title: Simvastatin treatment upregulates intestinal lipid secretion pathways in a rodent model of the metabolic syndrome.
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).
  
  
  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.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Faye
authors.initials: F
authors.lastname: Borthwick
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Rabban
authors.initials: R
authors.lastname: Mangat
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Warnakula
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Jacome-Sosa
authors.affiliation: Metabolic and Cardiovascular Diseases Laboratory, Molecular Cell Biology of Lipids Group, Alberta Diabetes and Mazankowski Heart Institutes, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Donna F
authors.initials: DF
authors.lastname: Vine
authors.affiliation: 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.
authors.forename: Spencer D
authors.initials: SD
authors.lastname: Proctor
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D002784:Cholesterol / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000188:drug therapy; D005508:Food Deprivation; D005786:Gene Expression Regulation; D006868:Hydrolysis; D007422:Intestines / Q000187:drug effects; D008055:Lipids / Q000097:blood*; D008071:Lipoprotein Lipase / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000188:drug therapy; D019518:Postprandial Period; D051381:Rats; D019821:Simvastatin / Q000097:blood / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation
chemical_list: D000924:Anticholesteremic Agents; D008055:Lipids; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin; D008071:Lipoprotein Lipase
keywords: Intestine; Lipids; Metabolic syndrome; Statins