Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage. The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD. Patients (5 male and 4 female; 44 +/- 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG. Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry. NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia. Of the TAG accounted for in liver, 59.0% +/- 9.9% of TAG arose from NEFAs; 26.1% +/- 6.7%, from DNL; and 14.9% +/- 7.0%, from the diet. The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD.     

Pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease related to excessive accumulation of hepatic fat, and represents a spectrum of liver disease ranging from fat accumulation alone (steatosis) to the more significant histologic finding of steatohepatitis. Nonalcoholic steatohepatitis is a progressive liver disease associated with increased risk of liver cirrhosis and cancer. NAFLD is becoming increasingly prevalent in the pediatric population in direct correlation with the emergence of childhood obesity as a significant pediatric health problem. The exact pathophysiology of NAFLD remains unclear, although the interplay of insulin resistance, oxidative stress, and release of proinflammatory cytokines are implicated in the process. The diagnostic workup and treatment for NAFLD and nonalcoholic steatohepatitis remains controversial. This review discusses current concepts regarding the natural history, pathophysiology, and management of pediatric patients with NAFLD.     

运动对高脂饮食诱导非酒精性脂肪肝的治疗作用

目的 观察运动对高脂饮食诱导非酒精性脂肪肝的治疗作用,并初步探讨其相关机制.方法 将30只Wistar大鼠分为对照组及高脂组,分别给予基础饲料和高脂饲料喂养;高脂组大鼠经喂养18周后制成胰岛素抵抗(IR)模型,并进一步细分为静息组和运动组,继续给予高脂饲料喂养,运动组同时进行游泳训练,共持续6周.于实验进行24周后处死各组大鼠,计算肝指数,观察肝脏病理学改变,检测各组大鼠肝脏甘油三酯(TG)含量,同时应用蛋白免疫印迹法检测肝脏组织一磷酸腺苷活化蛋白激酶(AMPK)磷酸化水平.结果 实验进行24周后,与对照组比较,静息组大鼠胰岛素敏感性显著降低,肝脏TG含量、肝指数明显增高,光镜下肝脏出现明显脂肪变性,肝脏内AMPK磷酸化水平降至对照组水平的50.8%;与静息组比较,运动组大鼠胰岛素敏感性明显提高,肝指数及肝脏TG含量均显著降低,光镜下可见肝脏脂肪变性程度明显改善,肝组织内AMPK磷酸化水平亦显著提高.结论 运动干预对高脂饮食诱导的非酒精性脂肪肝具有治疗作用,其机制可能与运动上调肝脏组织中AMPK磷酸化水平,从而改善IR及减少肝脏内TG含量有关.     

运动对高脂饮食诱导非酒精性脂肪肝的治疗作用

目的 观察运动对高脂饮食诱导非酒精性脂肪肝的治疗作用,并初步探讨其相关机制.方法 将30只Wistar大鼠分为对照组及高脂组,分别给予基础饲料和高脂饲料喂养;高脂组大鼠经喂养18周后制成胰岛素抵抗(IR)模型,并进一步细分为静息组和运动组,继续给予高脂饲料喂养,运动组同时进行游泳训练,共持续6周.于实验进行24周后处死各组大鼠,计算肝指数,观察肝脏病理学改变,检测各组大鼠肝脏甘油三酯(TG)含量,同时应用蛋白免疫印迹法检测肝脏组织一磷酸腺苷活化蛋白激酶(AMPK)磷酸化水平.结果 实验进行24周后,与对照组比较,静息组大鼠胰岛素敏感性显著降低,肝脏TG含量、肝指数明显增高,光镜下肝脏出现明显脂肪变性,肝脏内AMPK磷酸化水平降至对照组水平的50.8%;与静息组比较,运动组大鼠胰岛素敏感性明显提高,肝指数及肝脏TG含量均显著降低,光镜下可见肝脏脂肪变性程度明显改善,肝组织内AMPK磷酸化水平亦显著提高.结论 运动干预对高脂饮食诱导的非酒精性脂肪肝具有治疗作用,其机制可能与运动上调肝脏组织中AMPK磷酸化水平,从而改善IR及减少肝脏内TG含量有关.

