The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice.
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.
['Kannisto|K|K|', 'Rehnmark|S|S|', 'Slätis|K|K|', 'Webb|P|P|', 'Larsson|L|L|', 'Gåfvels|M|M|', 'Eggertsen|G|G|', 'Parini|P|P|']
D000085:Acetates D000818:Animals D001011:Aorta D001057:Apolipoproteins E D050197:Atherosclerosis D001647:Bile Acids and Salts D001692:Biological Transport D002784:Cholesterol D004195:Disease Models, Animal D008099:Liver D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D010636:Phenols D010840:Phytosterols D011973:Receptors, LDL D013261:Sterols D037042:Thyroid Hormone Receptors beta D013997:Time Factors
Thyroid receptor β Bile acid Intestinal cholesterol absorption ApoE knockout LDL-receptor