Control of cardiomyocyte lipoprotein lipase secretion following diabetes

During diabetes, when cardiac glucose utilization is impaired, the heart switches to exclusively using fatty acid (FA) for energy supply. This metabolic switching could lead to cardiomyocyte cell death, and eventually to heart disease. One mechanism for providing the heart with FA is lipoprotein lipase (LPL). LPL, synthesized in cardiomyocytes, is transferred to the vascular lumen where it catalyzes the breakdown of lipoprotein-triglyceride (TG) to provide FA to the heart. Following diabetes, heparin-releasable LPL activity at the coronary lumen increases by mechanisms that have yet to completely elucidated. Using diazoxide (DZ), an agent that decreases insulin secretion and causes hyperglycemia, we induced a substantial increase in LPL activity at the vascular lumen. In these hyperglycemic animals, we demonstrate that phosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actin cytoskeleton rearrangement. This structural rearrangement facilitated LPL translocation to the myocyte cell surface and eventually, the vascular lumen. Parallel to this mechanism, the robust phosphorylation of Hsp25 allowed PKCdelta to activate protein kinase D (PKD), an important kinase that regulates fission of vesicles from Golgi membranes. Rottlerin, a PKCdelta inhibitor, prevented PKD phosphorylation and the subsequent increase in coronary LPL. In myocytes in which PKD was silenced or a mutant form of PKCdelta was expressed, these cells were incapable of increasing LPL. Results from these studies could help in restricting cardiac LPL translocation, lowering FA delivery to the heart, and strategies to overcome contractile dysfunction following diabetes. We also evaluated the process which restricts LPL at the vascular lumen, especially during severe diabetes with its associated increase in hepatic lipoprotein TG secretion and adipose tissue lipolysis. Following severe hypoinsulinemia and hyperlipidemia induced by streptozotocin, we reported that activation of caspase-3, together with loss of 14-3-3zeta, restricted LPL translocation to the vascular lumen. When caspase-3 was inhibited, this compensatory response was lost, leading to profound lipid accumulation in the heart through promotion of LPL activity. Thus, although caspase-3 inhibition has been suggested to attenuate cardiac dysfunction, its inhibition following severe diabetes may induce cardiac damage through striking TG accumulation in the heart.