Rescue of cardiomyopathy in peroxisome proliferator-activated receptor-alpha transgenic mice by deletion of lipoprotein lipase identifies sources of cardiac lipids and peroxisome proliferator-activated receptor-alpha activators.
BACKGROUND
Emerging evidence in obesity and diabetes mellitus demonstrates that excessive myocardial fatty acid uptake and oxidation contribute to cardiac dysfunction. Transgenic mice with cardiac-specific overexpression of the fatty acid-activated nuclear receptor peroxisome proliferator-activated receptor-alpha (myosin heavy chain [MHC]-PPARalpha mice) exhibit phenotypic features of the diabetic heart, which are rescued by deletion of CD36, a fatty acid transporter, despite persistent activation of PPARalpha gene targets involved in fatty acid oxidation.


RESULTS
To further define the source of fatty acid that leads to cardiomyopathy associated with lipid excess, we crossed MHC-PPARalpha mice with mice deficient for cardiac lipoprotein lipase (hsLpLko). MHC-PPARalpha/hsLpLko mice exhibit improved cardiac function and reduced myocardial triglyceride content compared with MHC-PPARalpha mice. Surprisingly, in contrast to MHC-PPARalpha/CD36ko mice, the activity of the cardiac PPARalpha gene regulatory pathway is normalized in MHC-PPARalpha/hsLpLko mice, suggesting that PPARalpha ligand activity exists in the lipoprotein particle. Indeed, LpL mediated hydrolysis of very-low-density lipoprotein activated PPARalpha in cardiac myocytes in culture. The rescue of cardiac function in both models was associated with improved mitochondrial ultrastructure and reactivation of transcriptional regulators of mitochondrial function.


CONCLUSIONS
MHC-PPARalpha mouse hearts acquire excess lipoprotein-derived lipids. LpL deficiency rescues myocyte triglyceride accumulation, mitochondrial gene regulatory derangements, and contractile function in MHC-PPARalpha mice. Finally, LpL serves as a source of activating ligand for PPARalpha in the cardiomyocyte.
Duncan
Jennifer G
JG
Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Mo., USA.
Bharadwaj
Kalyani G
KG
Fong
Juliet L
JL
Mitra
Riddhi
R
Sambandam
Nandakumar
N
Courtois
Michael R
MR
Lavine
Kory J
KJ
Goldberg
Ira J
IJ
Kelly
Daniel P
DP
D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000493:pharmacokinetics; D005227:Fatty Acids / Q000493:pharmacokinetics; D005260:Female; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D014280:Triglycerides / Q000493:pharmacokinetics
D018955:CD36 Antigens; D015243:Cholesterol, VLDL; D005227:Fatty Acids; D047493:PPAR alpha; D014280:Triglycerides; D008071:Lipoprotein Lipase; D018995:Myosin Heavy Chains