title: Sex differences in the hepatic cholesterol sensing mechanisms in mice.
abstract: Cholesterol is linked to many multifactorial disorders, including different forms of liver disease where development and severity depend on the sex. We performed a detailed analysis of cholesterol and bile acid synthesis pathways at the level of genes and metabolites combined with the expression studies of hepatic cholesterol uptake and transport in female and male mice fed with a high-fat diet with or without cholesterol. Lack of dietary cholesterol led to a stronger response of the sterol sensing mechanism in females, resulting in higher expression of cholesterogenic genes compared to males. With cholesterol in the diet, the genes were down-regulated in both sexes; however, males maintained a more efficient hepatic metabolic flux through the pathway. Females had higher content of hepatic cholesterol but this was likely not due to diminished excretion but rather due to increased synthesis and absorption. Dietary cholesterol and sex were not important for gallbladder bile acids composition. Neither sex up-regulated Cyp7a1 upon cholesterol loading and there was no compensatory up-regulation of Abcg5 or Abcg8 transporters. On the other hand, females had higher expression of the Ldlr and Cd36 genes. These findings explain sexual dimorphism of cholesterol metabolism in response to dietary cholesterol in a high-fat diet in mice, which contributes to understanding the sex-basis of cholesterol-associated liver diseases.
authors.affiliation: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
authors.forename: Gregor
authors.initials: G
authors.lastname: Lorbek
authors.forename: Martina
authors.initials: M
authors.lastname: Perše
authors.forename: Simon
authors.initials: S
authors.lastname: Horvat
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D053898:Biosynthetic Pathways; D002784:Cholesterol / Q000378:metabolism*; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D059467:Transcriptome
chemical_list: D001647:Bile Acids and Salts; D012333:RNA, Messenger; D002784:Cholesterol
references.citation: J Appl Toxicol. 2006 Jul-Aug;26(4):381-4
references.pmid: 16705668
references.citation: Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):431-8
references.pmid: 19299327
references.citation: Nutr Metab (Lond). 2011 Jan 24;8:4
references.pmid: 21261989
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32
references.pmid: 14512514
references.citation: J Endocrinol. 2008 Sep;198(3):635-43
references.pmid: 18603607
references.citation: Am J Med. 2000 Apr 15;108(6):481-6
references.pmid: 10781781
references.citation: Cell Metab. 2012 May 2;15(5):665-74
references.pmid: 22560219
references.citation: Physiol Genomics. 2010 Aug;42(3):456-68
references.pmid: 20551147
references.citation: Hepatology. 2012 Oct;56(4):1300-10
references.pmid: 22531947
references.citation: Int J Med Sci. 2011 Mar 25;8(3):254-62
references.pmid: 21487569
references.citation: Adv Enzyme Regul. 1998;38:65-85
references.pmid: 9762347
references.citation: Hepatology. 1998 Oct;28(4):1088-94
references.pmid: 9755247
references.citation: J Clin Endocrinol Metab. 2009 Oct;94(10):3872-81
references.pmid: 19773396
references.citation: J Gastroenterol Hepatol. 2003 Nov;18(11):1272-82
references.pmid: 14535984
references.citation: Crit Rev Biochem Mol Biol. 2010 Jun;45(3):185-98
references.pmid: 20482385
references.citation: Genome Biol. 2002 Jun 18;3(7):RESEARCH0034
references.pmid: 12184808
references.citation: Hepatology. 2009 Oct;50(4):1263-72
references.pmid: 19637290
references.citation: BMC Mol Biol. 2010 Aug 16;11:60
references.pmid: 20712867
references.citation: Biol Sex Differ. 2012 Apr 04;3:9
