Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients

Abstract

BackgroundAngiopoietin-like protein 3 (ANGPTL3) is a major lipoprotein regulator and shows positive correlation with high-density lipoprotein-cholesterol (HDL-c) in population studies and ANGPTL3 mutated subjects. However, no study has looked its correlation with HDL components nor with HDL function in patients with type 2 diabetes mellitus (T2DM).MethodsWe studied 298 non-diabetic subjects and 300 T2DM patients who were randomly recruited in the tertiary referral centre. Plasma levels of ANGPTL3 were quantified by ELISA. Plasma samples were fractionated to obtain HDLs. HDL components including apolipoprotein A-I (apoA-I), triglyceride, serum amyloid A (SAA), phospholipid and Sphingosine-1-phosphate were measured. HDLs were isolated from female controls and T2DM patients by ultracentrifugation to assess cholesterol efflux against HDLs. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, body mass index and lipid lowering drugs were performed in male or female non-diabetic participants or diabetic patients, respectively.ResultsWe demonstrated that plasma level of ANGPTL3 was lower in female T2DM patients than female controls although no difference of ANGPTL3 levels was detected between male controls and T2DM patients. After adjusting for confounding factors, one SD increase of ANGPTL3 (164.6 ng/ml) associated with increase of 2.57 mg/dL cholesterol and 1.14 μg/mL apoA-I but decrease of 47.07 μg/L of SAA in HDL particles of non-diabetic females (p < 0.05 for cholesterol and SAA; p < 0.0001 for apoA-I). By contrast, 1-SD increase of ANGPTL3 (159.9 ng/ml) associated with increase of 1.69 mg/dl cholesterol and 1.25 μg/mL apoA-I but decrease of 11.70 μg/L of SAA in HDL particles of female diabetic patients (p < 0.05 for cholesterol; p < 0.0001 for apoA-I; p = 0.676 for SAA). Moreover, one SD increase of ANGPTL3 associated with increase of 2.11 % cholesterol efflux against HDLs in non-diabetic females (p = 0.071) but decrease of 1.46 % in female T2DM patients (p = 0.13) after adjusting for confounding factors.ConclusionsANGPTL3 is specifically correlated with HDL-c, apoA-I, SAA and HDL function in female non-diabetic participants. The decrease of ANGPTL3 level in female T2DM patients might contribute to its weak association to HDL components and function. ANGPTL3 could be considered as a novel therapeutic target for HDL metabolism for treating diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0450-1) contains supplementary material, which is available to authorized users.

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…LDL‐c (low‐density lipoprotein‐cholesterol) was computed from serum total cholesterol and HDL‐c and serum triglycerides by the Friedewald equation 23. Body mass index (BMI) was measured as described before 21. Pancreatic β‐cell function and insulin resistance were computed by Homeostasis Model of Assessment (Homa‐B and HOMA‐IR; http://www.dtu.ox.ac.uk/homacalculator/), using fasting insulin and glucose in the subjects.…”

“…Briefly, RAW264.7 macrophages were plated at the density of 1×10 5  cells/well in a 96‐well plate and maintained in DMEM plus 10% fetal bovine serum (Sigma‐Aldrich) for 2 hours. The adherent cells were first loaded with labeled cholesterol for 16 hours and then exposed to 2.5 μL plasma or 100 μg/mL HDLs for 4 hours 21, 27. When using plasma as cholesterol acceptor, they were treated with Serum Treatment Reagent prior to loading (Catalog K582‐100, Biovision).…”

“…23 Body mass index (BMI) was measured as described before. 21 Pancreatic b-cell function and insulin resistance were computed by Homeostasis Model of Assessment (Homa-B and HOMA-IR; http://www.dtu.ox.ac.uk/homacalculator/), using fasting insulin and glucose in the subjects. To assess kidney function, estimated glomerular filtration rate was calculated according to the formula.…”

“…Pathological alteration of HDL metabolism imbalances HDL components and thus abrogates the protective effects of HDLs in cardiovascular events 18, 19, 20. Previously, we demonstrated that ANGPTL3, another family member of ANGPTL4, is positively associated with apolipoprotein A‐I and HDL function in nondiabetic individuals 21. Interestingly, ANGPTL4 is present in HDLs isolated from mice and human plasma 22.…”

“…[18][19][20] Previously, we demonstrated that ANGPTL3, another family member of ANGPTL4, is positively associated with apolipoprotein A-I and HDL function in nondiabetic individuals. 21 Interestingly, ANGPTL4 is present in HDLs isolated from mice and human plasma. 22 However, limited data have determined whether and how ANGPTL4, as a component of HDLs, has any direct impact on HDL metabolism and its function.…”