Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy

Cheng, Lihong; Ding, Guoliang; Qin, Qianhong; Huang, Yao; Lewis, William; He, Nu; Evans, Ronald M.; Schneider, Michael; Brako, Florence A; Yan, Xiao; Chen, Yuqing E.; Yang, Qinglin

doi:10.1038/nm1116

Cited by 424 publications

(358 citation statements)

References 23 publications

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“…Alternatively, PPAR␦ may be responsible for some of these changes in gene expression because PPAR␦ has also been shown to regulate several genes involved in fatty acid transport and oxidation along with pdk4 expression. 38,39 On the basis of our data, we propose that initial inhibition of fatty acid oxidation, through loss of MCD, results in increased intracellular PPAR␣ or PPAR␦ ligands (ie, fatty acyl derivatives). The lack of increases in expression of either PPAR␣ or PPAR␦ (Data Supplement Figure, b and c) provides added support to this hypothesis.…”

Section: Dyck Et Al Reduced Ischemic Injury In MCD Ko Mouse Heartsmentioning

confidence: 82%

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

et al. 2006

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Background-Acute pharmacological inhibition of cardiac malonyl coenzyme A decarboxylase (MCD) protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. However, it is unknown whether chronic inhibition of MCD results in altered cardiac function, energy metabolism, or ischemic cardioprotection. Methods and Results-Mcd-deficient mice were produced and assessed for in vivo cardiac function as well as ex vivo cardiac function, energy metabolism, and ischemic tolerance. In vivo and ex vivo cardiac function was similar in wild-type and mcd Ϫ/Ϫ mice. Ex vivo working hearts from mcd Ϫ/Ϫ and wild-type mice displayed no significant differences in rates of fatty acid oxidation, glucose oxidation, or glycolysis. However, cardiac deletion of mcd resulted in an increased expression of genes regulating fatty acid utilization that may compensate for the loss of MCD protein and likely contributes to the absence of changes in energy metabolism in the aerobic heart. Despite the lack of changes in fatty acid utilization, hearts from mcd Ϫ/Ϫ mice displayed a marked preference for glucose utilization after ischemia, which correlated with a significant cardioprotection of ischemic hearts from mcd Ϫ/Ϫ mice compared with wild-type mice. Conclusions-Deletion of MCD markedly increases glucose oxidation and improves functional recovery of the heart after ischemia. As a result, chronic pharmacological inhibition of MCD may be a viable approach to treat myocardial ischemia. (Circulation. 2006;114:1721-1728.)

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Section: Dyck Et Al Reduced Ischemic Injury In MCD Ko Mouse Heartsmentioning

confidence: 82%

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

et al. 2006

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“…In cell culture, UCP2, UCP3, H-FABP, FAT/CD36, LPL, ACS and CPT1 were demonstrated to be PPARδ target genes (Muoio et al 2002;Dressel et al 2003). Overexpression of PPARδ in fat produced a lean phenotype due to increased oxidation of fats in adipocytes and resulted in white adipose tissue (WAT) that took on some brown adipose tissue (BAT) characteristics (Wang et al 2003) Cardiac metabolism is dependent on PPARδ and cardiomyocyte specific loss of PPARδ in mouse results in cardiomyopathy and reduced expression of β-oxidation genes (Cheng et al 2004). Consistently, ligand treatment (GW610742X) helped preserve β-oxidation in a rat model of congestive heart failure (Jucker et al 2007).…”

Section: Pparmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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“…Measurements of cellular palmitate oxidation rates were performed as described [16,17]. Cultured cardiomyocytes from 2 month-old rats treated with adiponectin (2 μg/ml) were pre-incubated in assay buffer containing [(in mMol/L), HEPES (20), NaH 2 PO 4 (1), MgSO 4 (0.4), CaCl 2 (1), NaCl (120), KCl (5), glucose (5), palmitic acid (0.2), oleic acid (0.2), pH 7.4] for 30 min at 37°C.…”

Section: C Palmitate Oxidation Assaymentioning

confidence: 99%

“…Glucose transport assays were performed in triplicate in 12-well (22 mm diameter) laminincoated tissue culture plates as described before [17]. Laminin-plated cardiomyocytes from 2 month-old rats were washed 3 times with PBS and cultured in 1 ml of glucose-and serum-free DMEM.…”

Section: Glucose Uptakes In Isolated Cardiomyocytesmentioning

confidence: 99%

Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor γ

Ding¹,

Qin²,

He³

et al. 2007

Journal of Molecular and Cellular Cardiology

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128

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Adiponectin is a protein hormone involved in maintaining energy homeostasis in metabolically active tissues. It enhances glucose and lipid metabolism via activation of AMP-dependent kinase (AMPK) in skeletal muscle and liver. Energy homeostasis is vital for the heart to work as a pump. In this study, we investigated whether adiponectin and its receptors are expressed in adult ventricular cardiomyocytes. We observed adiponectin transcript and protein in cultured ventricular cardiomyocytes isolated from adult rat, by quantitative real-time PCR, ELISA assays, Western blots, and immunofluorescent staining. In addition, we detected adiponectin receptor (AdipoR1 and AdipoR2) expression in the heart. AdipoR1 was expressed in rat myocardium at a level of about 50% of that in skeletal muscle; whereas adipoR2 was expressed at a similar level to that in liver. Rosiglitazone, a Peroxisome proliferator activated receptor γ (PPARγ) activator, substantially elevated expression of adiponectin in cultured cardiomyocytes and its secretion into cultured media. Rosiglitazone also increased adipoR1 and adipoR2 expression in cardiomyocytes. Treatment of recombinant globular adiponectin in cultured cardiomyocytes increased fatty acid oxidation and glucose uptake via activation of AMPK, suggesting a role for adiponectin in cardiac energy metabolism. Together, these data establish the existence of a local cardiac-specific adiponectin system that is regulated by PPARγ. Moreover, these findings indicate a role for adiponectin on normal myocardial energy homeostasis, in part, through the activation of AMPK.

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Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy

Cited by 424 publications

References 23 publications

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

Absence of Malonyl Coenzyme A Decarboxylase in Mice Increases Cardiac Glucose Oxidation and Protects the Heart From Ischemic Injury

Nuclear receptors, mitochondria and lipid metabolism

Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor γ

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