Fatty acid transport in adipocytes and the development of insulin resistance.
Fatty acid influx into adipocytes is a complex multifactoral process driven by biochemical and biophysical processes linking transmembrane flux to the ATP-dependent esterification of fatty acids. Adipocyte proteins implicated in free fatty acid (FFA) influx include CD36 functioning as a general lipid receptor, caveolin 1 functioning as a component of an endocytotic/exocytotic vesicular cycle and the acyl CoA synthetases (FATP1, ACSL1) catalysing esterification of lipids producing acyl CoAs. In adipocytes, CD36, ACSL1 and FATP1 translocate from intracellular sites to the plasma membrane in response to insulin thereby positioning these key proteins to facilitate FFA esterification. Lentiviral delivery of shRNA targeting FATP1 in 3T3-L1 adipocytes results in a complete loss of insulin-stimulated FFA uptake, decreased accumulation of TAG/DAG/MAG and potentiated insulin-stimulated 2-deoxyglucose uptake. Increased insulin-stimulated hexose uptake in FATP1 knockdown adipocytes is correlated with increased tyrosine phosphorylation and abundance of IRS1 protein. Evaluation of the lipid activated serine kinases implicated in insulin signalling reveals that S6K and JNK1 were not altered in abundance or phosphorylation in FATP1 knockdown adipocytes but that the phosphorylation of PKCtheta and abundance of IKKalpha/beta were significantly reduced. These results suggest lipid droplet pools in the adipocyte play a major role in regulating kinase cascades controlling insulin action.
Lobo
Sandra
S
Department of Biochemistty, Molecular Biology and Biophysics, The University of Minnesota, Minneapolis, MN 55455, USA.
Bernlohr
David A
DA
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D015398:Signal Transduction
D018955:CD36 Antigens; D051242:Caveolin 1; D005227:Fatty Acids; D007328:Insulin; D003066:Coenzyme A Ligases