Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

J Lipid Res. 2016 Nov;57(11):2073-2087. doi: 10.1194/jlr.P068585. Epub 2016 Aug 31.

Abstract

Atherogenic mixed dyslipidemia associates with oxidative stress and defective HDL antioxidative function in metabolic syndrome (MetS). The impact of statin treatment on the capacity of HDL to inactivate LDL-derived, redox-active phospholipid hydroperoxides (PCOOHs) in MetS is indeterminate. Insulin-resistant, hypertriglyceridemic, hypertensive, obese males were treated with pitavastatin (4 mg/day) for 180 days, resulting in marked reduction in plasma TGs (-41%) and LDL-cholesterol (-38%), with minor effects on HDL-cholesterol and apoAI. Native plasma LDL (baseline vs. 180 days) was oxidized by aqueous free radicals under mild conditions in vitro either alone or in the presence of the corresponding pre- or poststatin HDL2 or HDL3 at authentic plasma mass ratios. Lipidomic analyses revealed that statin treatment i) reduced the content of oxidizable polyunsaturated phosphatidylcholine (PUPC) species containing DHA and linoleic acid in LDL; ii) preferentially increased the content of PUPC species containing arachidonic acid (AA) in small, dense HDL3; iii) induced significant elevation in the content of phosphatidylcholine and phosphatidylethanolamine (PE) plasmalogens containing AA and DHA in HDL3; and iv) induced formation of HDL3 particles with increased capacity to inactivate PCOOH with formation of redox-inactive phospholipid hydroxide. Statin action attenuated LDL oxidability Concomitantly, the capacity of HDL3 to inactivate redox-active PCOOH was enhanced relative to HDL2, consistent with preferential enrichment of PE plasmalogens and PUPC in HDL3.

Trial registration: ClinicalTrials.gov NCT01595828.

Keywords: antioxidative activity; high density lipoprotein 3; lipidomics; low density lipoprotein; metabolic syndrome disease; oxidative stress; phospholipid hydroxides; pitavastatin.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antioxidants / administration & dosage
  • Apolipoprotein A-I / blood
  • Cholesterol, HDL / blood*
  • Cholesterol, LDL / blood
  • Dyslipidemias / blood
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / pathology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Oxidative Stress / drug effects*
  • Quinolines / administration & dosage*

Substances

  • APOA1 protein, human
  • Antioxidants
  • Apolipoprotein A-I
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Quinolines
  • pitavastatin

Associated data

  • ClinicalTrials.gov/NCT01595828