Mysore Raghavendra, Ortega Francisco J, Latorre Jèssica, Ahonen Maria, Savolainen-Peltonen Hanna, Fischer-Posovszky Pamela, Wabitsch Martin, Olkkonen Vesa M, Fernández-Real José M, Haridas P A Nidhina
Minerva Foundation Institute for Medical Research, Biomedicum 2U, FI-00290 Helsinki, Finland.
Department of Diabetes, Endocrinology, and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), ES-17190 Girona, Spain.
J Clin Endocrinol Metab. 2017 Nov 1;102(11):4001-4012. doi: 10.1210/jc.2017-00453.
Angiopoietin-like 8 (ANGPTL8) has been identified as a key regulator of lipid metabolism.
We addressed the correlation between ANGPTL8 messenger RNA (mRNA) with hallmark insulin-regulated and lipogenic genes in human adipose tissue (AT). The regulation of ANGPTL8 expression in adipocytes was studied after inflammatory challenge, and the role of microRNA (miRNA)-221-3p therein was investigated.
ANGPTL8 gene expression in subcutaneous AT (SAT) and visceral AT (VAT) was highly correlated with SLC2A4/GLUT4, ADIPOQ, fatty acyl synthase, and diacylglycerol O-acyltransferase 1. ANGPTL8 mRNA in human adipocytes was suppressed by the inflammatory impact of conditioned medium of lipopolysaccharide-stimulated macrophages, which markedly induced miR-221-3p. MiR-221-3p was shown to target the ANGPTL8 mRNA, and to reduce adipocyte ANGPTL8 protein expression. Analysis of SAT biopsies from 69 subjects ranging from lean to morbidly obese and of VAT of 19 female subjects biopsied during gynecologic surgery demonstrated a trend of negative correlation between ANGPTL8 and miR-221-3p. Significant negative correlation of ANGPTL8 and miR-221-3p was identified in presurgery SAT samples from 22 morbidly obese subjects undergoing bariatric surgery, but vanished after ∼2-year surgery-induced weight loss, which also resulted in a marked reduction of miR-221-3p. ANGPTL8 correlated negatively with the AT inflammatory gene phospholipase A2 G7, whereas miR-221-3p showed a significant positive correlation with this marker. Of note, no correlation was found between AT ANGPTL8 mRNA expression and plasma ANGPTL8.
The inflammation-induced miR-221-3p regulates ANGPTL8 expression in adipocytes. This miRNA impact may become especially prominent under pathologic conditions such as morbid obesity, putatively contributing to the impaired AT lipid metabolism in metabolic disease.
血管生成素样蛋白8（ANGPTL8）已被确定为脂质代谢的关键调节因子。
我们研究了人脂肪组织（AT）中ANGPTL8信使核糖核酸（mRNA）与标志性胰岛素调节和生脂基因之间的相关性。在炎症刺激后研究了脂肪细胞中ANGPTL8表达的调节，并研究了微小核糖核酸（miRNA）-221-3p在其中的作用。
皮下脂肪组织（SAT）和内脏脂肪组织（VAT）中的ANGPTL8基因表达与溶质载体家族2成员4/葡萄糖转运蛋白4（SLC2A4/GLUT4）、脂联素（ADIPOQ）、脂肪酰基合成酶和二酰甘油O-酰基转移酶1高度相关。人脂肪细胞中的ANGPTL8 mRNA受到脂多糖刺激的巨噬细胞条件培养基的炎症影响的抑制，脂多糖刺激的巨噬细胞条件培养基显著诱导miR-221-3p。已证明miR-221-3p靶向ANGPTL8 mRNA，并降低脂肪细胞ANGPTL8蛋白表达。对69名从消瘦到病态肥胖的受试者的SAT活检组织以及19名妇科手术中活检的女性受试者的VAT进行分析，结果显示ANGPTL8与miR-221-3p之间呈负相关趋势。在22名接受减肥手术的病态肥胖受试者术前的SAT样本中，ANGPTL8与miR-221-3p存在显著负相关，但在术后约2年手术引起的体重减轻后这种相关性消失，体重减轻也导致miR-221-3p显著降低。ANGPTL8与AT炎症基因磷脂酶A2 G7呈负相关，而miR-221-3p与该标志物呈显著正相关。值得注意的是，未发现AT中ANGPTL8 mRNA表达与血浆ANGPTL8之间存在相关性。
炎症诱导的miR-221-3p调节脂肪细胞中ANGPTL8的表达。在病态肥胖等病理条件下，这种miRNA的影响可能会尤为突出，推测其会导致代谢疾病中AT脂质代谢受损。
