Cardiac-Specific Overexpression of GLUT1 Prevents the Development of Heart Failure Attributable to Pressure Overload in Mice

Liao, Ronglih; Jain, Mohit; Cui, Lei; D’Agostino, Jessica; Aiello, Francesco; Luptak, Ivan; Ngoy, Soeun; Mortensen, Richard M.; Tian, Rong

doi:10.1161/01.cir.0000034049.61181.f3

Cited by 299 publications

(275 citation statements)

References 37 publications

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“…A reduction in FA oxidation and increased glucose utilization by the heart has been observed in several pathological conditions including ischemia/reperfusion injury and cardiac hypertrophy (36). In our model, loss of LpL in the heart increased glucose utilization.…”

Section: Northern Blot Analysis Of Genes Involved In Lipid Andsupporting

confidence: 58%

Cardiac-specific Knock-out of Lipoprotein Lipase Alters Plasma Lipoprotein Triglyceride Metabolism and Cardiac Gene Expression

Augustus

Yagyu

Haemmerle

et al. 2004

Journal of Biological Chemistry

116

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Fatty acids are the primary energy source for the heart. The heart acquires fatty acids associated with albumin or derived from lipoprotein lipase (LpL)-mediated hydrolysis of lipoprotein triglyceride (TG). We generated heart-specific LpL knock-out mice (hLpL0) to determine whether cardiac LpL modulates the actions of peroxisome proliferator-activated receptors and affects whole body lipid metabolism. Male hLpL0 mice had significantly elevated plasma TG levels and decreased clearance of postprandial lipids despite normal postheparin plasma LpL activity. Very large density lipoprotein-TG uptake was decreased by 72% in hLpL0 hearts. However, heart uptake of albumin-bound free fatty acids was not altered. Northern blot analysis revealed a decrease in the expression of peroxisome proliferatoractivated receptor ␣-response genes involved in fatty acid ␤-oxidation. Surprisingly, the expression of glucose transporters 1 and 4 and insulin receptor substrate 2 was increased and that of pyruvate dehydrogenase kinase 4 and insulin receptor substrate 1 was reduced. Basal glucose uptake was increased markedly in hLpL0 hearts. Thus, the loss of LpL in the heart leads to defective plasma metabolism of TG. Moreover, fatty acids derived from lipoprotein TG and not just albumin-associated fatty acids are important for cardiac lipid metabolism and gene regulation.The heart, unlike most skeletal muscles, is constantly undergoing contraction and relaxation, events that require a large amount of energy. Under normal conditions, the heart derives ϳ70% of its energy from the oxidation of long-chain fatty acids (FA) 1 and the remainder comes from glucose and lactate metabolism (1, 2). However, a number of conditions including fasting, aerobic exercise, and diabetes increase the contribution of FA to ATP production by the heart (3). FA are supplied to the heart from the hydrolysis of triglyceride (TG)-rich lipoproteins via lipoprotein lipase (LpL) (4) and via uptake of albuminbound FA derived from adipose TG stores. The relative importance of these two pathways for cardiac metabolism and regulation of FA-responsive genes is unknown. LpL controls FA uptake through the hydrolysis of TG in chylomicrons and very large density lipoproteins (VLDL) (5). Although most lipolysis of plasma TG is thought to occur in skeletal muscle and adipose, several lines of evidence suggest that cardiac muscle is an important site of regulation of plasma TG levels (4, 6). Cardiac muscle is the tissue with the greatest expression of LpL on a per gram basis (7). Moreover, mice expressing LpL only in the heart are able to maintain normal lipid levels (4, 6).We used the Cre-loxP recombination system to generate mice with a cardiac-specific ablation of the LpL gene to elucidate the role of cardiac LpL in heart and plasma lipoprotein metabolism and gene expression. This allowed us to investigate the role of LpL in the heart without directly altering LpL function and activity in skeletal muscle or adipose tissue. Our data show that the loss of LpL in the heart leads ...

