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Prevention of Diet-Induced Metabolic Dysregulation, Inflammation, and Atherosclerosis in Ldlr-/- Mice by Treatment With the ATP-Citrate Lyase Inhibitor Bempedoic Acid.
Samsoondar, Joshua P; Burke, Amy C; Sutherland, Brian G; Telford, Dawn E; Sawyez, Cynthia G; Edwards, Jane Y; Pinkosky, Stephen L; Newton, Roger S; Huff, Murray W.
Afiliação
  • Samsoondar JP; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Burke AC; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Sutherland BG; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Telford DE; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Sawyez CG; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Edwards JY; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Pinkosky SL; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Newton RS; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
  • Huff MW; From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; a
Arterioscler Thromb Vasc Biol ; 37(4): 647-656, 2017 04.
Article em En | MEDLINE | ID: mdl-28153881
ABSTRACT

OBJECTIVE:

Bempedoic acid (ETC-1002, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel low-density lipoprotein cholesterol-lowering compound. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. In this study, we tested the hypothesis that bempedoic acid would prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis. APPROACH AND

RESULTS:

Ldlr-/- mice were fed a high-fat, high-cholesterol diet (42% kcal fat, 0.2% cholesterol) supplemented with bempedoic acid at 0, 3, 10 and 30 mg/kg body weight/day. Treatment for 12 weeks dose-dependently attenuated diet-induced hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity. Compared to high-fat, high-cholesterol alone, the addition of bempedoic acid decreased plasma triglyceride (up to 64%) and cholesterol (up to 50%) concentrations, and improved glucose tolerance. Adiposity was significantly reduced with treatment. In liver, bempedoic acid prevented cholesterol and triglyceride accumulation, which was associated with increased fatty acid oxidation and reduced fatty acid synthesis. Hepatic gene expression analysis revealed that treatment significantly increased expression of genes involved in fatty acid oxidation while suppressing inflammatory gene expression. In full-length aorta, bempedoic acid markedly suppressed cholesteryl ester accumulation, attenuated the expression of proinflammatory M1 genes and attenuated the iNos/Arg1 ratio. Treatment robustly attenuated atherosclerotic lesion development in the aortic sinus by 44%, with beneficial changes in morphology, characteristic of earlier-stage lesions.

CONCLUSIONS:

Bempedoic acid effectively prevents plasma and tissue lipid elevations and attenuates the onset of inflammation, leading to the prevention of atherosclerotic lesion development in a mouse model of metabolic dysregulation.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: ATP Citrato (pro-S)-Liase / Receptores de LDL / Ácidos Dicarboxílicos / Inibidores Enzimáticos / Aterosclerose / Dislipidemias / Ácidos Graxos / Dieta Hiperlipídica / Inflamação / Fígado Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: ATP Citrato (pro-S)-Liase / Receptores de LDL / Ácidos Dicarboxílicos / Inibidores Enzimáticos / Aterosclerose / Dislipidemias / Ácidos Graxos / Dieta Hiperlipídica / Inflamação / Fígado Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article