title: Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases.
abstract: Following dexamethasone (DEX), cardiac energy generation is mainly through utilization of fatty acids (FA), with DEX animals demonstrating an increase in coronary lipoprotein lipase (LPL), an enzyme that hydrolyzes lipoproteins to FA. We examined the mechanisms by which DEX augments cardiac LPL. DEX was injected in rats, and hearts were removed, or isolated cardiomyocytes were incubated with DEX (0-8 h), for measurement of LPL activity and Western blotting. Acute DEX induced whole body insulin resistance, likely an outcome of a decrease in insulin signaling in skeletal muscle, but not cardiac tissue. The increase in luminal LPL activity after DEX was preceded by rapid nongenomic alterations, which included phosphorylation of AMPK and p38 MAPK, that led to phosphorylation of heat shock protein (HSP)25 and actin cytoskeleton rearrangement, facilitating LPL translocation to the myocyte cell surface. Unlike its effects in vivo, although DEX activated AMPK and p38 MAPK in cardiomyocytes, there was no phosphorylation of HSP25, nor was there any evidence of F-actin polymerization or an augmentation of LPL activity up to 8 h after DEX. Combining DEX with insulin appreciably enhanced cardiomyocyte LPL activity, which closely mirrored a robust elevation in phosphorylation of HSP25 and F-actin polymerization. Silencing of p38 MAPK, inhibition of PI 3-kinase, or preincubation with cytochalasin D prevented the increases in LPL activity. Our data suggest that, following DEX, it is a novel, rapid, nongenomic phosphorylation of stress kinases that, together with insulin, facilitates LPL translocation to the myocyte cell surface.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Girish
authors.initials: G
authors.lastname: Kewalramani
authors.forename: Prasanth
authors.initials: P
authors.lastname: Puthanveetil
authors.forename: Min Suk
authors.initials: MS
authors.lastname: Kim
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Vivian
authors.initials: V
authors.lastname: Lee
authors.forename: Nathania
authors.initials: N
authors.lastname: Hau
authors.forename: Elham
authors.initials: E
authors.lastname: Beheshti
authors.forename: Natalie
authors.initials: N
authors.lastname: Ng
authors.forename: Ashraf
authors.initials: A
authors.lastname: Abrahani
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D055372:AMP-Activated Protein Kinases; D000199:Actins / Q000378:metabolism; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins; D006321:Heart / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008297:Male; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D005938:Glucocorticoids; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase