The heart's extraordinary metabolic flexibility allows it to adapt to normal changes in physiology in order to preserve its function. Alterations in the metabolic profile of the heart have also been ...attributed to pathological conditions such as ischemia and hypertrophy; however, research during the past decade has established that cardiac metabolic adaptations can precede the onset of pathologies. It is therefore critical to understand how changes in cardiac substrate availability and use trigger events that ultimately result in heart dysfunction. This review examines the mechanisms by which the heart obtains fuels from the circulation or from mobilization of intracellular stores. We next describe experimental models that exhibit either an increase in glucose use or a decrease in FA oxidation, and how these aberrant conditions affect cardiac metabolism and function. Finally, we highlight the importance of alternative, relatively under-investigated strategies for the treatment of heart failure. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
•The heart adapts to normal changes in physiology by switching metabolic substrates.•Altered cardiac metabolism has also been identified under pathological conditions.•Increased glucose use may precede the onset of various pathologies.•Decreased fatty acid oxidation does not ameliorate dysfunction in multiple models.•Alternative strategies investigating transendothelial fuel transport are warranted.
Yeast Pah1p phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol. PAP plays a crucial role in lipid homeostasis by controlling the relative proportions ...of its substrate phosphatidate and its product diacylglycerol. The cellular amounts of these lipid intermediates influence the synthesis of triacylglycerol and the pathways by which membrane phospholipids are synthesized. Physiological functions affected by PAP activity include phospholipid synthesis gene expression, nuclear/endoplasmic reticulum membrane growth, lipid droplet formation, and vacuole homeostasis and fusion. Yeast lacking Pah1p PAP activity are acutely sensitive to fatty acid-induced toxicity and exhibit respiratory deficiency. PAP is distinguished in its cellular location, catalytic mechanism, and physiological functions from Dpp1p and Lpp1p lipid phosphate phosphatases that utilize a variety of substrates that include phosphatidate. Phosphorylation/dephosphorylation is a major mechanism by which Pah1p PAP activity is regulated. Pah1p is phosphorylated by cytosolic-associated Pho85p–Pho80p, Cdc28p-cyclin B, and protein kinase A and is dephosphorylated by the endoplasmic reticulum-associated Nem1p–Spo7p phosphatase. The dephosphorylation of Pah1p stimulates PAP activity and facilitates the association with the membrane/phosphatidate allowing for its reaction and triacylglycerol synthesis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
► PAP catalyzes the penultimate step in triacylglycerol synthesis. ► PAP plays a crucial role in lipid homeostasis and cell physiology. ► Multiple protein kinases phosphorylate PAP. ► Nem1p-Spo7p dephosphorylates PAP. ► Phosphorylation/dephosphorylation regulates PAP function.
A detailed cross‐section analysis of the chemical composition of sprayed Cu2ZnSnS4 thin films is presented. X‐ray diffraction (XRD), energy dispersive spectroscopy (EDS), X‐ray photoelectron ...spectroscopy (XPS), and Raman spectroscopy (with near‐IR, visible, and UV‐lasers) are used to demonstrate that while CZTS effectively forms within the bulk of the film, there is some degree of element segregation, formation of undesirable secondary phases, and the presence of a disordered kesterite structure across the film. Different penetration depths of the excitation signals correspond to the many different surface sensitive techniques employed in this work. XPS results reveal that the surface of Cu4ZnSnS4 (CZTS) films presents a high concentration of tin and zinc and a low sulfur concentration, while being highly depleted in copper. EDS, XRD, and infrared Raman spectroscopy confirm that the composition of as‐sprayed and sulfurized films is close to stoichiometric Cu2ZnSnS4. Resonant UV‐Raman spectroscopy helps to identify secondary phases located at the external surface of sprayed and sulfurized CZTS films (mainly ZnS, ZnO), while VIS‐Raman spectroscopy helps to identify a disordered kesterite structure close to the surface. Secondary phases need to be chemically etched when aiming at incorporating kesterite films obtained by spray pyrolysis into photovoltaic devices.
A detailed cross‐sectional analysis of a Cu2ZnSnS4 (kesterite) films obtained using chemical spray pyrolysis is presented. To do so, XRD, EDS, XPS, and Raman spectroscopy (with near‐IR, visible, and UV‐lasers) are employed to take advantage of the different penetration depths of the excitation signals of each technique that allows studying kesterite films composition and structure at different depths.
Periconceptional exposures to three parabens were, surprisingly, associated with dietary sources of these preservatives rather than personal care products, highlighting the utility of this method and ...need for more study of dietary parabens.
In the yeast Saccharomyces cerevisiae, the synthesis of phospholipids in the exponential phase of growth occurs at the expense of the storage lipid triacylglycerol. As exponential phase cells ...progress into the stationary phase, the synthesis of triacylglycerol occurs at the expense of phospholipids. Early work indicates a role of the phosphatidate phosphatase (PAP) in this metabolism; the enzyme produces the diacylglycerol needed for the synthesis of triacylglycerol and simultaneously controls the level of phosphatidate for the synthesis of phospholipids. Four genes (APP1, DPP1, LPP1, and PAH1) encode PAP activity in yeast, and it has been unclear which gene is responsible for the synthesis of triacylglycerol throughout growth. An analysis of lipid synthesis and composition, as well as PAP activity in various PAP mutant strains, showed the essential role of PAH1 in triacylglycerol synthesis throughout growth. Pah1p is a phosphorylated enzyme whose in vivo function is dependent on its dephosphorylation by the Nem1p-Spo7p protein phosphatase complex. nem1Δ mutant cells exhibited defects in triacylglycerol synthesis and lipid metabolism that mirrored those imparted by the pah1Δ mutation, substantiating the importance of Pah1p dephosphorylation throughout growth. An analysis of cells bearing PPAH1-lacZ and PPAH1-DPP1 reporter genes showed that PAH1 expression was induced throughout growth and that the induction in the stationary phase was stimulated by inositol supplementation. A mutant analysis indicated that the Ino2p/Ino4p/Opi1p regulatory circuit and transcription factors Gis1p and Rph1p mediated this regulation.
Background: Yeast Pah1p phosphatidate phosphatase produces diacylglycerol for triacylglycerol synthesis and controls phosphatidate content for phospholipid synthesis.
Results:PAH1 expression was induced throughout growth, stimulated by inositol supplementation, and mediated by the Ino2p/Ino4p/Opi1p regulatory circuit and transcription factors Gis1p and Rph1p.
Conclusion: Growth phase- and inositol-mediated expression of PAH1 regulates lipid synthesis.
Significance: Pah1p phosphatidate phosphatase is regulated by a transcriptional mechanism throughout growth.
PDF
