Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy

Self Cite

Plasma LDL levels and atherosclerosis both increase on a saturated fat-rich (SAT) diet. LDL cholesterol delivery to tissue may occur via uptake of the LDL particles or via selective uptake (SU), wherein cholesteryl ester (CE) enters cells without concomitant whole-particle uptake. It is not known how dietary fats might directly affect arterial LDL-CE uptake and whether SU is involved. Thus, mice that are relatively atherosclerosis resistant (C57BL/6) or susceptible to atherosclerosis (apoE -/-) were fed a chow or SAT diet and injected with double radiolabeled or fluorescent-labeled human LDL to independently trace LDL-CE core and whole-particle uptake, respectively. Our results show that a SAT diet increased contributions of SU to total arterial LDL-CE delivery in C57BL/6 and apoE -/-mice. The SAT diet increased plasma fatty acid and cholesterol levels; cholesterol, but not fatty acid, levels correlated with SU, as did the degree of atherosclerosis. Increased SU did not correlate with arterial scavenger receptor class B type I levels but paralleled increased lipoprotein lipase (LPL) levels and LPL distribution in the arterial wall. These studies suggest that arterial LDL-CE delivery via SU can be an important mechanism in vivo and that dietary influences on arterial LPL levels and atherogenesis modulate arterial LDL-CE delivery, cholesterol deposition, and SU.

Section: Methodsmentioning

confidence: 99%

Saturated fat–rich diet enhances selective uptake of LDL cholesteryl esters in the arterial wall

Seo¹,

Qi²,

Chang³

et al. 2005

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“…Two-dimensional echocardiography was performed in conscious mice using techniques described previously (Sonos 5500 system; Philips Medical Systems) (10). Two-dimensional echocardiographic images were obtained and recorded in a digital format.…”

Section: Figurementioning

confidence: 99%

“…Cardiac overexpression of PPARα increases FA oxidation, but it also leads to heart lipid accumulation (8). Severe obesity associated with defective leptin actions (9) and genetic alterations that increase heart lipid due to greater uptake (10) or increased FA trapping (11) also cause lipotoxic cardiomyopathies.…”

Section: Introductionmentioning

confidence: 99%

Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice

Son¹,

Park²,

Yamashita³

et al. 2007

Self Cite

308

278

Three forms of PPARs are expressed in the heart. In animal models, PPARγ agonist treatment improves lipotoxic cardiomyopathy; however, PPARγ agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARγ on heart function, we created transgenic mice expressing PPARγ1 in the heart via the cardiac α-myosin heavy chain (α-MHC) promoter. PPARγ1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARα-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARγ1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARγ agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.

“…The resulting derangements in cellular lipid homeostasis can lead to accumulation of lipid intermediates such as acyl-CoA thioesters, acylcarnitines, ceramides, and triglycerides, molecules that could confer cellular toxicity. Transgenic models in which proteins involved in FA uptake/delivery are overexpressed also exhibit lipid accumulation and systolic dysfunction (103,104). These hearts display evidence of myocyte dropout due to activation of apoptotic pathways.…”

Section: Do Derangements In Mitochondrial Energy Metabolism Cause Heamentioning

confidence: 99%

Mitochondrial energy metabolism in heart failure: a question of balance

Huss¹,

Kelly²

2005

184

208

"Mitochondrial energy metabolism in heart failure: A question of balance." The Journal of Clinical Investigation. 115,3. 547-555. (2005 The mitochondrion serves a critical role as a platform for energy transduction, signaling, and cell death pathways relevant to common diseases of the myocardium such as heart failure. This review focuses on the molecular regulatory events and downstream effector pathways involved in mitochondrial energy metabolic derangements known to occur during the development of heart failure. IntroductionAll cellular processes are driven by ATP-dependent pathways. The heart has perpetually high energy demands related to the maintenance of specialized cellular processes, including ion transport, sarcomeric function, and intracellular Ca 2+ homeostasis. Myocardial workload (energy demand) and energy substrate availability (supply) are in continual flux, yet the heart has a limited capacity for substrate storage. Thus, ATP-generating pathways must respond proportionately to dynamic fluctuations in physiological demands and fuel delivery. The time frame of such metabolic regulatory responses ranges from seconds to minutes (acute) or hours to days (chronic) and involves regulation at multiple levels, including allosteric control of enzyme activity via metabolic intermediates, signal transduction events, and the regulation of genes encoding rate-limiting enzymes and proteins. Metabolic regulation is inextricably linked with cardiac function. This metabolism-function relationship is relevant to diseases that lead to cardiac hypertrophy and heart failure. The progression to heart failure of any cause is associated with a gradual but progressive decline in the activity of mitochondrial respiratory pathways leading to diminished capacity for ATP production. Reduced capacity for energy transduction leads to secondary dysregulation of cellular processes critical for cardiac pump function, including Ca 2+ handling and contractile function, which results in a downward spiral of increased energy demand and diminished function. Evidence has emerged that energy deficiency can be a cause and an effect of heart failure. Cardiac metabolic regulatory events may also be adaptive in certain disease states. For example, in the ischemic heart, a reduction in mitochondrial oxidative capacity serves to reduce oxygen consumption in the context of limited O 2 availability. Many of the metabolic regulatory events that dictate fuel selection and capacity for ATP production in the normal and failing heart occur at the level of gene expression. The consequence of specific metabolic gene regulatory events as adaptive versus