The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice

K. Kannisto, S. Rehnmark, K. Slätis, P. Webb, L. Larsson, M. Gåfvels, G. Eggertsen, P. Parini

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)544-554
Number of pages11
JournalAtherosclerosis
Volume237
Issue number2
DOIs
StatePublished - Dec 1 2014

Keywords

  • ApoE knockout
  • Bile acid
  • Intestinal cholesterol absorption
  • LDL-receptor
  • Thyroid receptor β

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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