title: Impaired VLDL assembly: a novel mechanism contributing to hepatic lipid accumulation following ovariectomy and high-fat/high-cholesterol diets?
abstract: The aim of the present study was to identify molecular mechanisms involved in liver fat and cholesterol accumulation in ovariectomised (Ovx) rats fed with high-cholesterol diets. VLDL assembly and bile acid metabolism were specifically targeted. After being either Ovx or sham-operated, the rats were fed a standard diet or a high-fat diet containing 0, 0·25 or 0·5 % cholesterol for 6 weeks. Although Ovx rats exposed to dietary cholesterol intake accumulated the greatest amount of hepatic fat and cholesterol, plasma cholesterol levels were lower (P< 0·05) in these animals than in the corresponding control rats. Accompanying this observation, ovariectomy and dietary cholesterol intake resulted in a down-regulation (P< 0·05) of the expression of genes associated with VLDL assembly, including microsomal TAG transfer protein, diacylglycerol acyltransferase 2, acyl-CoA:cholesterol acyltransferase 2 and apoB-100 as well as genes associated with bile acid metabolism including farnesoid X receptor and bile salt export pump (P< 0·01). These results indicate that high-fat/high-cholesterol diets and ovariectomy concomitantly disrupt hepatic lipid output through defects in VLDL assembly and, most probably, secretion. The results also point to a defect in hepatic bile acid secretion. The present study offers novel insights into intrahepatic lipid metabolism, which may be relevant to metabolic complications found in postmenopausal women.
authors.affiliation: Department of Kinesiology,Université de Montréal, 2100, Boulevard Édouard-Montpetit,Montréal,QC,CanadaH3C 3J7.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Côté
authors.affiliation: Montfort Hospital Research Institute,Ottawa,ON,Canada.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Chapados
authors.affiliation: Department of Kinesiology,Université de Montréal, 2100, Boulevard Édouard-Montpetit,Montréal,QC,CanadaH3C 3J7.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lavoie
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000009:adverse effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism*; D015536:Down-Regulation; D004967:Estrogens / Q000172:deficiency*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D005260:Female; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D010052:Ovariectomy; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D053299:Apolipoprotein B-100; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D004967:Estrogens; D008079:Lipoproteins, VLDL; D018160:Receptors, Cytoplasmic and Nuclear; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; D000099150:Receptor, Farnesoid X-Activated; C490548:Abcb11 protein, rat; C106092:microsomal triglyceride transfer protein