Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice

Lee, Young; Naseem, R. Haris; Duplomb, Laurence; Park, Byung‐Hyun; Garry, Daniel J.; Richardson, James A.; Schaffer, Jean E.; Unger, Roger H

doi:10.1073/pnas.0405499101

Cited by 136 publications

(102 citation statements)

References 25 publications

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“…It has been suggested that the primary physiological role of leptin is to prevent FA accumulation in nonadipose tissues, such as skeletal muscle, liver, pancreas, and heart (52). In mice with severe lipotoxic cardiomyopathy, induced transgenically by cardiomyocyte-specific overexpression of the acyl-CoA synthase, elevations in plasma leptin levels completely prevented the dilated cardiomyopathy, elevations in myocardial TG stores, and cardiomyocyte hypertrophy (27). Similarly, during dietary-induced obesity, hyperleptinemia protected nonadipocytes from steatosis and lipotoxicity (28).…”

Section: Discussionmentioning

confidence: 97%

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

Rennison¹,

McElfresh²,

Okere³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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November 17, 2006; doi:10.1152/ajpheart.01021.2006.-Lipid accumulation in nonadipose tissue due to enhanced circulating fatty acids may play a role in the pathophysiology of heart failure, obesity, and diabetes. Accumulation of myocardial lipids and related intermediates, e.g., ceramide, is associated with decreased contractile function, mitochondrial oxidative phosphorylation, and electron transport chain (ETC) complex activities. We tested the hypothesis that the progression of heart failure would be exacerbated by elevated myocardial lipids and an associated ceramide-induced inhibition of mitochondrial oxidative phosphorylation and ETC complex activities. Heart failure (HF) was induced by coronary artery ligation. Rats were then randomly assigned to either a normal (10% kcal from fat; HF, n ϭ 8) or high saturated fat diet (60% kcal from saturated fat; HF ϩ Sat, n ϭ 7). Sham-operated animals (sham; n ϭ 8) were fed a normal diet. Eight weeks postligation, left ventricular (LV) function was assessed by echocardiography and catheterization. Subsarcolemmal and interfibrillar mitochondria were isolated from the LV. Heart failure resulted in impaired LV contractile function [decreased percent fractional shortening and peak rate of LV pressure rise and fall (ϮdP/dt)] and remodeling (increased end-diastolic and end-systolic dimensions) in HF compared with sham. No further progression of LV dysfunction was evident in HF ϩ Sat. Mitochondrial state 3 respiration was increased in HF ϩ Sat compared with HF despite elevated myocardial ceramide. Activities of ETC complexes II and IV were elevated in HF ϩ Sat compared with HF and sham. High saturated fat feeding following coronary artery ligation was associated with increased oxidative phosphorylation and ETC complex activities and did not adversely affect LV contractile function or remodeling, despite elevations in myocardial ceramide. oxidative phosphorylation; electron transport chain; ceramide; lipotoxicity FATTY ACIDS (FA) are the dominant energy source for the adult mammalian heart and also are utilized for membrane biosynthesis, generation of lipid signaling molecules, posttranslational protein modification, and transcriptional regulation (43). Chronic exposure to FA can result in an imbalance between FA uptake and utilization that potentially can trigger cytotoxic mechanisms, leading to cell dysfunction or death, a phenomenon known as lipotoxicity. Extensive clinical and animal studies have shown that excess lipid accumulation in nonadipose tissue due to enhanced circulating FA may play an important role in pathophysiological conditions such as heart failure, obesity, insulin resistance, and diabetes (15,43,58).A loss of synchronization between FA availability and utilization in cardiomyocytes, despite otherwise normal or upregulated ␤-oxidation capacity, can lead to an increase in the accumulation of tissue ceramide (24). Ceramide, a lipid signaling molecule, has been implicated in the formation of reactive oxygen species and peroxidation of membrane lipids (11), a...

