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Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development.

Authors
  • Zhou, Enchen1, 2
  • Hoeke, Geerte1, 2
  • Li, Zhuang1, 2
  • Eibergen, Arthur C1, 2
  • Schonk, Amber W1, 2
  • Koehorst, Martijn3
  • Boverhof, Renze3
  • Havinga, Rick4
  • Kuipers, Folkert3, 4
  • Coskun, Tamer5
  • Boon, Mariëtte R1, 2
  • Groen, Albert K3, 4, 6
  • Rensen, Patrick C N1, 2
  • Berbée, Jimmy F P1, 2
  • Wang, Yanan1, 2
  • 1 Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. , (Netherlands)
  • 2 Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands. , (Netherlands)
  • 3 Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. , (Netherlands)
  • 4 Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. , (Netherlands)
  • 5 Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA. , (India)
  • 6 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. , (Netherlands)
Type
Published Article
Journal
Cardiovascular Research
Publisher
Oxford University Press
Publication Date
Aug 01, 2020
Volume
116
Issue
10
Pages
1710–1720
Identifiers
DOI: 10.1093/cvr/cvz253
PMID: 31589318
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development. APOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective β3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged β3-AR agonism reduced faecal BA excretion (-31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (-49%) and non-high-density lipoprotein cholesterol (-56%), tended to further attenuate atherosclerotic lesion area (-54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (-26%), thereby further increasing the plaque stability index (+44%). BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

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