Raghavendra Mysore1, Francisco J Ortega2,3, Jèssica Latorre2, Maria Ahonen1, Hanna Savolainen-Peltonen4,5, Pamela Fischer-Posovszky6, Martin Wabitsch6, Vesa M Olkkonen1,7, José M Fernández-Real2,3, P A Nidhina Haridas1. 1. Minerva Foundation Institute for Medical Research, Biomedicum 2U, FI-00290 Helsinki, Finland. 2. Department of Diabetes, Endocrinology, and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), ES-17190 Girona, Spain. 3. CIBER de la Fisiopatología de la Obesidad y la Nutrición (CB06/03) and Instituto de Salud Carlos III, ES-28029 Madrid, Spain. 4. University of Helsinki and Helsinki University Hospital, Obstetrics and Gynecology, FI-00029 HUS, Helsinki, Finland. 5. Folkhälsan Research Center, Biomedicum 1, FI-00290 Helsinki, Finland. 6. Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, D-89075 Ulm, Germany. 7. Department of Anatomy, Faculty of Medicine, FI-00014 University of Helsinki, Finland.
Abstract
Context: Angiopoietin-like 8 (ANGPTL8) has been identified as a key regulator of lipid metabolism. Design: 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. Results: 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. Conclusions: 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.
Context:Angiopoietin-like 8 (ANGPTL8) has been identified as a key regulator of lipid metabolism. Design: 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. Results: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. Conclusions: 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.
Authors: Drahomira Holmannova; Lenka Borska; Ctirad Andrys; Pavel Borsky; Jan Kremlacek; Kvetoslava Hamakova; Vit Rehacek; Andrea Malkova; Tereza Svadlakova; Vladimir Palicka; Jan Krejsek; Zdenek Fiala Journal: J Immunol Res Date: 2020-05-20 Impact factor: 4.818