Faye Borthwick1, Rabban Mangat1, Samantha Warnakula1, Miriam Jacome-Sosa1, Donna F Vine1, Spencer D Proctor2. 1. Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada. 2. Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada. Electronic address: Spencer.Proctor@ualberta.ca.
Abstract
OBJECTIVE: Statins are widely used for the treatment of hyperlipidemia to reduce cardiovascular disease (CVD) risk. Intriguingly, recent reports suggest that whilst statins are effective in reducing hepatic cholesterol synthesis, they in turn may up-regulate intestinal cholesterol absorption. The direct effects and/or mechanisms of this phenomenon remain largely unknown. The aim of this study was to investigate the potential for statins to increase intestinal lipid absorption and/or secretion in a rodent model of the metabolic syndrome (MetS). METHODS AND RESULTS: Mets JCR:LA-cp rats received a 1% cholesterol diet containing Simvastatin (0.01% w/w), for 8 weeks. Fasting and postprandial plasma biochemical profile was assessed using enzymatic assays and a modified apoB48 (chylomicron; CM) western blotting protocol. Statin treatment reduced fasting plasma TG (-49%), cholesterol (-24%) and postprandial plasma apoB48 (-58%). The intestinal secretion of lipids into mesenteric lymph was assessed using lymph fistulae procedures. Interestingly, MetS rats treated with statin secreted greater cholesterol (1.9-fold) and TG (1.5-fold) per apoB48 particle, into mesenteric lymph. This was shown to be as a result of simvastatin-induced increase in intestinal cholesterol absorption (31.5%). Experiments using in vivo inhibition of lipoprotein lipase (LPL; poloxamer-407) demonstrated statin treatment reduced hepatic cholesterol secretion (-49%), but significantly increased hepatic (73%) TG secretion in MetS rats. Statin treatment also increased the expression of genes involved in lipid synthesis (Hmgcr, Srebp1, Fas, Acc; 33-67%) and reduced those involved in efflux (Abca1, Abcg8; -36 to 73%) in enterocytes and liver of MetS rats versus untreated control. CONCLUSIONS: In a rodent model of MetS, statin treatment adversely up-regulates intestinal lipid secretion as a result of increased intestinal cholesterol absorption, and increases the intestinal expression of genes involved in lipid synthesis; effects which may confound clinical benefits to remnant dyslipidemia.
OBJECTIVE: Statins are widely used for the treatment of hyperlipidemia to reduce cardiovascular disease (CVD) risk. Intriguingly, recent reports suggest that whilst statins are effective in reducing hepatic cholesterol synthesis, they in turn may up-regulate intestinal cholesterol absorption. The direct effects and/or mechanisms of this phenomenon remain largely unknown. The aim of this study was to investigate the potential for statins to increase intestinal lipid absorption and/or secretion in a rodent model of the metabolic syndrome (MetS). METHODS AND RESULTS: Mets JCR:LA-cp rats received a 1% cholesterol diet containing Simvastatin (0.01% w/w), for 8 weeks. Fasting and postprandial plasma biochemical profile was assessed using enzymatic assays and a modified apoB48 (chylomicron; CM) western blotting protocol. Statin treatment reduced fasting plasma TG (-49%), cholesterol (-24%) and postprandial plasma apoB48 (-58%). The intestinal secretion of lipids into mesenteric lymph was assessed using lymph fistulae procedures. Interestingly, MetS rats treated with statin secreted greater cholesterol (1.9-fold) and TG (1.5-fold) per apoB48 particle, into mesenteric lymph. This was shown to be as a result of simvastatin-induced increase in intestinal cholesterol absorption (31.5%). Experiments using in vivo inhibition of lipoprotein lipase (LPL; poloxamer-407) demonstrated statin treatment reduced hepatic cholesterol secretion (-49%), but significantly increased hepatic (73%) TG secretion in MetS rats. Statin treatment also increased the expression of genes involved in lipid synthesis (Hmgcr, Srebp1, Fas, Acc; 33-67%) and reduced those involved in efflux (Abca1, Abcg8; -36 to 73%) in enterocytes and liver of MetS rats versus untreated control. CONCLUSIONS: In a rodent model of MetS, statin treatment adversely up-regulates intestinal lipid secretion as a result of increased intestinal cholesterol absorption, and increases the intestinal expression of genes involved in lipid synthesis; effects which may confound clinical benefits to remnant dyslipidemia.
Authors: Miriam Jacome-Sosa; Elizabeth J Parks; Richard S Bruno; Esra Tasali; Gary F Lewis; Barbara O Schneeman; Tia M Rains Journal: Adv Nutr Date: 2016-03-15 Impact factor: 8.701
Authors: M Kupreeva; A Diane; R Lehner; R Watts; M Ghosh; S Proctor; D Vine Journal: Am J Physiol Endocrinol Metab Date: 2018-08-28 Impact factor: 4.310
Authors: Francisco J Zapatero-Belinchón; Rebecca Moeller; Lisa Lasswitz; Marco van Ham; Miriam Becker; Graham Brogden; Ebba Rosendal; Wenjie Bi; Belén Carriquí-Madroñal; Koushikul Islam; Annasara Lenman; Antonia P Gunesch; Jared Kirui; Thomas Pietschmann; Anna K Överby; Lothar Jänsch; Gisa Gerold Journal: iScience Date: 2021-11-18