title: Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction.
abstract: Long-chain fatty acids (FAs) are the predominant energy substrate utilized by the adult heart. The heart can utilize unesterified FA bound to albumin or FA obtained from lipolysis of lipoprotein-bound triglyceride (TG). We used heart-specific lipoprotein lipase knock-out mice (hLpL0) to test whether these two sources of FA are interchangeable and necessary for optimal heart function. Hearts unable to obtain FA from lipoprotein TG were able to compensate by increasing glucose uptake, glycolysis, and glucose oxidation. HLpL0 hearts had decreased expression of pyruvate dehydrogenase kinase 4 and increased cardiomyocyte expression of glucose transporter 4. Conversely, FA oxidation rates were reduced in isolated perfused hLpL0 hearts. Following abdominal aortic constriction expression levels of genes regulating FA and glucose metabolism were acutely up-regulated in control and hLpL0 mice, yet all hLpL0 mice died within 48 h of abdominal aortic constriction. Older hLpL0 mice developed cardiac dysfunction characterized by decreased fractional shortening and interstitial and perivascular fibrosis. HLpL0 hearts had increased expression of several genes associated with transforming growth factor-beta signaling. Thus, long term reduction of lipoprotein FA uptake is associated with impaired cardiac function despite a compensatory increase in glucose utilization.
authors.affiliation: Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, New York 10032, USA.
authors.forename: Ayanna S
authors.initials: AS
authors.lastname: Augustus
authors.forename: Jonathan
authors.initials: J
authors.lastname: Buchanan
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hirata
authors.forename: Hye-Lim
authors.initials: HL
authors.lastname: Noh
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'armiento
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002250:Carbon Radioisotopes; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004452:Echocardiography; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D007700:Kinetics; D008071:Lipoprotein Lipase / Q000032:analysis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D010725:Phosphocreatine / Q000031:analogs & derivatives / Q000032:analysis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D002250:Carbon Radioisotopes; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D010725:Phosphocreatine; C025403:phosphocreatinine; D000255:Adenosine Triphosphate; D002784:Cholesterol; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D008071:Lipoprotein Lipase; D005947:Glucose