Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes

Abstract

Cardiomyocytes use glucose as well as fatty acids for ATP production. These substrates are transported into the cell by glucose transporter 4 (GLUT4) and the fatty acid transporter CD36. Besides being located at the sarcolemma, GLUT4 and CD36 are stored in intracellular compartments. Raised plasma insulin concentrations and increased cardiac work will stimulate GLUT4 as well as CD36 to translocate to the sarcolemma. As so far studied, signaling pathways that regulate GLUT4 translocation similarly affect CD36 translocation. During the development of insulin resistance and type 2 diabetes, CD36 becomes permanently localized at the sarcolemma, whereas GLUT4 internalizes. This juxtaposed positioning of GLUT4 and CD36 is important for aberrant substrate uptake in the diabetic heart: chronically increased fatty acid uptake at the expense of glucose. To explain the differences in subcellular localization of GLUT4 and CD36 in type 2 diabetes, recent research has focused on the role of proteins involved in trafficking of cargo between subcellular compartments. Several of these proteins appear to be similarly involved in both GLUT4 and CD36 translocation. Others, however, have different roles in either GLUT4 or CD36 translocation. These trafficking components, which are differently involved in GLUT4 or CD36 translocation, may be considered novel targets for the development of therapies to restore the imbalanced substrate utilization that occurs in obesity, insulin resistance and diabetic cardiomyopathy.

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…One of the major regulators of "beat to beat" glu- cose uptake in the myocardium is the AMP-activated protein kinase (AMPK) (16), which plays a central role in cellular energy sensing and homeostasis (17). Phosphorylation of Thr-172 of the AMPK␣ catalytic subunit is crucial for the activation of the AMPK complex (18), subsequently resulting in an increase in cellular glucose uptake (16,19). In Mlip Ϫ/Ϫ hearts, phosphorylation of AMPK␣-Thr-172 was lower than in Mlip ϩ/ϩ hearts, despite similar expression and phosphoryla- tion of the regulatory AMPK␤ subunits (Fig.…”

Insulin and AMPK regulate FA translocase/CD36 plasma membrane recruitment in cardiomyocytes via Rab GAP AS160 and Rab8a Rab GTPase

“…For example, persistent relocation of CD36 from intracellular stores to the sarcolemma is observed in the diabetic myocardium and is proposed to result in accumulation of lipid moieties with negative effects on heart metabolism and function ( 1,5,(12)(13)(14). The permanent relocation of CD36 to the plasma membrane is an early event in insulin resistance that precedes and strongly correlates with intracellular retention of the insulinsensitive glucose transporter GLUT4 ( 2 ). This highlights the importance of a better understanding of the events that regulate surface CD36 traffi cking, an area that remains little studied.…”

Structure of, and functional insight into the GLUT family of membrane transporters

“…[144][145][146][147][148][149][150][151][152][153][154] GLUT4 trafficking and recycling are also regulated independently from the insulin signal, which is referred to as a general (insulin-independent) pathway and that the movement of GLUT4 is also controlled by muscle contraction. Muscle contraction activates several signaling messengers, including calcium, nitric oxide, and reactive oxygen species within the muscle cells themselves, that regulate glucose homeostasis endogenously.…”