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Section: Discussionmentioning

confidence: 97%

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

Rennison¹,

McElfresh²,

Okere³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Depending on the degree of overexpression, these mice develop cardiac lipid accumulation and dilated cardiomyopathy, potentially as a consequence of increased apoptosis (Chiu et al, 2001). Interestingly, adenovirus-mediated hyperleptinemia prevented cardiac dysfunction and lipid overload in these mice (Lee et al, 2004). The mechanisms for this effect are not clear but could include decreased delivery of fatty acids to the heart or increased AMP-activated protein kinase (AMPK) activation in the heart leading to increased rates of fatty acid oxidation.…”

Section: Genetically Engineered Mice To Evaluate Potential Mechanismsmentioning

confidence: 99%

Rodent models of diabetic cardiomyopathy

Bugger

Abel

2009

Disease Models &Amp; Mechanisms

244

198

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Diabetic cardiomyopathy increases the risk of heart failure in individuals with diabetes, independently of co-existing coronary artery disease and hypertension. The underlying mechanisms for this cardiac complication are incompletely understood. Research on rodent models of type 1 and type 2 diabetes, and the use of genetic engineering techniques in mice, have greatly advanced our understanding of the molecular mechanisms responsible for human diabetic cardiomyopathy. The adaptation of experimental techniques for the investigation of cardiac physiology in mice now allows comprehensive characterization of these models. The focus of the present review will be to discuss selected rodent models that have proven to be useful in studying the underlying mechanisms of human diabetic cardiomyopathy, and to provide an overview of the characteristics of these models for the growing number of investigators who seek to understand the pathology of diabetes-related heart disease.

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“…52 Others have suggested a causal link between lipid accumulation and cardiac dysfunction, 53,54 with myocardial lipid accumulation resulting from either an overexpression or underexpression of fatty acid enzymes. 53 Interestingly, we observed decreased myocardial lipid deposition with fenofibrate and increased myocardial PPAR-␣, PGC-1␣, and phosphoacetyl coenzyme A carboxylase protein expression.…”

Section: Lebrasseur Et Almentioning

confidence: 99%

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

et al. 2007

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Abstract-Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferatoractivated receptor-␣ agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (nϭ14) or treated with fenofibrate 100 mg/kg per day (nϭ12) for 1 week before and 4 weeks after surgery. Key Words: fibrosis Ⅲ aldosterone Ⅲ hypertension Ⅲ cardiac remodeling Ⅲ matrix metalloproteinases Ⅲ peroxisome proliferator-activated receptor-␣ D iastolic heart failure (HF) refers to "HF with preserved left ventricular (LV) ejection fraction" 1-3 and is observed in almost half of the patients who present with clinical HF. 2 Hypertension, a significant risk factor for diastolic dysfunction and HF, 4 is frequently associated with cardiac remodeling and LV hypertrophy (LVH). 5 Similarly, LVH and diastolic dysfunction are associated with matrix metalloproteinase (MMP) activation that favors decreased extracellular matrix degradation and increased interstitial collagen, 6 thus perpetuating fibrosis. Tissue inhibitors of metalloproteinases (TIMPs) may predict HF in chronic hypertension. 7 Likewise, aldosterone antagonists (used in chronic HF and in hypertension) exert positive effects by downregulating MMP activity. 8 -11 Despite the increasing incidence of diastolic HF and elevated mortality rates, 12 there remains a paucity of therapies that target these potential underlying mechanism(s).Fenofibrate, a peroxisome proliferator-activated receptor-␣ (PPAR-␣) agonist, is used clinically for the treatment of dyslipidemias. Intriguingly, fibrates are being considered as possible therapeutic agents for the treatment of cardiac remodeling. 13 The myocardial effects of fenofibrate are independent of its lipid-lowering actions and are partly due to PPAR-␣-mediated suppression of inflammatory transcription factors (eg, nuclear factor-B and activating protein-1) 14 -16 and inhibition of macrophage recruitment. 17 Inhibition of nuclear factor-B with fenofibrates in hypertension prevents the development of diastolic dysfunction. 18 We previously demonstrated in isolated adult cardiomyocytes that fenofibrate

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Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice

Cited by 136 publications

References 25 publications

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction

Rodent models of diabetic cardiomyopathy

Effects of Fenofibrate on Cardiac Remodeling in Aldosterone-Induced Hypertension

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