Inflammation increases plasma angiopoietin-like protein 4 in subjects with the metabolic syndrome and type 2 diabetes

background Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages. objective To assess whether systemic low grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). design We studied 335 male subjects: healthy controls (Controls), subjects with the metabolic syndrome without inflammation (MetS-I) and with low grade inflammation (MetS+I), and T2DM patients. All non-diabetic subjects included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C-reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro . horse-radish peroxidase for 20 min, and tetramethyl benzidine substrate reagent for 6 min. The reaction was stopped by addition of 50 µl of 10% H 2 SO 4 , and the absorbance was measured at 450 nm.

[1]  L. Velloso,et al.  Type 2 diabetes mellitus—an autoimmune disease? , 2013, Nature Reviews Endocrinology.

[2]  H. Lamb,et al.  Dietary modulation of plasma angiopoietin-like protein 4 concentrations in healthy volunteers and in patients with type 2 diabetes. , 2013, The American journal of clinical nutrition.

[3]  H. Lamb,et al.  Effect of lifestyle intervention plus rosiglitazone or placebo therapy on left ventricular mass assessed with cardiovascular magnetic resonance in the metabolic syndrome , 2011, Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance.

[4]  D. Clegg,et al.  Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. , 2011, The Journal of clinical investigation.

[5]  N. Tan,et al.  Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. , 2010, Cell metabolism.

[6]  H. Hendriks,et al.  Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[7]  Jeroen J. Bax,et al.  Pioglitazone Improves Cardiac Function and Alters Myocardial Substrate Metabolism Without Affecting Cardiac Triglyceride Accumulation and High-Energy Phosphate Metabolism in Patients With Well-Controlled Type 2 Diabetes Mellitus , 2009, Circulation.

[8]  K. V. van Dijk,et al.  Angptl4 Upregulates Cholesterol Synthesis in Liver via Inhibition of LPL- and HL-Dependent Hepatic Cholesterol Uptake , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[9]  T. Olivecrona,et al.  Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue , 2006, Proceedings of the National Academy of Sciences.

[10]  J. Flier,et al.  TLR4 links innate immunity and fatty acid-induced insulin resistance. , 2006, The Journal of clinical investigation.

[11]  Paul Zimmet,et al.  The metabolic syndrome—a new worldwide definition , 2005, The Lancet.

[12]  W. Wahli,et al.  The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment* , 2004, Journal of Biological Chemistry.

[13]  Z. Bloomgarden,et al.  Inflammation and insulin resistance. , 2003, Diabetes care.

[14]  Gary L Myers,et al.  Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. , 2003, Circulation.

[15]  P. Chambon,et al.  Characterization of the Fasting-induced Adipose Factor FIAF, a Novel Peroxisome Proliferator-activated Receptor Target Gene* , 2000, The Journal of Biological Chemistry.

[16]  B. Spiegelman,et al.  Peroxisome Proliferator-Activated Receptor γ Target Gene Encoding a Novel Angiopoietin-Related Protein Associated with Adipose Differentiation , 2000, Molecular and Cellular Biology.