Abstract：

Objective To observe the effect of exercise on nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet and explore the mechanism.Methods Thirty healthy male rats were randomly divided into a normal control group( NC group) and a high-fat group( HF group), fed with normal chow and high-fat diet, respectively.Eighteen weeks later, the high-fat established as insulin resistance model and group was randomly divided into high-fat diet control group (HC group) and high-fat diet exercise group (HE group).HC group was continually given high-fat diet; HE group accepted swimming training for 6 weeks.After 24 weeks, the insulin sensitivity index (ISI) was calculated.After rats were sacrificed, weight of liver and body were measured to calculate liver mass index.Liver histology was detected by hematoxylin and eosin staining.Hepatic triglyceride content was detected.Phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) level was detected by Western blot technique.Results At the 18th week, compared to NC group, ISI of HF group decreased obviously.It suggested that insulin resistance appeared in HF group.At the 24th week, compared to NC group, ISI of HC group decreased significantly.But hepatic triglycefide content and liver mass index both increased.Pathology observation under light microscope showed obvious liver steatosis in HC group.Phosphorylation of AMPK level in HC group decreased to 50.8% of NC group.Exercise greatly improved the liver mass index, hepatic triglyceride content and ISI as well as liver steatosis compared to HC group.Phosphorylation of AMPK was also elevated to 78.1% of NC group in HE group.However,compared to NC group, liver mass index and hepatic triglyceride content increased simultaneously, while ISI and phosphorylation of AMPK level obviously decreased in HE group.Conclusion Elevated level of phosphorylation of AMPK contributed to improve insulin resistance and decrease the hepatic triglyceride content.Exercise could markedly improve NAFLD induced by high-fat diet through elevating phosphorylation of AMPK in liver.     

运动对高脂饮食诱导非酒精性脂肪肝的治疗作用

目的 观察运动对高脂饮食诱导非酒精性脂肪肝的治疗作用,并初步探讨其相关机制.方法 将30只Wistar大鼠分为对照组及高脂组,分别给予基础饲料和高脂饲料喂养;高脂组大鼠经喂养18周后制成胰岛素抵抗(IR)模型,并进一步细分为静息组和运动组,继续给予高脂饲料喂养,运动组同时进行游泳训练,共持续6周.于实验进行24周后处死各组大鼠,计算肝指数,观察肝脏病理学改变,检测各组大鼠肝脏甘油三酯(TG)含量,同时应用蛋白免疫印迹法检测肝脏组织一磷酸腺苷活化蛋白激酶(AMPK)磷酸化水平.结果 实验进行24周后,与对照组比较,静息组大鼠胰岛素敏感性显著降低,肝脏TG含量、肝指数明显增高,光镜下肝脏出现明显脂肪变性,肝脏内AMPK磷酸化水平降至对照组水平的50.8%;与静息组比较,运动组大鼠胰岛素敏感性明显提高,肝指数及肝脏TG含量均显著降低,光镜下可见肝脏脂肪变性程度明显改善,肝组织内AMPK磷酸化水平亦显著提高.结论 运动干预对高脂饮食诱导的非酒精性脂肪肝具有治疗作用,其机制可能与运动上调肝脏组织中AMPK磷酸化水平,从而改善IR及减少肝脏内TG含量有关.     

PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.     

非酒精性脂肪肝治疗进展

近年来随着生活水平的改善和生活方式的改变，非酒精性脂肪肝的发病率不断升高，其病因和发病机制尚未完全明了，针对脂肪肝的治疗尚缺乏有效的药物。本文就近年来对非酒精性脂肪肝的治疗进展作一综述。     

弹性酶治疗高脂血症性非酒精性脂肪性肝病的临床观察

目的观察弹性酶肠溶片治疗高脂血症性非酒精性脂肪性肝病的有效性、安全性及耐受性,为临床应用提供依据.方法将76例高脂血症性非酒精性脂肪性肝病患者,随机分为弹性酶组（n=44）,口服弹性酶肠溶片（300 IU/粒）,每次2粒,每日3次,疗程60天,安慰剂组（n=32）,口服安慰剂（淀粉）,剂量及疗程相同;治疗前、治疗30天、60天分别检测肝、肾功能、血脂,并B超随访.结果 6例患者治疗中失访,70例患者纳入疗效统计.弹性酶组总有效率为85%（34/40）,安慰剂组总有效率为20%（6/30）,两组比较差异有统计学意义（P=0.000）;弹性酶组肝功能、血脂明显改善,两组比较差异有统计学意义（P《0.05）;弹性酶对肾功能无明显毒副作用.结论弹性酶肠溶片具有改善肝功能、降低血脂、防治高脂血症性非酒精性脂肪性肝病的作用.     

非酒精性脂肪肝的药物治疗进展

非酒精性脂肪肝(NAFLD)已逐渐成为我国第一大肝病,其危害不仅可进展为非酒精性脂肪性肝炎(NASH)、肝硬化、肝细胞癌,而且作为代谢综合征(MS)的重要组分与心脑血管疾病密切相关,日益受到相关学科研究者的重视。NAFLD的治疗除了肝病本身,也应包括患者可能并存的异常代谢组分如肥胖、高脂血症、胰岛素抵抗(IR)、2型糖尿病(T2DM)等。NAFLD的治疗包括非药物治疗——生活方式改变、药物治疗两方面,前者为治疗NAFLD的基础。目前治疗NAFLD的药物主要包括胰岛素增敏剂、抗氧化剂、微生态制剂、降脂药、减肥药、保肝抗炎药物及中药。     

非酒精性脂肪肝肝纤维化评分与脂肪肝及胰岛素抵抗的相关性研究

目的分析非酒精性脂肪肝肝纤维化评分（NAFLDFS）与非酒精性脂肪肝（NAFLD）及胰岛素抵抗（瓜）的相关性。方法以来自江苏徐州地区的2622例健康体检人群为研究对象,检测受试者的血清谷丙转氨酶（“r）,谷草转氨酶（AsT）,血小板计数（PLT）,血清白蛋白（ALB）,空腹血糖（FBG）,餐后2h血糖（PBG）,空腹胰岛素（Fins）等相关生化指标,计算出NAFLDFS及胰岛素抵抗指数（HOMA2-IR）,将研究对象按非酒精性脂肪肝纤维化评分的低诊断阈值（～1．455）及高诊断阈值（0．676）分成三组,A1组：NAFLDFS〈-1．455;A2组：0．676≥NAFLDFS≥-1．455和A3组NAFLDFS〉0．676。Pearson分析肝纤维化评分与各指标相关性;运用二元Logistic回归计算NAFLDFS与NAFLD、IR的风险性。结果随着NAFLDFS值增高,年龄（Age）、体重（Weight）、体重指数（BMI）、腰围（wc）、臀围（Hip）、糖化血红蛋白（HbAlc）、颈围（NC）、FBG、PBG、Fins、收缩压（SBP）、舒张压（DBP）、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL-C）水平逐渐增高,且三组问的差异有统计学意义;而ALT、AST、PLT、ALB、高密度脂蛋白（HDL．c）随着NAFLDFS值的增高而减小。Pearson分析显示Age、NC、WC、Hip、Weight、BMI、HbAlc、FBG、PBG、PLT与NAFLDFS正相关。随着NAFLDFS值的增加,NAFLD与取的患病风险（OR）也增加。NAFLD的患病风险由1．22（OR=1．22）增加到1．79（OR=1．79）：IR的患病风险由1．13（OR=1．13）增加到1．91（OR=1．91）;进一步校正性别及年龄后,NAFLD的患病风险由1．15（OR=1．15）增加到1．53（OR=1．53）;IR的患病风险由1．15（OR=1．15）增加到2．02（OR=2．02）。结论NAFLDFS与NAFLDF及瓜密切相关,在临床上可将其作为简易评价NAFLD及IR的指标。     

A simpler diagnostic formula for screening nonalcoholic fatty liver disease

ObjectiveTo increase the accuracy of non-invasive diagnosis of nonalcoholic fatty liver disease (NAFLD), clinical and laboratory NAFLD indicators were integrated into a diagnostic formula.MethodsA total of 141 patients with clinically diagnosed NAFLD and 30 healthy controls were enrolled. We collected case history, body weight, height and mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase, blood urea nitrogen and blood uric acid (UA), serum creatinine, plasma total cholesterol, triglyceride, low density lipoprotein, glycosylated hemoglobin, fasting plasma glucose, fasting insulin, ultrasonic tests, Fibroscans, and other data. Linear correlation, multiple linear regressions, and receiver operating characteristic (ROC) curve methods were used to process and analyze the collected data. The performance of Fibroscan and our diagnostic formula was compared in reference to the findings of liver biopsy.ResultsThe identified NAFLD diagnostic indices consisted of BMI, ALT, AST and UA. A regression formula was proposed as: CAP = 113.163 + 0.252 * ALT + 6.316 * BMI. Diagnosis of the area under the ROC curve was 0.927, the sensitivity was 87.68%, and specificity was 90%. The cutoff was 277.67 (p < 0.01). The accuracy of the NAFLD diagnosis with the proposed formula was significantly higher than FibroScan (82.6% vs 69.6%; p = 0.005).ConclusionsNAFLD diagnosis with the proposed formula demonstrated both high sensitivity and specificity, and its accuracy was significantly higher than FibroScan. This formula only utilized non-invasive clinical and laboratory findings and the calculation was simple. It can be conveniently used for clinical diagnosis of NAFLD.     

非酒精性脂肪性肝病发病机制的研究现状

非酒精性脂肪性肝病(NAFLD)是目前全球最常见的慢性肝病,其发病率逐年上升。近十年的研究表明,NAFLD是一种多系统疾病,影响肝脏以外的器官代谢和免疫通路的作用,是代谢综合征在肝脏的表现,其发病机制尚不明确,目前认为与血脂异常、胰岛素抵抗以及氧化应激、内质网应激相关。本综述针对NAFLD的发病机制的研究现状进行简单阐述。