Regulation and Functions of Cardiac Lipins

  • Author / Creator
    Kok, Bernard P.C.
  • 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.

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  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
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  • Institution
    University of Alberta
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  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Lehner, Richard (Pediatrics)
    • Michalak, Marek (Biochemistry)
    • Lopaschuk, Gary D. (Pediatrics)
    • Hatch, Grant M. (Pharmacology & Therapeutics)