references.pmid: 22475005
references.citation: Metabolism. 2008 Sep;57(9):1241-7
references.pmid: 18702950
references.citation: Genome Res. 2006 Aug;16(8):995-1004
references.pmid: 16825664
references.citation: Comput Biol Med. 2013 Jun;43(5):471-80
references.pmid: 23566393
references.citation: Am J Physiol. 1999 May;276(5):G1117-24
references.pmid: 10330001
references.citation: Pharmacol Ther. 2010 Jul;127(1):19-40
references.pmid: 20420853
references.citation: PLoS One. 2011;6(8):e23506
references.pmid: 21858147
references.citation: Cell Metab. 2011 Mar 2;13(3):260-73
references.pmid: 21356516
references.citation: BMC Res Notes. 2011 Nov 24;4:513
references.pmid: 22115060
references.citation: J Biol Chem. 2006 Sep 22;281(38):27816-26
references.pmid: 16857673
references.citation: Genome Biol. 2007;8(2):R19
references.pmid: 17291332
references.citation: Endocrinology. 2004 Apr;145(4):1972-9
references.pmid: 14684613
references.citation: Curr Gerontol Geriatr Res. 2010;:420139
references.pmid: 20454643
references.citation: J Biol Chem. 2002 May 24;277(21):18793-800
references.pmid: 11901146
references.citation: Drug Metab Dispos. 1998 Dec;26(12):1199-201
references.pmid: 9860928
references.citation: J Lipid Res. 2011 Feb;52(2):289-98
references.pmid: 21097822
references.citation: J Lipids. 2011;2011:101242
references.pmid: 22007308
references.citation: Cell. 2006 Jan 13;124(1):35-46
references.pmid: 16413480
references.citation: Biol Reprod. 2002 Oct;67(4):1115-24
references.pmid: 12297526
references.citation: J Gastroenterol Hepatol. 2008 Nov;23(11):1635-48
references.pmid: 18752564
references.citation: Molecules. 2013 Apr 04;18(4):4002-17
references.pmid: 23558541
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Jul 15;877(22):2081-6
references.pmid: 19525158
references.citation: Acta Paediatr. 2010 Aug;99(8):1218-23
references.pmid: 20298493
references.citation: Cleve Clin J Med. 2013 Mar;80(3):187
references.pmid: 23456471
references.citation: Eur J Clin Invest. 2009 Aug;39(8):631-48
references.pmid: 19496803
references.citation: Endocrinology. 2003 Sep;144(9):3895-903
references.pmid: 12933663
references.citation: J Lipid Res. 1993 Oct;34(10):1637-59
references.pmid: 8245716
references.citation: Hepatol Res. 2008 Mar;38(3):219-24
references.pmid: 18047583
references.citation: Mol Med. 2012 Dec 06;18:1346-55
references.pmid: 22952059
references.citation: J Clin Invest. 2001 Sep;108(6):905-15
references.pmid: 11560960
references.citation: J Lipid Res. 1997 Feb;38(2):315-23
references.pmid: 9162751
references.citation: J Endocrinol. 2010 Mar;204(3):233-40
references.pmid: 19837721
references.citation: J Biol Chem. 2013 Jun 28;288(26):18707-15
references.pmid: 23696639
references.citation: Clin Chem. 1982 Jan;28(1):5-8
references.pmid: 7035003
references.citation: Autoimmun Rev. 2008 Sep;7(8):626-30
references.pmid: 18603021
references.citation: Hepatology. 2011 Mar;53(3):800-9
references.pmid: 21374659
references.citation: J Lipids. 2011;2011:783976
references.pmid: 21773052
references.citation: Hepatology. 2008 Aug;48(2):474-86
references.pmid: 18666236
references.citation: Cell Metab. 2006 Sep;4(3):185-98
references.pmid: 16950136
references.citation: CMAJ. 2007 Mar 13;176(6):S1-44
references.pmid: 17353516
references.citation: J Biol Chem. 2002 Feb 8;277(6):3801-4
references.pmid: 11733542
references.citation: J Lipid Res. 2003 Nov;44(11):2109-19
references.pmid: 12897189
references.citation: Front Biosci (Landmark Ed). 2009 Jan 01;14(7):2584-98
references.pmid: 19273221
references.citation: J Womens Health Gend Based Med. 2001 Oct;10(8):757-64
references.pmid: 11703888
references.citation: Biochim Biophys Acta. 1980 Dec 1;633(2):154-61
references.pmid: 7193053