C.Båvik and V.Sapin contributed equally to this workThe gene encoding cellular retinol (ROL, vitA)-binding protein type I (CRBPI) has been inactivated. Mutant mice fed a vitA-enriched diet are healthy and fertile. They do not present any of the congenital abnormalities related to retinoic acid (RA) deficiency, indicating that CRBPI is not indispensable for RA synthesis. However, CRBPI deficiency results in an~50% reduction of retinyl ester (RE) accumulation in hepatic stellate cells. This reduction is due to a decreased synthesis and a 6-fold faster turnover, which are not related to changes in the levels of RE metabolizing enzymes, but probably reflect an impaired delivery of ROL to lecithin:retinol acyltransferase. CRBPI-null mice fed a vitA-deficient diet for 5 months fully exhaust their RE stores. Thus, CRBPI is indispensable for efficient RE synthesis and storage, and its absence results in a waste of ROL that is asymptomatic in vitA-sufficient animals, but leads to a severe syndrome of vitA deficiency in animals fed a vitA-deficient diet.

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␥-Secretase inhibition represents a major therapeutic strategy for lowering amyloid ␤ (A␤) peptide production in Alzheimer's disease (AD).Progress toward clinical use of ␥-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The ␥-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A␤ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of ␥-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A␤ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious ␥-secretase targeting strategy for AD.

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This review summarizes the available data on the effects of dioxins on retinoid levels, retinoid-related enzyme activities, and toxicological endpoints that have been correlated to retinoid effects. Similarities between dioxin toxicity and retinoid deficiency as well as retinoid excess are pointed out. Several possible levels of interaction between the dioxin and the retinoid signaling pathways are discussed, including the involvement of the Ah receptor, altered retinoic acid homeostasis, and an altered set point for retinoid storage. A hypothesis for the effect of dioxins on retinoids is suggested. In this hypothesis, comprising two cascades of effects on the molecular level, the effect of dioxins on retinoic acid levels is central.