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Permanent link (DOI): https://doi.org/10.7939/R30B09

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Regulation and Functions of Cardiac Lipins Open Access

Descriptions

Other title
Subject/Keyword
glycerolipid
phosphatidate
lipin
heart
fld
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Kok, Bernard P.C.
Supervisor and department
Brindley, David N. (Biochemistry)
Examining committee member and department
Michalak, Marek (Biochemistry)
Lopaschuk, Gary D. (Pediatrics)
Hatch, Grant M. (Pharmacology & Therapeutics)
Lehner, Richard (Pediatrics)
Department
Department of Biochemistry
Specialization

Date accepted
2012-06-11T15:29:56Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The heart requires an uninterrupted supply of fuels to sustain its physiological function. Fatty acids are the predominant substrates and endogenous triglyceride turnover contributes significantly to fatty acid oxidation. Lipins are cytosolic, bifunctional enzymes involved in both glycerolipid synthesis and fatty acid oxidation. All three mammalian lipins (lipin-1, -2 and -3) function as phosphatidate phosphatases (PAP) in glycerolipid synthesis. Lipin-1 also acts as a transcriptional co-activator with peroxisome proliferator-activated receptor-α (PPARα) and PPARγ co-activator-1α (PGC-1α) to upregulate genes involved in hepatic fatty acid oxidation. We demonstrated that the fatty acid, oleate, stimulates the translocation of cytosolic lipin-1 and -2 onto membranes. Less-phosphorylated forms of lipins associated with membranes preferentially compared to hyperphosphorylated lipins. We showed preliminary evidence that lipin-1B can interact with the protein phosphatase-1γ catalytic subunit, which could mediate lipin dephosphorylation and promote membrane binding. We also showed that the gene expressions of the lipins are upregulated in neonatal rat ventricular myocytes by glucocorticoid- and cAMP-dependent signalling, which is reflective of fasting, whereas insulin acts antagonistically. The predominant lipin isoform in the heart is lipin-1 and we showed that lipin-1 deficient (fatty liver dystrophy, fld) mice had impaired systolic function. However, lipin-1 deficiency does not impair glycerolipid synthesis in perfused working hearts. Thus, lipin-2 and -3 in the heart are sufficient to sustain physiological activity. Furthermore, we demonstrated that only a small proportion of the cytosolic PAP activity is required for glycerolipid synthesis in cardiomyocytes. However, there was an aberrant accumulation of newly synthesized phosphatidate in fld hearts, accompanied by hyper-activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway and increased endoplasmic reticulum stress response. We conclude that the cardiac dysfunction in fld mice stems from systemic effects of whole-body lipin-1 deficiency, the accumulation of phosphatidate and increased stress response. Overall, our studies have delineated the regulation of cardiac lipins and we have shown that the presence of three lipin isoforms can sustain cardiac glycerolipid synthesis. Finally, the interaction of lipin-1 with protein phosphatase 1γ provides an avenue to determining how its subcellular localization and thus, physiological actions are regulated.
Language
English
DOI
doi:10.7939/R30B09
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Kok BP, Kienesberger PC, Dyck JR, Brindley DN. Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice. J Lipid Res. 2012 Jan;53(1):105-18.Donkor J, Zhang P, Wong S, O'Loughlin L, Dewald J, Kok BP, Brindley DN, Reue K. A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2. J Biol Chem. 2009 Oct 23;284(43):29968-78.

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