Integrin-Dependent Akt1 Activation Regulates PGC-1 Expression and Fatty Acid Oxidation

Abstract

Background: Poly-N-acetyl glucosamine nanofibers derived from a marine diatom have been used to increase cutaneous wound healing. These nanofibers exert their activity by specifically activating integrins, which makes them a useful tool for dissecting integrin-mediated pathways. We have shown that short-fiber poly-N-acetyl glucosamine nanofiber (sNAG) treatment of endothelial cells results in increased cell motility and metabolic rate in the absence of increased cell proliferation. Results: Using a Seahorse Bioanalyzer to measure oxygen consumption in real time, we show that sNAG treatment increases oxygen consumption rates, correlated with an integrin-dependent activation of Akt1. Akt1 activation leads to an increase in the expression of the transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). This is not due to increased mitochondrial biogenesis, but is associated with an increase in the expression of pyruvate dehydrogenase kinase 4 (PDK4), suggesting regulation of fatty acid oxidation. Blockade of fatty acid oxidation with etomoxir, an O-carnitine palmitoyltransferase-1 inhibitor, blocks the sNAG-dependent increased oxygen consumption. ³H-palmitate uptake experiments indicate a PDK4-dependent increase in fatty acid oxidation, which is required for nanofiber-induced cell motility. Conclusions: Our findings imply a linear pathway whereby an integrin-dependent activation of Akt1 leads to increased PGC-1α and PDK4 expression resulting in increased energy production by fatty acid oxidation.

Gene expression pattern of glucose transporters in the skeletal muscles of newly hatched chicks

“…1(B)). Since the gene expression of PGC-1α was induced by activated AKT signaling in human umbilical vein endothelial cells, 26) these results suggest that PGC-1α might be related to the expression level of GLUT1 in the skeletal muscle of newly hatched chicks. Although the newly hatched chicks are adapted to metabolize lipid and protein substrate from egg yolk and albumen, the first feeding leads them to drastic alterations in glucose metabolism.…”

Preparation of a novel composite nanofiber gel-encapsulated human placental extract through layer-by-layer self-assembly

“…Short poly-N-acetyl glucosamine (sNAG) nanofibers have been found to activate the integrin receptor on the surface of platelets, promote the formation of fibrous protein complexes and cell proliferation and migration, and stimulate the release of a variety of growth factors (6,7). The activated integrin receptor was also found to increase the expression of vascular endothelial growth factor (VEGF) and accelerate the formation of new blood vessels through a transcriptional factor-dependent signaling pathway (8).…”

pGlcNAc Nanofiber Treatment of Cutaneous Wounds Stimulate Increased Tensile Strength and Reduced Scarring via Activation of Akt1

“…Mechanistic studies using these nanofibers in vitro and in vivo , have shown that these fibers directly bind to and stimulate integrin mediated outside/in signal transduction that is, at least in part, dependent on Akt1 activation [ 15 , 16 ]. This activity appears to be due to their unique three dimensional beta quaternary structure.…”

“…This activity appears to be due to their unique three dimensional beta quaternary structure. We have shown that nanofiber stimulation results in increased metabolism [ 17 ], increased endothelial cell motility and angiogenesis [ 16 ] and importantly to enhanced innate immune responses leading to antibacterial activity [ 8 ]. These findings indicate that pGlcNAc nanofibers may provide a combinatorial therapy using a single FDA approved agent.…”