TY - JOUR
T1 - Colesevelamenhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development
AU - Zhou, Enchen
AU - Hoeke, Geerte
AU - Li, Zhuang
AU - Eibergen, Arthur C.
AU - Schonk, Amber W.
AU - Koehorst, Martijn
AU - Boverhof, Renze
AU - Havinga, Rick
AU - Kuipers, Folkert
AU - Coskun, Tamer
AU - Boon, Mariette R.
AU - Groen, Albert K.
AU - Rensen, Patrick C. N.
AU - Berbee, Jimmy F. P.
AU - Wang, Yanan
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Aims 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 and results APOE∗3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective b3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged b3-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%). Conclusion 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.
AB - Aims 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 and results APOE∗3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective b3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged b3-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%). Conclusion 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.
KW - Atherosclerosis
KW - Bile acid metabolism
KW - Brown adipose tissue
KW - Cholesterol turnover
KW - Hyperlipidaemia
UR - http://www.scopus.com/inward/record.url?scp=85088676905&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/cvr/cvz253
DO - https://doi.org/10.1093/cvr/cvz253
M3 - Article
C2 - 31589318
SN - 0008-6363
VL - 116
SP - 1710
EP - 1720
JO - Cardiovascular research
JF - Cardiovascular research
IS - 10
ER -