CCAAT/Enhancer Binding Protein α (C/EBPα) in Adipose Tissue Regulates Genes in Lipid and Glucose Metabolism and a Genetic Variation in C/EBPα Is Associated with Serum Levels of Triglycerides

• Published in: The journal of clinical endocrinology and metabolism Vol. 93; no. 12; pp. 4880 - 4886
• Main Authors: Olofsson, Louise E., Orho-Melander, Marju, William-Olsson, Lena, Sjöholm, Kajsa, Sjöström, Lars, Groop, Leif, Carlsson, Björn, Carlsson, Lena M. S., Olsson, Bob
• Format: Journal Article
• Language: English
• Published: Washington Oxford University Press 01.12.2008
• Subjects: Adipogenesis; Adiponectin; Adipose tissue; Body fat; CCAAT/enhancer-binding protein; CD36 antigen; Coenzyme A; Diabetes mellitus (non-insulin dependent); Diacylglycerol O-acyltransferase; Dietary restrictions; Diglycerides; DNA microarrays; Gene expression; Gene polymorphism; Genetic diversity; Glucose; Glucose metabolism; Hexokinase; Lipid metabolism; Lipids; Lipoprotein lipase; Metabolic syndrome; Population genetics; Protein turnover; Serum levels; Triglycerides
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2008-0574

Context: CCAAT/enhancer binding protein α (C/EBPα) is a transcription factor involved in adipogenesis and hepatic glucose and lipid metabolism. Objective: The aim of the study was to test the hypothesis that adipose tissue C/EBPα regulates genes in lipid and glucose metabolism and to test for an association between a polymorphism in C/EBPα and metabolic parameters. Design and Methods: Adipose tissue C/EBPα mRNA expression was analyzed at four time points in obese subjects with (n = 12) and without (n = 12) the metabolic syndrome during caloric restriction (450 kcal/d for 16 wk) using DNA microarray and real-time PCR. Adenoviral overexpression of C/EBPα was used to identify genes regulated by C/EBPα in 3T3-L1 cells. Association between a genetic variation in C/EBPα (rs12691) and metabolic parameters was tested in the Swedish Obese Subjects (SOS) study (n = 528) and replicated in Finnish individuals from the Botnia type 2 diabetes study (n = 4866). Results: During caloric restriction, adipose tissue C/EBPα mRNA levels were reduced in subjects with the metabolic syndrome (P = 0.024) and correlated to metabolic parameters. In 3T3-L1 cells, C/EBPα regulated the expression of adiponectin; hexokinase 2; lipoprotein lipase; diacylglycerol O-acyltransferase 1 and 2; ATP-binding cassette, sub-family D, member 2; acyl-coenzyme A synthetase long-chain family member 1; CD36; and hydroxysteroid 11-β dehydrogenase 1. Furthermore, the expression of the human homologs, except adiponectin, correlated to C/EBPα mRNA levels in human adipose tissue. The AA genotype of rs12691 was associated with higher serum triglyceride levels in the SOS study (P = 0.022), and this association was replicated in the Botnia study (P = 0.041). Conclusions: Adipose tissue C/EBPα regulates several genes in glucose and lipid metabolism, and a genetic variation in C/EBPα is associated with triglycerides in two independent populations.