title: Increased plasma levels of oxysterols, in vivo markers of oxidative stress, in patients with familial combined hyperlipidemia: reduction during atorvastatin and fenofibrate therapy.
abstract: Familial combined hyperlipidemia (FCHL), the most common inherited disorder of lipid metabolism, is associated with an increased risk of atherosclerosis that is not fully explained by the metabolic disturbances of these patients. Oxidative damage to lipid components accumulating in the plasma of FCHL patients might contribute to explaining this lack of evidence. Cholesterol is one of the preferential targets of oxidation in LDL and this may contribute to setting a proatherogenetic phenotype in FCHL. We investigated plasma oxysterols (7-ketocholesterol and 7beta-hydroxycholesterol) and alpha-tocopherol as in vivo hallmarks of lipid-related oxidative stress. Oxidative stress hallmarks were measured in 45 FCHL patients and 54 sex- and age-matched healthy controls; in FCHL patients, oxidative stress and lipid profile parameters were also assessed in response to lipid-lowering drugs in a 24-week randomized, open-label trial with atorvastatin or fenofibrate. FCHL patients showed markedly increased levels of oxysterols (p < 0.001) and reduced alpha-tocopherol/total lipids (p < 0.001) compared to controls. These differences were independent of the presence of clinical atherosclerosis and persisted after correction for hyperlipidemia. Atorvastatin and fenofibrate significantly improved the lipid profile and caused a comparable decrease in plasma oxysterols, with the normalization of 7-ketocholesterol and a significant reduction of 7beta-hydroxycholesterol (p < 0.001). These drugs also decreased the ratio of alpha-tocopherol/total lipids by more than 30% (p < 0.001). In conclusion, FCHL patients showed increased hallmarks of cholesterol oxidation and decreased levels of alpha-tocopherol/total lipids. Atorvastatin and fenofibrate displayed comparable efficiency in decreasing oxysterols, but they further decreased lipid-corrected alpha-tocopherol levels in plasma. More research work is needed to understand the clinical meaning of these findings, which may help to understand the role of oxidative stress in FCHL and lipid-lowering therapy.
authors.affiliation: Department of Clinical and Applied Medical Therapy, University La Sapienza, 00161 Rome, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Arca
authors.forename: Silvia
authors.initials: S
authors.lastname: Natoli
authors.forename: Fausta
authors.initials: F
authors.lastname: Micheletta
authors.forename: Sara
authors.initials: S
authors.lastname: Riggi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Di Angelantonio
authors.forename: Anna
authors.initials: A
authors.lastname: Montali
authors.forename: Teresa Maria
authors.initials: TM
authors.lastname: Antonini
authors.forename: Roberto
authors.initials: R
authors.lastname: Antonini
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
authors.forename: Luigi
authors.initials: L
authors.lastname: Iuliano
mesh_terms: D000328:Adult; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D004338:Drug Combinations; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D006950:Hyperlipidemia, Familial Combined / Q000097:blood* / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007653:Ketocholesterols / Q000097:blood*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018384:Oxidative Stress; D011758:Pyrroles / Q000627:therapeutic use*; D024502:alpha-Tocopherol / Q000097:blood
chemical_list: D015415:Biomarkers; D004338:Drug Combinations; D006538:Heptanoic Acids; D006888:Hydroxycholesterols; D000960:Hypolipidemic Agents; D007653:Ketocholesterols; D008055:Lipids; D008074:Lipoproteins; D011758:Pyrroles; C011724:cholest-5-en-3 beta,7 alpha-diol; D000069059:Atorvastatin; D024502:alpha-Tocopherol; C003001:7-ketocholesterol; D011345:Fenofibrate