A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease.

Obesity and the associated pathologies including dyslipidemia, insulin resistance, type 2 diabetes, and cardiovascular disease constitute a major threat to global human health. Yet, the genetic factors that differentially predispose individuals to this cluster of pathologies are unclear. The fatty acid-binding protein aP2 is a cytoplasmic lipid chaperon expressed in adipocytes and macrophages. Mice with aP2 deficiency are partially resistant to obesity-induced insulin resistance and type 2 diabetes, have lower circulating triglycerides, and exhibit marked protection against atherosclerosis. Here, we demonstrate a functionally significant genetic variation at the aP2 locus in humans that results in decreased adipose tissue aP2 expression due to alteration of the CAAT box/enhancer-binding protein binding and reduced transcriptional activity of the aP2 promoter. In population genetic studies with 7,899 participants, individuals that carry this T-87C polymorphism had lower serum triglyceride levels and significantly reduced risk for coronary heart disease and type 2 diabetes compared with subjects homozygous for the WT allele. Taken together, our results indicate that reduction in aP2 activity in humans generate a metabolically favorable phenotype that is similar to aP2 deficiency in experimental models.

[1]  J. Manson,et al.  A prospective study of lipoprotein(a) and risk of coronary heart disease among women with type 2 diabetes , 2005, Diabetologia.

[2]  K. Wellen,et al.  Inflammation, stress, and diabetes. , 2005, The Journal of clinical investigation.

[3]  J. Suttles,et al.  The Fatty Acid-binding Protein, aP2, Coordinates Macrophage Cholesterol Trafficking and Inflammatory Activity , 2005, Journal of Biological Chemistry.

[4]  Keita Kono,et al.  Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. , 2005, Cell metabolism.

[5]  Q. Tong,et al.  Interaction between GATA and the C/EBP Family of Transcription Factors Is Critical in GATA-Mediated Suppression of Adipocyte Differentiation , 2005, Molecular and Cellular Biology.

[6]  Jing Ma,et al.  Inflammatory markers and the risk of coronary heart disease in men and women. , 2004, The New England journal of medicine.

[7]  H. Campos,et al.  Arachidonic acid in adipose tissue is associated with nonfatal acute myocardial infarction in the central valley of Costa Rica. , 2004, The Journal of nutrition.

[8]  Jeffrey B. Boord,et al.  Combined Adipocyte-Macrophage Fatty Acid–Binding Protein Deficiency Improves Metabolism, Atherosclerosis, and Survival in Apolipoprotein E–Deficient Mice , 2004, Circulation.

[9]  L. Makowski,et al.  Fatty acid binding proteins--the evolutionary crossroads of inflammatory and metabolic responses. , 2004, The Journal of nutrition.

[10]  Nader Rifai,et al.  Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. , 2004, Diabetes care.

[11]  F. Spener,et al.  Fatty acid-binding proteins--insights from genetic manipulations. , 2004, Progress in lipid research.

[12]  S. Peñuelas,et al.  Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages. , 2004, Biochemical and biophysical research communications.

[13]  J. Manson,et al.  Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. , 2004, JAMA.

[14]  E. Rimm,et al.  Alcohol Consumption Patterns and HbA1c, C-Peptide and Insulin Concentrations in Men , 2003, Journal of the American College of Nutrition.

[15]  R. Parker,et al.  Role of the fatty acid binding protein mal1 in obesity and insulin resistance. , 2003, Diabetes.

[16]  W. Garvey,et al.  The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. , 2002, Atherosclerosis.

[17]  Jeffrey B. Boord,et al.  Adipocyte Fatty Acid–Binding Protein, aP2, Alters Late Atherosclerotic Lesion Formation in Severe Hypercholesterolemia , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[18]  A. Hamsten,et al.  Fatty acid binding protein expression in different adipose tissue depots from lean and obese individuals , 2001, Diabetologia.

[19]  Jeffrey B. Boord,et al.  Lack of macrophage fatty-acid–binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis , 2001, Nature Medicine.

[20]  S. Bonner-Weir,et al.  Improved Glucose and Lipid Metabolism in Genetically Obese Mice Lacking aP2. , 2000, Endocrinology.

[21]  A. Saltiel.  Series introduction: the molecular and physiological basis of insulin resistance: emerging implications for metabolic and cardiovascular diseases. , 2000, The Journal of clinical investigation.

[22]  R. Parker,et al.  Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/- mice. , 1999, Diabetes.

[23]  Bruce M. Spiegelman,et al.  Uncoupling of Obesity from Insulin Resistance Through a Targeted Mutation in aP2, the Adipocyte Fatty Acid Binding Protein , 1996, Science.

[24]  M. Lane,et al.  Cell-free transcription directed by the 422 adipose P2 gene promoter: activation by the CCAAT/enhancer binding protein. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Smith,et al.  Human adipocyte lipid-binding protein: purification of the protein and cloning of its complementary DNA. , 1989, Biochemistry.

[26]  B. Spiegelman,et al.  Adipocyte P2 gene: developmental expression and homology of 5'-flanking sequences among fat cell-specific genes. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Mokdad,et al.  Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. , 2003, JAMA.