Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats.
Free fatty acids, not triglycerides, are associated with non-alcoholic liver injury progression in high fat diet induced obese rats.
复制标题
DOI：
10.1186/s12944-016-0194-7
复制
发表时间：
2016-02-11
影响因子：
4.5
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Liu J;Han L;Zhu L;Yu Y
非酒精性脂肪性肝病(NAFLD)通常与肥胖和代谢综合征有关，其发病率在全球范围内呈上升趋势。然而，从单纯性脂肪变性到非酒精性脂肪性肝炎的具体机制尚不清楚。本研究旨在观察高脂饮食诱导的NAFLD肥胖大鼠24周内血和肝脏中甘油三酯(TG)和游离脂肪酸(FFA)水平的时间依赖性变化，以阐明高FFA水平在肝损伤发展中的作用。将雄性Wistar大鼠随机分为3组(n = 30只/组)：对照组喂标准饲料，高脂饲料组喂高脂饲料，阿昔莫司组喂饲高脂饲料+阿昔莫司(100 mg/kg/d，ig)8、16、24周。治疗结束后，采集血液和肝脏样本进行生化分析、免疫印迹分析和组织病理学研究。HFD组和Acipimox组的内脏脂肪/体重和肝脏/体重比均高于对照组。HFD组大鼠血和肝组织中甘油三酯和游离脂肪酸浓度升高，并伴有血清丙氨酸氨基转移酶(ALT)和肝组织丙二醛(MDA)水平升高以及肝碎片上的巨/微泡脂肪变性。高脂饲料组大鼠肝脏甘油三酯水平与阿昔莫司组相似(p >； 0.05)，但后者血液和肝脏中游离脂肪酸浓度显著低于阿昔莫司组(p <； 0.05)。阿昔莫司组ALT、丙二醛水平正常，肝组织学改变轻于高脂组(NAFLD活性评分：8、16、24周分别为2.14 ± 0.14、2.43 ± 0.20、2.63 ± 0.26；24周时p <； 0.05)。甘油二酯酰基转移酶2(DGAT2)蛋白表达水平与阿昔莫司组相似(p >； 0.05)，而肉毒碱棕榈酰转移酶1a(CPT-1a)蛋白表达水平高于阿昔莫司组。肝脏TG积聚不会导致肝脏细胞损伤；相反，游离脂肪酸或其代谢产物通过增加氧化应激而导致肝脏损伤。建议预防非酒精性肝损伤进展的治疗努力应集中于减轻转运到肝脏或在肝脏中合成的脂肪酸的负担。
The incidence of non-alcoholic fatty liver disease (NAFLD), commonly associated with obesity and metabolic syndrome, is increasing worldwide. However, the specific mechanisms that mediate the progression from simple steatosis to non-alcoholic steatohepatitis remain largely unclear. This study aimed to investigate the timedependent changes of triglyceride (TG) and free fatty acid (FFA) levels in the blood and liver over 24 weeks in high-fat diet-induced obese rats with NAFLD and to clarify the role of high FFA levels in the progression of liver injury. Male Wistar rats were randomly divided into three groups (n = 30 per group): the Control group, fed standard chow; the High-fat diet (HFD) group, fed high-fat chow; and the Acipimox group, fed an HFD plus acipimox (100 mg/kg/d, ig) for 8, 16 and 24 weeks. After treatment, blood and liver samples were collected for biochemical analyses, western blotting analysis and a histopathological study. The visceral fat/weight and liver/body weight ratios were higher in both the HFD and Acipimox groups than in the Control group. The TG and FFA concentrations in blood and liver were increased in the HFD group and associated with elevated serum alanine aminotransferase (ALT) and liver malondialdehyde (MDA) levels and macro/microvesicular steatosis on hepatic fragments. Although the TG levels in the liver were similar between the HFD and Acipimox groups (p > 0.05), the FFA concentrations in the blood and liver were much lower in the latter group (p < 0.05). The Acipimox group showed normal ALT and MDA levels as well as less severe hepatic histological changes than did the HFD group (NAFLD activity score: 2.14 ± 0.14, 2.43 ± 0.20 and 2.63 ± 0.26 at 8, 16 and 24 weeks, respectively; p < 0.05 versus the HFD group at 24 weeks). The diacylglycerol acyltransferase 2 (DGAT2) protein levels were similar between the HFD and Acipimox groups (p > 0.05), but the protein expression level of carnitine palmitoyltransferase 1a (CPT-1a) was higher in the Acipimox group. Liver TG accumulation does not cause cellular injury in the liver; rather, FFAs or their metabolites are responsible for liver injury via increased oxidative stress. It is suggested that the therapeutic efforts to prevent non-alcoholic liver injury progression should be focused on reducing the burden of fatty acids transported to the liver or those being synthesized in the liver.