Modification of cell response to insulin by membrane-acting agents in rat white adipocytes: Analysis of structural features by computational simulation

The effect of membrane-acting agents, biscoclaurine alkaloids (cepharanthin e, tetrandrine, isotetrandrine), carbobenzoxy-D-Phe-L-Phe-Gly (z-FFG), and tyrphostin AG17, on the insulin-involved fatty acid synthesis by an beta -a gonist (e.g., isoproterenol) in adipocytes was examined. The alkaloids dose -dependently enhanced the insulin-involved fatty acid synthesis in rat whit e adipocytes, stabilized the C-6-NBD-PC (1-acyl-2-[6-[(7-nitro-2,1,3-benzox adiazol-4-yl)amino]-caproyl]-sn-glycero-3-phosphatidylcholine) model membra ne, and suppressed the phospholipase A(2)-induced phospholipid degradation. In contrast, z-FFG had no effect on the fatty acid synthesis or the membra ne stability. Tyrphostin AG17 suppressed insulin action, but promoted the m odel membrane stabilization. In the same culture conditions as for the fatt y acid synthesis assay, cepharanthine, z-FFG and tyrphostin AG17 had no eff ect on the transcript levels of glucose transporter isoforms (GLUT 1, 4) an d hexokinase isozymes (HK I, II) in rat white adipocytes. Thus, these membr ane-acting agents modify the insulin action via a chancre in the cell membr ane condition, and do not directly act on the insulin-involved glucose meta bolism. Then we analyzed the structural conformation of these membrane-acti ng agents by computational simulations. The alkaloids had an elliptic macro cyclic structure, and the order of ellipticity (cepharanthine > tetrandrine > isotetrandrine) agreed with that of the modifying ability for insulin ac tion. The distribution of electrostatic potential fields of these alkaloids was essentially equal by turn in surrounding with the dipole moments. Both in z-FFG and tyrphostin AG17, the distribution pattern of electrostatic po tential fields was different from that of the alkaloids. Judging from these results, we concluded that the electrostatic potential field is a good ind ex of the modification of insulin action, and the elliptic structure in the se alkaloids is regarded with the modification of insulin action. (C) 2001 Elsevier Science Ltd. All rights reserved.