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Background  Cytochrome P450 1b1 (Cyp1b1) deletion and dietary retinol deficiency during pregnancy (GVAD) affect perinatal liver functions regulated by Srebp.  Cyp1b1  is not expressed in perinatal liver but appears in the E9.5 embryo, close to sites of retinoic acid (RA) signaling.    Hypothesis  Parallel effects of Cyp1b1 and retinol on postnatal Srebp derive from effects in the developing liver or systemic signaling.    Approach  Cluster postnatal increases in hepatic genes in relation to effects of GVAD or Cyp1b1 deletion. Sort expression changes in relation to genes regulated by Srebp1 and Srebp2.Test these treatments on embryos at E9.5, examining changes at the site of liver initiation. Use in situ hybridization to resolve effects on mRNA distributions of  Aldh1a2  and  Cyp26a1  (RA homeostasis);  Hoxb1  and  Pax6  (RA targets). Assess mice lacking  Lrat  and  Rbp4  (DKO mice) that severely limits retinol supply to embryos.    Results  At birth, GVAD and Cyp1b1 deletion stimulate gene markers of hepatic stellate cell (HSC) activation but also suppress  Hamp . These treatments then selectively prevent the postnatal onset of genes that synthesize cholesterol ( Hmgcr ,  Sqle ) and fatty acids ( Fasn ,  Scd1 ), but also direct cholesterol transport ( Ldlr ,  Pcsk9 ,  Stard4 ) and retinoid synthesis ( Aldh1a1 ,  Rdh11 ). Extensive support by Cyp1b1 is implicated, but with distinct GVAD interventions for Srebp1 and Srebp2. At E9.5,  Cyp1b1  is expressed in the septum transversum mesenchyme (STM) with β-carotene oxygenase ( Bco1 ) that generates retinaldehyde. STM provides progenitors for the HSC and supports liver expansion. GVAD and Cyp1b1-/- do not affect RA-dependent  Hoxb1  and  Pax6 . In DKO embryos, RA-dependent  Cyp26a1  is lost but  Hoxb1  is sustained with  Cyp1b1  at multiple sites.    Conclusion  Cyp1b1-/- suppresses genes supported by Srebp. GVAD effects distinguish Srebp1 and Srebp2 mediation. Srebp regulation overlaps appreciably in cholesterol and retinoid homeostasis. Bco1/Cyp1b1 partnership in the STM may contribute to this later liver regulation.

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development