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Section: Northern Blot Analysis Of Genes Involved In Lipid Andsupporting

confidence: 58%

Cardiac-specific Knock-out of Lipoprotein Lipase Alters Plasma Lipoprotein Triglyceride Metabolism and Cardiac Gene Expression

Augustus

Yagyu

Haemmerle

et al. 2004

Journal of Biological Chemistry

116

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“…Conversely, the levels of GLUT4 could have affected heart function by allowing the hearts to utilize more glucose. Others have noted that transgenic expression of cardiac-specific GLUT1 is protective for ischemia-induced cardiac dysfunction (24). Our studies demonstrate a connection between GLUT4 gene expression and lipids and demonstrate that hLpL GPI hearts have reduced expression that is improved along with the reduction of cardiac lipids due to transgenic expression of apoB.…”

Section: Discussionsupporting

confidence: 60%

Apolipoprotein B Production Reduces Lipotoxic Cardiomyopathy

Yokoyama

Yagyu

et al. 2004

Journal of Biological Chemistry

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Lipid accumulation is associated with cardiac dysfunction in diabetes and obesity. Transgenic mice expressing non-transferable lipoprotein lipase (LpL) with a glycosylated phosphatidyl-inositol (GPI) anchor in cardiomyocytes have dilated cardiomyopathy. However, the mechanisms responsible for lipid accumulation and cardiomyopathy are not clear. Hearts from 3-month-old mice expressing GPI-anchored human LpL (hLpL GPI ) mice had increased fatty acid oxidation and heart failure genes and decreased glucose transporter genes. 6-month-old mice had increased mRNA expression and activation of the apoptosis marker caspase-3. Moreover, hLpL GPI hearts had significant cytochrome c release from mitochondria to cytosol. Low density lipoprotein uptake was greater in hLpL GPI hearts, and this was associated with more intracellular apolipoprotein B (apoB). To test whether lipid accumulation in the hLpL GPI heart is reduced by cardiac expression of apoB, hLpL GPI mice were bred with transgenic human apoB (HuB)-expressing mice. Hearts of HuB/hLpL GPI mice had less triglyceride (38%) and free fatty acids (19%), secreted more apoB, and expressed less atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and more glucose transporter 4 (GLUT4). The increased mortality of the mice was abrogated by the transgenic expression of apoB. Therefore, we hypothesize that cardiac apoB expression improves cardiomyopathy by increasing lipid resecretion from the heart.

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“…In mice, AAC was performed in anesthetized (pentobarbital 15 mg/kg, IP) and ventilated animals (age 12-16 weeks) as described (47). After anterolateral thoracotomy, aortic constriction was induced by ligating the ascending aorta around a 25-guage needle using 7-0 silk suture.…”

Section: Aortic Banding and Transthoracic Echocardiography In Rodentsmentioning

confidence: 99%

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

Fisch

Gray

Heymans

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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191

230

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Cardiac hypertrophy is a common response to injury and hemodynamic stress and an important harbinger of heart failure and death. Herein, we identify the Kruppel-like factor 15 (KLF15) as an inhibitor of cardiac hypertrophy. Myocardial expression of KLF15 is reduced in rodent models of hypertrophy and in biopsy samples from patients with pressure-overload induced by chronic valvular aortic stenosis. Overexpression of KLF15 in neonatal rat ventricular cardiomyocytes inhibits cell size, protein synthesis and hypertrophic gene expression. KLF15-null mice are viable but, in response to pressure overload, develop an eccentric form of cardiac hypertrophy characterized by increased heart weight, exaggerated expression of hypertrophic genes, left ventricular cavity dilatation with increased myocyte size, and reduced left ventricular systolic function. Mechanistically, a combination of promoter analyses and gel-shift studies suggest that KLF15 can inhibit GATA4 and myocyte enhancer factor 2 function. These studies identify KLF15 as part of a heretofore unrecognized pathway regulating the cardiac response to hemodynamic stress.

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Cardiac-Specific Overexpression of GLUT1 Prevents the Development of Heart Failure Attributable to Pressure Overload in Mice

Cited by 299 publications

References 37 publications

Cardiac-specific Knock-out of Lipoprotein Lipase Alters Plasma Lipoprotein Triglyceride Metabolism and Cardiac Gene Expression

Cardiac-specific Knock-out of Lipoprotein Lipase Alters Plasma Lipoprotein Triglyceride Metabolism and Cardiac Gene Expression

Apolipoprotein B Production Reduces Lipotoxic Cardiomyopathy

Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy

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