Acute diabetes moderates trafficking of cardiac lipoprotein lipase through p38 mitogen-activated protein kinase-dependent actin cytoskeleton organization.
OBJECTIVE
Heart disease is a leading cause of death in diabetes and could occur because of excessive use of fatty acid for energy generation. Our objective was to determine the mechanisms by which AMP-activated protein kinase (AMPK) augments cardiac lipoprotein lipase (LPL), the enzyme that provides the heart with the majority of its fatty acid.


METHODS
We used diazoxide in rats to induce hyperglycemia or used 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and thrombin to directly stimulate AMPK and p38 mitogen-activated protein kinase (MAPK), respectively, in cardiomyocytes.


RESULTS
There was a substantial increase in LPL at the coronary lumen following 4 h of diazoxide. In these diabetic animals, phosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actin cytoskeleton rearrangement to facilitate LPL translocation to the myocyte surface and, eventually, the vascular lumen. AICAR activated AMPK, p38 MAPK, and Hsp25 in a pattern similar to that seen with diabetes. AICAR also appreciably enhanced LPL, an effect reduced by preincubation with the p38 MAPK inhibitor SB202190 or by cytochalasin D, which inhibits actin polymerization. Thrombin activated p38 MAPK in the absence of AMPK phosphorylation. Comparable with diabetes, activation of p38 MAPK and, subsequently, Hsp25 phosphorylation and F-actin polymerization corresponded with an enhanced LPL activity. SB202190 and silencing of p38 MAPK also prevented these effects induced by thrombin and AICAR, respectively.


CONCLUSIONS
We propose that AMPK recruitment of LPL to the cardiomyocyte surface (which embraces p38 MAPK activation and actin cytoskeleton polymerization) represents an immediate compensatory response by the heart to guarantee fatty acid supply when glucose utilization is compromised.
Kim
Min Suk
MS
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada.
Kewalramani
Girish
G
Puthanveetil
Prasanth
P
Lee
Vivian
V
Kumar
Ujendra
U
An
Ding
D
Abrahani
Ashraf
A
Rodrigues
Brian
B
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D003331:Coronary Vessels / Q000201:enzymology; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D003981:Diazoxide / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D020868:Gene Silencing; D006352:Heart Ventricles; D008071:Lipoprotein Lipase / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014304:Triolein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D000199:Actins; D005227:Fatty Acids; D034741:RNA, Small Interfering; D014304:Triolein; D048051:p38 Mitogen-Activated Protein Kinases; D008071:Lipoprotein Lipase; D003981:Diazoxide