糖尿病发病率的迅速上升,代谢相关脂肪性肝病(metabolic-dysfunction associated fatty liver disease,MAFLD)[曾用名非酒精性脂肪肝(nonalcoholic fatty liver disease,NAFLD)]已成为世界上最为常见的肝脏疾病.MAFL...     

益生菌对肥胖儿童和青少年非酒精脂肪肝的影响

目的：评估益生菌对非酒精性脂肪肝的生化指标及超声分级的影响。方法：回顾性分析64例非酒精性脂肪肝肥胖患者三盲试验。患者随机分为2组,分别服用益生菌制剂或安慰剂,治疗3疗程。结果：益生菌组,谷丙转氨酶平均水平从32.8±19.6U/L下降至23.1±9.5 U/L（P=0.002）,天冬氨酸转氨酶平均水平从32.2±15.7U/L下降至24.3±7.7U/L（P= 0.002）,患者的胆固醇、低密度脂蛋白、甘油三酯以及腰围显著降低,而体重、身体质量指数、体重指数z评分没有显著改变;安慰剂组,研究前后各项指标无显著变化,无统计学差异。肝超声分级,益生菌组转阴17例（53.12%）、安慰剂组转阴5例（15.62%）。结论：益生菌可以有效地改善肥胖儿童非酒精性脂肪肝病症。     

GPR50在肥胖及相关疾病中的作用研究进展

G蛋白偶联受体家族(GPCRs)是真核细胞膜表面最大的一类膜蛋白受体,能够被细胞外的多肽、糖类、脂类、离子、生物胺等激活,被认为参与了80％以上的细胞信号转导过程,是细胞信号转导中重要的蛋白质.GPCRs广泛参与生殖、发育、内分泌以及代谢等多种生理过程,同时与免疫性疾病、中枢神经系统疾病、糖尿病、心脏病、癌症等疾病的发...     

非酒精性脂肪肝的发病机制及药物治疗

非酒精性脂肪肝是多种病因导致的慢性疾病,发病率有上升趋势。脂肪肝发生发展与肝内脂肪合成排出动态平衡、激素、胰岛素抵抗等有关,目前还缺少有效治疗药物。综述非酒精性脂肪肝的发病机制、中西药物治疗进展,以期为该领域研究提供借鉴,脂肪肝治疗药物开发提供依据。     

非酒精性脂肪肝的发病机制及药物治疗

非酒精性脂肪肝是多种病因导致的慢性疾病,发病率有上升趋势。脂肪肝发生发展与肝内脂肪合成排出动态平衡、激素、胰岛素抵抗等有关,目前还缺少有效治疗药物。综述非酒精性脂肪肝的发病机制、中西药物治疗进展,以期为该领域研究提供借鉴,脂肪肝治疗药物开发提供依据。     

Niemann-Pick C1-Like 1 deletion in mice prevents high-fat diet-induced fatty liver by reducing lipogenesis

Niemann-Pick C1-Like 1 (NPC1L1) mediates intestinal absorption of dietary and biliary cholesterol. Ezetimibe, by inhibiting NPC1L1 function, is widely used to treat hypercholesterolemia in humans. Interestingly, ezetimibe treatment appears to attenuate hepatic steatosis in rodents and humans without a defined mechanism. Overconsumption of a high-fat diet (HFD) represents a major cause of metabolic disorders including fatty liver. To determine whether and how NPC1L1 deficiency prevents HFD-induced hepatic steatosis, in this study, we fed NPC1L1 knockout (L1-KO) mice and their wild-type (WT) controls an HFD, and found that 24 weeks of HFD feeding causes no fatty liver in L1-KO mice. Hepatic fatty acid synthesis and levels of mRNAs for lipogenic genes are substantially reduced but hepatic lipoprotein-triglyceride production, fatty acid oxidation, and triglyceride hydrolysis remain unaltered in L1-KO versus WT mice. Strikingly, L1-KO mice are completely protected against HFD-induced hyperinsulinemia under both fed and fasted states and during glucose challenge. Despite similar glucose tolerance, L1-KO relative WT mice are more insulin sensitive and in the overnight-fasted state display significantly lower plasma glucose concentrations. In conclusion, NPC1L1 deficiency in mice prevents HFD-induced fatty liver by reducing hepatic lipogenesis, at least in part, through attenuating HFD-induced insulin resistance, a state known to drive hepatic lipogenesis through elevated circulating insulin levels.     

Lycopus lucidus Turcz Water Extract Ameliorates the Metabolic Disorder by Up-Regulated Major Urinary Protein Expression in High-Fat Diet-Induced Obesity

Despite a century of research on obesity, metabolic disorders and their complications, including dyslipidemia, insulin resistance, and fatty liver disease remain a serious global health problem. Lycopus lucidus Turcz (LT) is a traditional medicine used for its anti-inflammatory properties that has not been evaluated for its efficacy in improving obesity. In this study, mice were fed a normal diet (n = 10) or obesity was induced with a high-fat diet (HFD, n = 20, 60% kcal from fat) for 4 weeks. The HFD mice were then divided into two groups, one of which received LT supplementation with water extract for 13 weeks [HFD (n = 10) or HFD with LT water extract (n = 10, 1.5%)]. LT reduced body and adipose tissue weight by elevating energy expenditure by increasing fatty oxidation in epididymal white adipose tissue (eWAT) and muscle. LT ameliorated dyslipidemia and hepatic steatosis by restricting lipogenesis. Additionally, LT normalized the impaired glucose homeostasis by diet-induced obesity to improve pancreatic islet dysfunction with increasing hepatic major urinary protein expression. Moreover, LT attenuated the inflammation and collagen accumulation in the liver and eWAT. In conclusion, these results suggest that LT can treat obesity-related metabolic disorders such as adiposity, dyslipidemia, hepatic steatosis, insulin resistance, and inflammation.     

Autotaxin/lysophosphatidic acid signaling mediates obesity‐related cardiomyopathy in mice and human subjects

Obesity is associated with increased cardiovascular morbidity and mortality, but the direct signals to initiate or exaggerate cardiomyopathy remain largely unknown. Present study aims to explore the pathophysiological role of autotaxin/lysophosphatidic acid (LPA) in the process of cardiomyopathy during obesity. Through utilizing mouse model and clinical samples, present study investigates the therapeutic benefits of autotaxin inhibitor and clinical correlation to obesity‐related cardiomyopathy. The elevated circulating levels of autotaxin are closely associated with cardiac parameters in mice. Administration with autotaxin inhibitor, PF‐8380 effectively attenuates high fat diet‐induced cardiac hypertrophy, dysfunction and inflammatory response. Consistently, autotaxin inhibition also decreases circulating LPA levels in obese mice. In in vitro study, LPA directly initiates cell size enlargement and inflammation in neonatal cardiomyocytes. More importantly, circulating levels of autotaxin are positively correlated with cardiac dysfunction and hypertrophy in 55 patients. In conclusion, present study uncovers the correlation between circulating autotaxin and cardiac parameters in mice and human patient, and provided solid evidence of the therapeutic application of autotaxin inhibitor in combating obesity‐related cardiomyopathy.     

Insulin Resistance in Obesity and Its Molecular Control

The Wistar fatty rat is a model of obese non-insulin-dependent diabetes mellitus. Males, but not females, develop hyperglycemia, glucouria and polyuria within 8 weeks of age. The regulation of gene expression by insulin has been shown to be differentially impaired in the liver of the fatty rats. The genes resistant to insulin include glucokinase gene and phosphoenolpyruvate carboxykinase gene. In contrast, L-type pyruvate kinase gene responds to insulin normally, raising the possibility that the signaling pathway from the insulin receptor to the insulin-resistant genes, but not to the insulin-sensitive genes, is defective at a point beyond the receptor kinase in the fatty rats. On the other hand, female fatty rats develop hyperglycemia only when they are given sucrose for several weeks. This treatment causes a decrease in gucokinase while enzymes involved in gluconeo genesis are increased. Chronic feeding of sucrose also leads to hypertriglycemia and visceral fat accumulation, which is more frequently associated with abnormalities in glucose and lipid metabolisms. Fructose is believed to be the responsible component of sucrose for these effects. Hypertriglyceridemic effect of fructose is mainly due to an increase in hepatic production of VLDL. Most enzymes related to lipogenesis in the liver are induced by dietary fructose even in diabetes. L-type pyruvate kinase is one of such enzymes. Cis-acting element named PKL-III in the 5′-flanking region of this gene is shown to be responsive to dietary fructose as well as to dietary glucose. Thus, identification and characterization of a protein bound to this element could help in the further understanding of the molecular mechanism of the fructose actions.