Wild-type mice, inhibition studies

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

Overall, these in vivo observations indicate that the presence of heterologous PrP can interfere with disease and that this interference is dependent on expression level. Support for this hypothesis has come from studies in Sc+-MNB cells. Expression of a heterologous mouse PrP-sen mutated at 1 or 2 residues significantly inhibited PrP-res formation from the wild-type endogenous mouse PrP-sen (Pig. 5) (Priola et al,... 

Studies with Mtp mice and MTP inhibitors suggest that MTP promotes the movement of TG from cytosolic lipid droplets, or from a TG pool within the ER membrane, across the ER membrane and into a lumenal, apo B-free TG pool that can subsequently be used for VLDL assembly. The existence of such a pool of apo B-free TG in the ER lumen was demonstrated in mouse hepatocytes in which inhibition of MTP decreased the pool of apo B-free TG within the microsomal lumen (J.E. Vance, 2002). Furthermore, ultrastruc-tural analysis of Mtp hepatocytes compared to wild-type hepatocytes showed that the ER and Golgi lumina of cells lacking MTP contained very few lipid-staining particles of the size of VLDLs. Consistent with these observations, Mtp mouse livers contain an increased number of cytosolic lipid droplets (S.G. Young, 1998). An apo B-free lumenal TG pool was also observed in enterocytes from mice that lacked apo B synthesis in the intestine (R.L Hamilton, 1998). 

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