The goal of this study is to identify a mechanism regulating cholesterol accumulation in cystic fibrosis (CF) cells. Both CFTR activation and expression are regulated by the cAMP pathway, and it is hypothesized that a feedback response involving this pathway may be involved in the phenotype of cholesterol accumulation. To examine the role of the cAMP pathway in cholesterol accumulation, two CF-model cell lines were treated with Rp-cAMPS and cholesterol visualized by filipin staining. Rp-cAMPS treatment eliminates cholesterol accumulation in CF cells, whereas 8-Br-cAMP treatment leads to cholesterol accumulation in WT cells. To confirm these findings in an independent model system, the role of cAMP in modulating cholesterol accumulation in Niemann-Pick type C fibroblasts was also examined. Expression of the protein related to NPC, NPC1, is also directly regulated by cAMP, therefore, it is postulated that NPC cells exhibit the same cAMP-mediated control of cholesterol accumulation. Cholesterol accumulation in NPC cells is also reduced by the presence of Rp-cAMPS. Expression of -arrestin-2 (arr2), a marker of cellular response to cAMP signaling, is significantly elevated in CF-model cells, Cftr -/- MNE, primary tissue obtained by nasal scrapes from CF subjects, and in NPC fibroblasts compared to respective controls.