title: The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis.
abstract: The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol; conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7 alpha-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.
authors.affiliation: Prince Henry's Institute of Medical Research and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. kylie.hewitt@med.monash.edu.au
authors.forename: Kylie N
authors.initials: KN
authors.lastname: Hewitt
authors.forename: Wah Chin
authors.initials: WC
authors.lastname: Boon
authors.forename: Yoko
authors.initials: Y
authors.lastname: Murata
authors.forename: Margaret E E
authors.initials: ME
authors.lastname: Jones
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000097:blood / Q000493:pharmacokinetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D002785:Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001141:Aromatase; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D004967:Estrogens; D006903:Hydroxymethylglutaryl CoA Reductases; D008074:Lipoproteins; D011973:Receptors, LDL; D002785:Sterol O-Acyltransferase; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D000097587:Sterol O-Acyltransferase 2; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C497391:Srebf2 protein, mouse