High-fat feeding in cardiomyocyte-restricted PPARdelta knockout mice leads to cardiac overexpression of lipid metabolic genes but fails to rescue cardiac phenotypes.
Peroxisome proliferator-activated receptor delta (PPARdelta) is an essential determinant of basal myocardial fatty acid oxidation (FAO) and bioenergetics. We wished to determine whether increased lipid loading affects the PPARdelta deficient heart in transcriptional regulation of FAO and in the development of cardiac pathology. Cardiomyocyte-restricted PPARdelta knockout (CR-PPARdelta(-/-)) and control (alpha-MyHC-Cre) mice were subjected to 48 h of fasting and to a long-term maintenance on a (28 weeks) high-fat diet (HFD). The expression of key FAO proteins in heart was examined. Serum lipid profiles, cardiac pathology, and changes of various transduction signaling pathways were also examined. Mice subjected to fasting exhibited upregulated transcript expression of FAO genes in the CR-PPARdelta(-/-) hearts. Moreover, long-term HFD in CR-PPARdelta(-/-) mice induced a strikingly greater transcriptional response. After HFD, genes encoding key FAO enzymes were expressed remarkably more in CR-PPARdelta(-/-) hearts than in those of control mice. Despite the marked rise of FAO gene expression, corresponding protein expression remained low in the CR-PPARdelta(-/-) heart, accompanied by abnormalities in sarcomere structures and mitochondria that were similar to those of CR-PPARdelta(-/-) hearts with regular chow feeding. The CR-PPARdelta(-/-) mice displayed increased expression of PPARgamma co-activator-1alpha (PGC-1alpha) and PPARalpha in the heart with deactivated Akt and p42/44 MAPK signaling in response to HFD. We conclude that PPARdelta is an essential determinant of myocardial FAO. Increased lipid intake activates cardiac expression of FAO genes via PPARalpha/PGC-1alpha pathway, albeit it is not sufficient to improve cardiac pathology due to PPARdelta deficiency.
Li
Yuquan
Y
Department of Nutrition Sciences, University of Alabama at Birmingham, 1675 University Blvd, Birmingham, AL 35294-3360, USA.
Cheng
Lihong
L
Qin
Qianhong
Q
Liu
Jian
J
Lo
Woo-kuen
WK
Brako
Lowrence A
LA
Yang
Qinglin
Q
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage* / Q000494:pharmacology*; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation / Q000187:drug effects
D004041:Dietary Fats; D005227:Fatty Acids; D047493:PPAR alpha; D047494:PPAR delta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3