M John Chapman1, Alexina Orsoni2, Paul Robillard3, Patrice Therond4, Philippe Giral5. 1. National Institute for Health and Medical Research (INSERM), Pitié-Salpêtrière University Hospital, Paris, France; Department of Endocrinology-Metabolism, Pitié-Salpêtrière University Hospital, Paris, France; Pierre et Marie Curie University-Paris 6, Paris, France. Electronic address: john.chapman@upmc.fr. 2. National Institute for Health and Medical Research (INSERM), Pitié-Salpêtrière University Hospital, Paris, France; Service de Biochimie, AP-HP, HUPS, Bicetre University Hospital, Le Kremlin Bicetre, France. 3. National Institute for Health and Medical Research (INSERM), Pitié-Salpêtrière University Hospital, Paris, France. 4. Service de Biochimie, AP-HP, HUPS, Bicetre University Hospital, Le Kremlin Bicetre, France; EA 7357, Paris-Sud University and Paris-Saclay University, Chatenay-Malabry, France. 5. INSERM UMR1166 and Cardiovascular Prevention Units, ICAN-Institute of CardioMetabolism and Nutrition, AP-HP, Pitie-Salpetriere University Hospital, Paris, France.
Abstract
BACKGROUND: Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. OBJECTIVE: We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. METHODS: Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. RESULTS: Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment. CONCLUSION: Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.
BACKGROUND: Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. OBJECTIVE: We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. METHODS: Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. RESULTS: Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment. CONCLUSION: Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.
Authors: M John Chapman; Alexina Orsoni; Ricardo Tan; Natalie A Mellett; Anh Nguyen; Paul Robillard; Philippe Giral; Patrice Thérond; Peter J Meikle Journal: J Lipid Res Date: 2020-04-15 Impact factor: 5.922