title: The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice.
abstract: Thyroid hormone reduces plasma cholesterol and increases expression of low-density lipoprotein receptor (LDL-R) in liver, an effect mediated by thyroid receptor β (TRβ). The selective TRβ modulator GC-1 also enhances several steps in reverse cholesterol transport and can decrease serum cholesterol independently of LDL-R. To test whether GC-1 reduces atherosclerosis and to determine which mechanisms are active, we treated ApoE deficient mice with atherogenic diet ± GC-1. GC-1 reduced cholesteryl esters in aorta after 20 weeks. Serum free and esterified cholesterol were reduced after 1 and 10 weeks, but not 20 weeks. Hepatic bile acid synthesis and LDL-R expression was elevated after 1, 10 and 20 weeks, without changes in hepatic de novo cholesterol synthesis. GC-1 increased faecal neutral sterols and reduced serum campesterol after 1 week, indicating reduced intestinal cholesterol absorption. After 20 weeks, GC-1 increased faecal bile acids, but not faecal neutral sterols. Hepatic scavenger receptor B1 (SR-B1) expression was decreased by GC-1. We conclude that GC-1 delays the onset of atherosclerosis in ApoE deficient mice. Since ApoE is needed for hepatic cholesterol reabsorption by LDL-R, this supports the idea that GC-1 reduces serum cholesterol independently of LDL-R by increasing hepatic bile acid synthesis. GC-1 lipid-lowering effects in ApoE deficient mice may also be partly due to reduced intestinal cholesterol absorption. Since reductions in serum cholesterol are reversed at longer times, these GC-1 dependent effects may not be enough for sustained cholesterol reduction in long term treatments.
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Kannisto
authors.affiliation: Axcentua Pharmaceuticals AB, Huddinge, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Rehnmark
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Slätis
authors.affiliation: Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Webb
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Larsson
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Gåfvels
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Eggertsen
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine Karolinska Institutet, Stockholm, Sweden. Electronic address: paolo.parini@ki.se.
authors.forename: P
authors.initials: P
authors.lastname: Parini
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000737:chemistry; D001692:Biological Transport; D002784:Cholesterol / Q000031:analogs & derivatives / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010636:Phenols / Q000494:pharmacology*; D010840:Phytosterols / Q000097:blood; D011973:Receptors, LDL / Q000378:metabolism; D013261:Sterols / Q000737:chemistry; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000085:Acetates; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; C413355:GC 1 compound; D010636:Phenols; D010840:Phytosterols; D011973:Receptors, LDL; D013261:Sterols; D037042:Thyroid Hormone Receptors beta; C021273:campesterol; D002784:Cholesterol
keywords: ApoE knockout; Bile acid; Intestinal cholesterol absorption; LDL-receptor; Thyroid receptor β