title: Targeted Proteomics Identifies Paraoxonase/Arylesterase 1 (PON1) and Apolipoprotein Cs as Potential Risk Factors for Hypoalphalipoproteinemia in Diabetic Subjects Treated with Fenofibrate and Rosiglitazone.
abstract: Low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels contribute to the excess rate of cardiovascular events seen in subjects with type 2 diabetes. Fenofibrate treatment partially reverses dyslipidemia in these subjects. However, a paradoxical marked reduction in HDL-C and HDL's major protein, apolipoprotein A-I, is a complication of fenofibrate in combination with rosiglitazone, an insulin-sensitizing agent. Risk factors for this condition, termed hypoalphalipoproteinemia, have yet to be identified. Using a case-control study design with subjects enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, we tested the hypothesis that alterations in HDL's protein cargo predispose diabetic subjects to fenofibrate/rosiglitazone-induced hypoalphalipoproteinemia. HDL was isolated from blood obtained from controls (no decreases or increase in HDL-C while receiving fenofibrate/rosiglitazone therapy) and cases (developed hypoalphalipoproteinemia after fenofibrate/rosiglitazone treatment) participating in the ACCORD study before they began fenofibrate/rosiglitazone treatment. HDL proteins were quantified by targeted parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) with isotope dilution. This approach demonstrated marked increases in the relative concentrations of paraoxonase/arylesterase 1 (PON1), apolipoprotein C-II (APOC2), apolipoprotein C-I, and apolipoprotein H in the HDL of subjects who developed hypoalphalipoproteinemia. The case and control subjects did not differ significantly in baseline HDL-C levels or other traditional lipid risk factors. We used orthogonal biochemical techniques to confirm increased levels of PON1 and APOC2. Our observations suggest that an imbalance in HDL proteins predisposes diabetic subjects to develop hypoalphalipoproteinemia on fenofibrate/rosiglitazone therapy.
authors.affiliation: From the ‡Department of Medicine, University of Washington, Seattle, WA, 98109; ronsein@iq.usp.br.
authors.forename: Graziella E
authors.initials: GE
authors.lastname: Ronsein
authors.affiliation: § Columbia University College of Physicians and Surgeons, Department of Medicine, New York, NY 10032;
authors.forename: Gissette
authors.initials: G
authors.lastname: Reyes-Soffer
authors.affiliation: From the ‡Department of Medicine, University of Washington, Seattle, WA, 98109;
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: ¶Children's Hospital Oakland Research Institute, Oakland, CA 94609.
authors.forename: Michael
authors.initials: M
authors.lastname: Oda
authors.affiliation: § Columbia University College of Physicians and Surgeons, Department of Medicine, New York, NY 10032;
authors.forename: Henry
authors.initials: H
authors.lastname: Ginsberg
authors.affiliation: From the ‡Department of Medicine, University of Washington, Seattle, WA, 98109;
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
mesh_terms: D000368:Aged; D053304:Apolipoprotein C-II / Q000378:metabolism*; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000097:blood / Q000517:prevention & control*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000009:adverse effects*; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000139:chemically induced*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D008075:Lipoproteins, HDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D040901:Proteomics / Q000379:methods*; D012307:Risk Factors; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D053304:Apolipoprotein C-II; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D011345:Fenofibrate