Neutral sphingomyelinase action stimulates signal transduction of tumor necrosis factor-α (tnf-α) in the induction of low density lipoprotein (ldl) receptor in hepatocytes and fibroblasts

We have investigated biochemical mechanism of signaling in cultured human skin fibroblasts and hepatocytes. We found that TNF-α or mutated TNF-α peptides that specifically activate either the p⁵⁵ or p⁷⁵ receptors can activate neutral sphingomyelinase (N-SMase). This phenomena observed in hepatocytes was accompanied by a time-dependent activation of LDL receptors. Significant increase in LDL receptor occurred within 15-30 minutes of incubation of cells with TNF-α and mutant peptides. Maximum increase (2-fold) in LDL receptor occurred 3 hours after incubation with agonists. In fibroblasts, TNF-α and p⁵⁵, TNF-α mutant but not p⁷⁵ TNF-α mutant stimulated N-SMase activity, LDL binding and cholesteryl ester synthesis. The relatively low affinity of fibroblast p⁷⁵ receptors for the p⁷⁵ mutants may explain the observation above. In sum, induction of LDL receptor by TNF-α might be mediated through N-SMase.