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

Zhou, E., Hoeke, G., Li, Z., Eibergen, A. C., Schonk, A. W., Koehorst, M., Boverhof, R., Havinga, R., Kuipers, F., Coskun, T., Boon, M. R., Groen, A. K., Rensen, P. C. N., Berbée, J. F. P. & Wang, Y., 2019, In : Cardiovascular Research. 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

METHODS AND RESULTS: 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 fecal 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 fecal 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%).

CONCLUSIONS: 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 hyperlipidemia and cardiovascular diseases.

A TRANSLATIONAL PERSPECTIVE: Current therapeutic strategies are unable to prevent the majority of cardiovascular disease (CVD)-relating morbidities and mortalities, illustrating the need for new therapeutic strategies. Brown fat has been shown as an emerging target to combat hyperlipidemia and atherosclerosis. Here we showed that prolonged brown fat activation promotes bile acid (BA) reabsorption, resulting in elevated plasma BA and hepatic cholesterol content, both of which are reversed by additional BA sequestration. Importantly, combining BA sequestration with brown fat activation further lowers plasma cholesterol and reduces atherosclerosis development, indicating the combination therapy as a new therapeutic strategy to treat hyperlipidemia, and ultimately CVD.

Original languageEnglish
Number of pages11
JournalCardiovascular Research
Publication statusE-pub ahead of print - 2019

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