Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake and<i>De Novo</i>Fatty Acid Synthesis

Ge, Fengxia; Hu, Chunguang; Hyodo, Eiichi; Arai, Kotaro; Zhou, Shengli; Lobdell, Harrison; Walewski, José L.; Homma, Shunichi; Berk, Paul D.

doi:10.1155/2012/205648

Cited by 49 publications

(55 citation statements)

References 55 publications

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“…Whether the same is true in T2DM hearts is unclear. In electron micrographs LDs can be easily detected in type 2 diabetic ( db/db ) (Boudina et al, 2007) or ob/ob (Ge et al, 2012) but not in WT mice hearts. In cells LDs can be readily visualized using the fluorescent FA analog (dodecanoic acid) BODIPY that labels neutral lipids in cytoplasmic droplets (Walther and Farese, 2012).…”

Section: Mitochondrial Cellular and Organ Mechanisms For Managing Lmentioning

confidence: 99%

Mitochondrial and cellular mechanisms for managing lipid excess

2014

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Current scientific debates center on the impact of lipids and mitochondrial function on diverse aspects of human health, nutrition and disease, among them the association of lipotoxicity with the onset of insulin resistance in skeletal muscle, and with heart dysfunction in obesity and diabetes. Mitochondria play a fundamental role in aging and in prevalent acute or chronic diseases. Lipids are main mitochondrial fuels however these molecules can also behave as uncouplers and inhibitors of oxidative phosphorylation. Knowledge about the functional composition of these contradictory effects and their impact on mitochondrial-cellular energetics/redox status is incomplete. Cells store fatty acids (FAs) as triacylglycerol and package them into cytoplasmic lipid droplets (LDs). New emerging data shows the LD as a highly dynamic storage pool of FAs that can be used for energy reserve. Lipid excess packaging into LDs can be seen as an adaptive response to fulfilling energy supply without hindering mitochondrial or cellular redox status and keeping low concentration of lipotoxic intermediates. Herein we review the mechanisms of action and utilization of lipids by mitochondria reported in liver, heart and skeletal muscle under relevant physiological situations, e.g., exercise. We report on perilipins, a family of proteins that associate with LDs in response to loading of cells with lipids. Evidence showing that in addition to physical contact, mitochondria and LDs exhibit metabolic interactions is presented and discussed. A hypothetical model of channeled lipid utilization by mitochondria is proposed. Direct delivery and channeled processing of lipids in mitochondria could represent a reliable and efficient way to maintain reactive oxygen species (ROS) within levels compatible with signaling while ensuring robust and reliable energy supply.

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Section: Mitochondrial Cellular and Organ Mechanisms For Managing Lmentioning

confidence: 99%

Mitochondrial and cellular mechanisms for managing lipid excess

2014

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“…Finally, increased expression of genes involved in fatty acid synthesis was observed in murine models of lipotoxicity and obesity-related cardiac dysfunction. It remains to be determined if these changes represent an adaptation that attempts to limit lipotoxic injury [120]. …”

Section: Part 2 Lipotoxicity and Cardiac Functionmentioning

confidence: 99%

Mechanisms of Lipotoxicity in the Cardiovascular System

2012

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Cardiovascular diseases account for approximately one third of all deaths globally. Obese and diabetic patients have a high likelihood of dying from complications associated with cardiovascular dysfunction. Obesity and diabetes increase circulating lipids that upon tissue uptake, may be stored as triglyceride, or may be metabolized in other pathways, leading to the generation of toxic intermediates. Excess lipid utilization or activation of signaling pathways by lipid metabolites may disrupt cellular homeostasis and contribute to cell death, defining the concept of lipotoxicity. Lipotoxicity occurs in multiple organs, including cardiac and vascular tissues, and a number of specific mechanisms have been proposed to explain lipotoxic tissue injury. In addition, recent data suggests that increased tissue lipids may also be protective in certain contexts. This review will highlight recent progress toward elucidating the relationship between nutrient oversupply, lipotoxicity, and cardiovascular dysfunction. The review will focus in two sections on the vasculature and cardiomyocytes respectively.

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“…Possible mechanisms of mitochondrial dysfunction in MHD include respiratory chain uncoupling from ATP synthesis [8], increased reactive oxygen species (ROS) production [6], altered biogenesis [9,10], and/or impaired quality control [11]. However, elucidating the specific role of cardiomyocyte lipid excess in the pathogenesis of MHD can be confounded by systemic metabolic changes that occur with obesity (inflammation, insulin resistance, circulating factors) [12,13]. Thus, this study sought to test the effect of increased cardiomyocyte FA accumulation on mitochondrial structure, function, and oxidant production in the absence of systemic metabolic perturbations.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload

Elezaby

Sverdlov

et al. 2015

Journal of Molecular and Cellular Cardiology

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Background Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-specific overexpression of the fatty acid transport protein FATP1 have increased cardiomyocyte FA uptake and develop MHD in the absence of systemic lipotoxicity, obesity or diabetes. We utilized this model to assess 1) the effect of cardiomyocyte lipid accumulation on mitochondrial structure and energetic function and 2) the role of lipid-driven transcriptional regulation, signaling, toxic metabolite accumulation, and mitochondrial oxidative stress in lipid-induced MHD. Methods Cardiac lipid species, lipid-dependent signaling, and mitochondrial structure / function were examined from FATP1 mice. Cardiac structure and function were assessed in mice overexpressing both FATP1 and mitochondrial-targeted catalase. Results FATP1 hearts exhibited a net increase (+12%) in diacylglycerol, with increases in several very long-chain diacylglycerol species (+160-212%, p<0.001) and no change in ceramide, sphingomyelin, or acylcarnitine content. This was associated with an increase in phosphorylation of PKCα and PKCδ, and a decrease in phosphorylation of AKT and expression of CREB, PGC1α, PPARα and the mitochondrial fusion genes MFN1, MFN2 and OPA1. FATP1 overexpression also led to marked decreases in mitochondrial size (-49%, p<0.01), complex II-driven respiration (-28.6%, p<0.05), activity of isolated complex II (-62%, p=0.05), and expression of complex II subunit B (SDHB) (-60% and -31%, p<0.01) in the absence of change in ATP synthesis. Hydrogen peroxide production was not increased in FATP1 mitochondria, and cardiac hypertrophy and diastolic dysfunction were not attenuated by overexpression of catalase in mitochondria in FATP1 mice. Conclusions Excessive delivery of FAs to the cardiac myocyte in the absence of systemic disorders leads to activation of lipid-driven signaling and remodeling of mitochondrial structure and function.

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Cardiomyocyte Triglyceride Accumulation and Reduced Ventricular Function in Mice with Obesity Reflect Increased Long Chain Fatty Acid Uptake andDe NovoFatty Acid Synthesis

Cited by 49 publications

References 55 publications

Mitochondrial and cellular mechanisms for managing lipid excess

Mitochondrial and cellular mechanisms for managing lipid excess

Mechanisms of Lipotoxicity in the Cardiovascular System

Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload

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