Hypothetical model depicting how sphingomyelin might regulate SREBPs in 3T3-F442A adipocytes.

<p>Illustration of how an SM-initiated signal transduction pathway leads to SREBP modulation. Two cell models of membrane SM enrichment were investigated in this report (1) by adding exogenous sphingomyelins in the culture medium of differentiated cells or (2) by inhibiting N-SMase with GW4869 or GSH. In turn, SM contents increase in membranes (caveolae). Membrane SM accumulation promotes a rigid state of the membrane and caveolin accumulation and regulates the Ras-Raf-ERK MAP kinase pathway, inhibiting SREBP-1. By inhibiting KSR, which is the putative target of ceramide, SM acts to amplify the signal provided to the Raf/ERK MAP kinase cascade. In turn, by affecting SREBP-1, SM induces SREBP-2. The increased levels of SREBP-2 are consistent with increased CHOL synthesis. In SM-enriched adipocytes, a higher amount of CHOL is required to maintain raft and caveolae assembly. Caveolin transports the neo-synthesized CHOL toward the cell surface, thus increasing the caveolin-2 levels in the plasma membrane. In SM-depleted cells, the opposite mechanism could be effective.