KLF15 and PPAR<i>α</i>Cooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation

Prosdocimo, Domenick A.; John, Jenine E.; Zhang, Lilei; Efraim, Elizabeth S; Zhang, Rongli; Liao, Xudong; Jain, Mukesh K.

doi:10.1155/2015/201625

Cited by 55 publications

(49 citation statements)

References 56 publications

(100 reference statements)

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“…For example, in adipocytes, KLF5 cooperates with PPARδ to induce transcription of the Pparg2 gene and, in doing so, promotes adipogenesis (21,41). In cardiomyocytes, KLF15 cooperates with PPARα in regulating lipid metabolism (42). Conversely, activation of GR signaling can induce a number of KLFs (e.g., KLF9, KLF11, and KLF15) in specific physiologic or pathologic contexts (43)(44)(45).…”

Section: Methodsmentioning

confidence: 99%

“…FAO rate was determined by release of ]-oleic acid as described previously (47). Glycolysis rate and mitochondrial respiration rate in NRVMs were assessed using a Seahorse XFp Extracellular Flux Analyzer with the XFp Glycolysis Stress Test Kit and the XFp Cell Mito Stress Test Kit, respectively (Seahorse Bioscience) (42). For in vitro autophagy studies, NRVMs were infected with indicated adenovirus for 72 hours, followed by treatment with 20 μmol/l CCCP with or without 100 nmol/l BFA for 2 hours (35) (CCCP, Sigma-Aldrich, C2759; BFA, Sigma-Aldrich, B1793).…”

Section: Methodsmentioning

confidence: 99%

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Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

Liao

Zhang

Lü

et al. 2015

Journal of Clinical Investigation

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110

113

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

Liao

Zhang

Lü

et al. 2015

Journal of Clinical Investigation

Self Cite

110

113

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“…Although all PPARs bind as heterodimers to their cognate DNA elements with the retinoid X receptor (RXR), they may also interact with other transcription factors. For instance, recent work has shown that the Kruppel-like factor 15 (KLF15) interacts directly with PPARα in the heart to regulate genes involved in FAO (Prosdocimo et al 2014(Prosdocimo et al , 2015.…”

Section: Biogenic Machinery: Transcriptional Networkmentioning

confidence: 99%

Mitochondrial biogenesis and dynamics in the developing and diseased heart

2015

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The mitochondrion is a complex organelle that serves essential roles in energy transduction, ATP production, and a myriad of cellular signaling events. A finely tuned regulatory network orchestrates the biogenesis, maintenance, and turnover of mitochondria. The high-capacity mitochondrial system in the heart is regulated in a dynamic way to generate and consume enormous amounts of ATP in order to support the constant pumping function in the context of changing energy demands. This review describes the regulatory circuitry and downstream events involved in mitochondrial biogenesis and its coordination with mitochondrial dynamics in developing and diseased hearts.The adult human heart generates and consumes kilogram quantities of ATP daily to support normal pump function. Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for nearly all of the ATP production (>95%) in adult mammalian hearts (Ashrafian et al. 2007). The creatine phosphate shuttle system delivers the high-energy phosphate groups from the site of production in the mitochondria to myofibrils to regenerate ATP consumed during contraction. As such, the heart requires an enormous mitochondrial biogenic capacity to support the high demand for ATP production. In fact, >40% of the cytoplasmic space (Hom and Sheu 2009) in adult cardiac myocytes is occupied by mitochondria densely packed between sarcomeres, around the nucleus, and in the subsarcolemma. The development and maturation of this specialized high-capacity mitochondrial system in the heart occur largely during the perinatal and postnatal developmental stages. The process begins with a major surge in mitochondrial biogenesis at birth. Following this biogenic surge, there is a period of maturation that involves a dramatic increase in dynamics (mitophagy, fusion, and fission), leading to redistribution and dense packing of the specialized mature mitochondria along myofibrils. This cellular architecture facilitates the transfer of high-energy phosphates between the mitochondria and the contractile apparatus. The resultant mature mitochondrial system is capable of high-capacity oxidation of fuels such as fatty acid, the predominant fuel substrate for the adult heart. This review focuses on current knowledge of the regulatory circuitry and mechanisms involved in the maturation and maintenance of this specialized high-capacity mitochondrial system in developing and adult mammalian hearts. Mitochondrial biogenesis: circuitry and regulatory mechanisms Mitochondrial genomic and energy transduction machineryThe mitochondrion is a double-membrane organelle with an ion-permeable inner membrane and an outer membrane permeable to factors <5 kDa (Balaban 1990). This complex membrane structure enables ATP generation via OXPHOS. An electrochemical gradient established across the inner membrane drives OXPHOS and ATP synthesis. This gradient involves electrons donated from reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH 2 ) generated by oxidation of acetyl-CoA...

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“…For instance, sirtuin 1 (Sirt1) has been shown to directly dimerize with PPARα, resulting in displacement of RXR and reduced fatty acid utilization (32). In addition, Krüppel-like factor 15 (KLF15) interacts directly with PPARα to cooperatively activate FAO gene expression (33). Loss of KLF15 results in reduced cardiac FAO rates and markedly reduced mitochondrial FAO gene expression (34).…”

Section: Brief Overview Of Cardiac Fuel and Energy Metabolismmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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KLF15 and PPARαCooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation

Cited by 55 publications

References 56 publications

Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

Mitochondrial biogenesis and dynamics in the developing and diseased heart

Cardiac nuclear receptors: architects of mitochondrial structure and function

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