title: The pathophysiological role of oxidized cholesterols in epicardial fat accumulation and cardiac dysfunction: a study in swine fed a high caloric diet with an inhibitor of intestinal cholesterol absorption, ezetimibe.
abstract: Oxidized cholesterols (oxycholesterols) in food have been recognized as strong atherogenic components, but their tissue distributions and roles in cardiovascular diseases remain unclear. To investigate whether accumulation of oxycholesterols is linked to cardiac morphology and function, and whether reduction of oxycholesterols can improve cardiac performance, domestic male swine were randomized to a control diet (C), high caloric diet (HCD) or HCD+Ezetimibe, an inhibitor of intestinal cholesterol absorption, group (HCD+E) and evaluated for: (1) distribution of oxycholesterol components in serum and tissues, (2) levels of oxycholesterol-related enzymes, (3) paracardial and epicardial coronary fat thickness, and (4) cardiac performance. Ezetimibe treatment for 8weeks attenuated increases in oxycholesterols in the HCD group almost completely in liver, but reduced only levels of 4β-hydroxycholesterol in left ventricular (LV) myocardium. Ezetimibe treatment altered the expression of genes for cholesterol and fatty acid metabolism and decreased the expression of CYP3A46, which catabolizes cholesterol to 4β-hydroxycholesterol, strongly in liver. An increase in epicardial fat thickness and impaired cardiac performance in the HCD group were improved by ezetimibe treatment, and the improvement was closely related to the reduction in levels of 4β-hydroxycholesterol in LV myocardium. In conclusion, an increase in oxycholesterols in the HCD group was closely related to cardiac hypertrophy and dysfunction, as well as an increase in epicardial fat thickness. Ezetimibe may directly reduce oxycholesterol in liver and LV myocardium, and improve cardiac morphology and function.
authors.affiliation: Department of Cardio-Diabetes Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Electronic address: mshimabukuro-ur@umin.ac.jp.
authors.forename: Michio
authors.initials: M
authors.lastname: Shimabukuro
authors.affiliation: Department of Bioresource and Bioenvironmental Sciences, Graduate School of Kyushu University, Fukuoka, Japan.
authors.forename: Chinami
authors.initials: C
authors.lastname: Okawa
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Bioresource and Bioenvironmental Sciences, Graduate School of Kyushu University, Fukuoka, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yanagi
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Uematsu
authors.affiliation: Department of Cardiovascular Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sugasawa
authors.affiliation: Department of Cardiovascular Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kurobe
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Joo-Ri
authors.initials: JR
authors.lastname: Kim-Kaneyama
authors.affiliation: Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Lei
authors.affiliation: Department of Diagnostic Radiology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Takao
authors.affiliation: Department of Bioresource and Bioenvironmental Sciences, Graduate School of Kyushu University, Fukuoka, Japan.
authors.forename: Yasutake
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Fukuda
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Soeki
authors.affiliation: Department of Cardiovascular Surgery, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitagawa
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.affiliation: Department of Bioresource and Bioenvironmental Sciences, Graduate School of Kyushu University, Fukuoka, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Cardiovascular Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects* / Q000473:pathology; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D002784:Cholesterol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D000069438:Ezetimibe / Q000627:therapeutic use; D005765:Gastrointestinal Agents / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006331:Heart Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006888:Hydroxycholesterols / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D006963:Hyperphagia / Q000503:physiopathology; D007408:Intestinal Absorption / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000009:adverse effects* / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010496:Pericardium; D011897:Random Allocation; D034421:Sus scrofa
chemical_list: D000924:Anticholesteremic Agents; D005765:Gastrointestinal Agents; D006888:Hydroxycholesterols; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D000069438:Ezetimibe
keywords: Cardiac function; Cardiac hypertrophy; Epicardial fat; Obesity; Oxycholesterol