title: Perfusion of hearts with triglyceride-rich particles reproduces the metabolic abnormalities in lipotoxic cardiomyopathy.
abstract: Hearts with overexpression of anchored lipoprotein lipase (LpL) by cardiomyocytes (hLpL(GPI) mice) develop a lipotoxic cardiomyopathy. To characterize cardiac fatty acid (FA) and triglyceride (TG) metabolism in these mice and to determine whether changes in lipid metabolism precede cardiac dysfunction, hearts from young mice were perfused in Langendorff mode with [14C]palmitate. In hLpL(GPI) hearts, FA uptake and oxidation were decreased by 59 and 82%, respectively. This suggests reliance on an alternative energy source, such as TG. Indeed, these hearts oxidized 88% more TG. Hearts from young hLpL(GPI) mice also had greater uptake of intravenously injected cholesteryl ester-labeled Intralipid and VLDL. To determine whether perfusion of normal hearts would mimic the metabolic alterations found in hLpL(GPI) mouse hearts, wild-type hearts were perfused with [14C]palmitate and either human VLDL or Intralipid (0.4 mM TG). Both sources of TG reduced [14C]palmitate uptake (48% with VLDL and 45% with Intralipid) and FA oxidation (71% with VLDL and 65% with Intralipid). Addition of either heparin or LpL inhibitor P407 to Intralipid-containing perfusate restored [14C]palmitate uptake and confirmed that Intralipid inhibition requires local LpL. Our data demonstrate that reduced FA uptake and oxidation occur before mechanical dysfunction in hLpL(GPI) lipotoxicity. This physiology is reproduced with perfusion of hearts with TG-containing particles. Together, the results demonstrate that cardiac uptake of TG-derived FA reduces utilization of albumin-FA.
authors.affiliation: Dept. of Medicine, Columbia Univ., 630 West 168th St., New York, NY 10032, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Pillutla
authors.forename: Yuying C
authors.initials: YC
authors.lastname: Hwang
authors.forename: Ayanna
authors.initials: A
authors.lastname: Augustus
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagyu
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Johnston
authors.forename: Michiyo
authors.initials: M
authors.lastname: Kaneko
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000367:Age Factors; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage; D066298:In Vitro Techniques; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010168:Palmitates / Q000008:administration & dosage / Q000378:metabolism*; D010477:Perfusion
chemical_list: D004791:Enzyme Inhibitors; D005217:Fat Emulsions, Intravenous; D010168:Palmitates; D008071:Lipoprotein Lipase