Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD
Decreased lipid metabolism but increased FA biosynthesis are coupled with changes in liver microRNAs in obese subjects with NAFLD
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DOI：
10.1038/ijo.2017.21
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发表时间：
2017-04-01
影响因子：
4.9
通讯作者：
Ortega, F. J.
中科院分区：
文献类型：
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作者：
Latorre, J.;Moreno-Navarrete, J. M.;Ortega, F. J.
背景/目的：许多关于肝脏miRNAs与肥胖和非酒精性脂肪性肝病（NAFLD）相关的争议需要额外的验证。本研究旨在调查基因和肝脏miRNA的变异在肥胖患者的样本有或没有NAFLD和人hepatocyte（HH）.SUBJECTS/METHODS：共招募了60名非连续肥胖妇女减肥手术后。受试者被分为NAFLD（n = 17），临界（n = 24）和正常酶谱，肝组织学和超声评估的对照组（n = 19）。在8名没有肝病迹象的肥胖女性和11名NAFLD患者中进行了744种miRNAs的分析。在扩展样本中测试了与从头脂肪酸（FA）生物合成、摄取、转运和β-氧化、葡萄糖代谢和炎症相关的基因的额外验证和表达。在HepG 2细胞和原代HH中检测了NAFLD相关基因和miRNAs的诱导，这些基因和miRNAs用棕榈酸（PA）、棕榈酸酯和油酸的组合、或高糖、以及模拟NAFLD中胰岛素抵抗的胰岛素（HG）处理。扩展样本的分析证实，在患有NAFLD的肥胖受试者中，miR-139- 5 p、miR-30 b-5 p、miR-122- 5 p和miR-422 a减少，而miR-146 b-5 p增加。多元线性回归分析显示，在控制混杂因素后，NAFLD可独立解释miR-139- 5 p（P = 0.005）、miR-30 b-5 p（P = 0.005）、miR-122- 5 p（P = 0.021）、miR-422 a（P = 0.007）和miR-146 a（P = 0.033）的表达差异。肝脏中miR-122- 5 p的减少与FA使用受损相关。炎症和巨噬细胞相关基因的表达与miR-30 b-5 p、miR-139- 5 p和miR-422 a的降低相反，而miR-146 b-5 p的增加与FABP 4相关，并降低葡萄糖代谢和FA动员。在部分协议，PA（而不是HG）导致减少miR-139- 5 p，miR-30 b5 p，miR-422 a和miR-146 a在体外，在平行增加脂肪生成和脂肪酸转运，减少葡萄糖代谢和减少FA oxidation.CONCLUSION：这项研究证实了减少肝脏葡萄糖和脂质代谢，但增加脂肪酸生物合成加上五个独特的miRNAs的变化肥胖NAFLD患者。
BACKGROUND/OBJECTIVE: Many controversies regarding the association of liver miRNAs with obesity and nonalcoholic fatty liver diseases (NAFLD) call for additional validations. This study sought to investigate variations in genes and hepatic miRNAs in a sample of obese patients with or without NAFLD and human hepatocytes (HH).SUBJECTS/METHODS: A total of 60 non-consecutive obese women following bariatric surgery were recruited. Subjects were classified as NAFLD (n = 17), borderline (n = 24) and controls (n = 19) with normal enzymatic profile, liver histology and ultrasound assessments. Profiling of 744 miRNAs was performed in 8 obese women with no sign of hepatic disease and 11 NAFLD patients. Additional validation and expression of genes related to de novo fatty acid (FA) biosynthesis, uptake, transport and beta-oxidation; glucose metabolism, and inflammation was tested in the extended sample. Induction of NAFLD-related genes and miRNAs was examined in HepG2 cells and primary HH treated with palmitic acid (PA), a combination of palmitate and oleic acid, or high glucose, and insulin (HG) mimicking insulin resistance in NAFLD.RESULTS: In the discovery sample, 14 miRNAs were associated with NAFLD. Analyses in the extended sample confirmed decreased miR-139-5p, miR-30b-5p, miR-122-5p and miR-422a, and increased miR-146b-5p in obese subjects with NAFLD. Multiple linear regression analyses disclosed that NAFLD contributed independently to explain miR-139-5p (P = 0.005), miR-30b-5p (P = 0.005), miR-122-5p (P = 0.021), miR-422a (P = 0.007) and miR-146a (P = 0.033) expression variance after controlling for confounders. Decreased miR-122-5p in liver was associated with impaired FA usage. Expression of inflammatory and macrophage-related genes was opposite to decreased miR-30b-5p, miR-139-5p and miR-422a, whereas increased miR-146b-5p was associated with FABP4 and decreased glucose metabolism and FA mobilization. In partial agreement, PA (but not HG) led to decreased miR-139-5p, miR-30b5p, miR-422a and miR-146a in vitro, in parallel with increased lipogenesis and FA transport, decreased glucose metabolism and diminished FA oxidation.CONCLUSION: This study confirms decreased liver glucose and lipid metabolism but increased FA biosynthesis coupled with changes in five unique miRNAs in obese patients with NAFLD.