title: Pharmacological interference with intestinal bile acid transport reduces plasma cholesterol in LDL receptor/apoE deficiency.
abstract: Reduction of plasma cholesterol by statins is fundamental to prevent coronary heart disease. Such therapy is often sub-optimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the enzyme Cyp7a1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of PR835, a drug belonging to a new class of lipid-lowering agents that inhibit the Slc10a2 protein, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. Cyp7a1 enzyme activity and mRNA were induced several-fold, and hepatic HMG CoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed to induction of other known hepatic lipoprotein receptors and indicate the presence of new points of targeting in lipid-lowering therapy.
authors.affiliation: Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gälman
authors.forename: Ann-Margret
authors.initials: AM
authors.lastname: Ostlund-Lindqvist
authors.forename: Anna
authors.initials: A
authors.lastname: Björquist
authors.forename: Sandra
authors.initials: S
authors.lastname: Schreyer
authors.forename: Lennart
authors.initials: L
authors.lastname: Svensson
authors.forename: Bo
authors.initials: B
authors.lastname: Angelin
authors.forename: Mats
authors.initials: M
authors.lastname: Rudling
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D000069059:Atorvastatin; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000172:deficiency* / Q000235:genetics; D027981:Symporters; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D006538:Heptanoic Acids; D029363:Organic Anion Transporters, Sodium-Dependent; C471468:PR835; D011758:Pyrroles; D012333:RNA, Messenger; D018110:Receptors, Lipoprotein; D027981:Symporters; D013841:Thiazepines; C071908:sodium-bile acid cotransporter; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase