MECHANISM OF ACTIVATION AND FUNCTIONAL-SIGNIFICANCE OF THE LIPOLYSIS-STIMULATED RECEPTOR - EVIDENCE FOR A ROLE AS CHYLOMICRON REMNANT RECEPTOR

In cultured human and rat cells, the lipolysis-stimulated receptor (LS R), when activated by free fatty acids (FFA), mediates the binding of apoprotein B- and apoprotein E-containing lipoproteins and their subse quent internalization and degradation. To better understand the physio logical role of LSR, we developed a biochemical assay that optimizes b oth the activation and binding steps and, thus, allows the estimation of the number of LSR binding sites expressed in the livers of living a nimals. With this technique, a strong inverse correlation was found in rats between the apparent number of LSR binding sites in liver and th e postprandial plasma triglyceride concentration (r = -0.828, p < 0.00 1, n = 12). No correlation existed between the number of LSR and plasm a triglycerides measured in the same animals after 24 h of fasting. Th e same membrane binding assay was used to elucidate the mechanism by w hich FFA induce lipoprotein binding to LSR. The LSR activation step wa s mediated by direct interaction of FFA with LSR candidate proteins of apparent molecular masses of 115 and 90 kDa and occurred independentl y of the membrane lipid environment. The FFA-induced conformational sh ift that revealed the lipoprotein binding site remained fully reversib le upon removal of the FFA. However, occupancy of the site by the apop rotein ligand stabilized the active form of LSR. Comparison of the eff ect of different FFA alone or in combination indicated that the same b inding site is revealed by different FFA and that the length and satur ation of the FFA monomeric carbon chain are critical in determining th e potency of the FFA activating effect. We propose that the LSR pathwa y represents a limiting step for the cellular uptake of intestinally d erived triglyceride-rich lipoproteins and speculate that FFA liberated by lipolysis initiate this process by altering the conformation of LS R to reveal the lipoprotein binding site.