Abstract

Objective. Heart disease is a leading cause of death in diabetes, and could occur due to excessive utilization of fatty acid (FA) for energy generation. Our objective was to determine the mechanisms by which AMPK augments cardiac lipoprotein lipase (LPL), the enzyme that provides the heart with majority of its FA.

Research Design and Methods. We used diazoxide (DZ) in rats to induce hyperglycemia, or AICAR and thrombin to directly stimulate AMPK and p38 MAPK respectively in cardiomyocytes.

Results. There was a substantial increase in LPL at the coronary lumen following 4 h of DZ. In these diabetic animals, phosphorylation of AMPK, p38 MAPK, and Hsp25 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 pre-incubation with the p38 MAPK inhibitor SB202190, or cytochalasin D that inhibits actin polymerization. Thrombin activated p38 MAPK in the absence of AMPK phosphorylation. Comparable to 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 FA supply when glucose utilization is compromised.