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

Abstract

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

Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

“…Igfbp1 expression is affected by diet and sex [ 41 , 43 ], therefore, differences in these variables may explain the discrepancy. The finding of altered expression of lipid metabolism genes and lipid composition in Cyp1b1 -KO mice is also consistent with our results [ 41 , 43 , 82 ]. Similarly interesting is the identification of differentially expressed redox genes, including several upregulated cytochrome P450 family members (e.g., cyp24a1 ), suggesting that they may compensate, at least partially, cyp1b1 LoF.…”

Null cyp1b1 Activity in Zebrafish Leads to Variable Craniofacial Defects Associated with Altered Expression of Extracellular Matrix and Lipid Metabolism Genes

“…Igfbp1 expression is affected by diet and sex [41,43], therefore differences in these variables may explain the discrepancy. Also consistent with our results is the finding of altered expression of lipid metabolism genes and lipid composition in Cyp1b1-KO mice [41,43,82]. Similarly interesting is the identification of differentially expressed redox genes, including several upregulated cytochrome P450 family members (e.g., cyp24a1), suggesting that they may compensate, at least partially, cyp1b1 LoF.…”

DNA Repair and Replication-Related Gene Signature Based on Tumor Mutation Burden Reveals Prognostic and Immunotherapy Response in Gastric Cancer

“…CYP1B1 encodes a member of the cytochrome P450 enzyme superfamily. Cytochrome P450 proteins are monooxygenases that catalyze many reactions involving drug metabolism and the synthesis of cholesterol, steroids, and other lipids [44]. Kwon et al demonstrated that the oncogenic molecular mechanism of CYP1B1 action is associated with specificity protein one-mediated gene regulation, which induces cancer cell proliferation and migration [45].…”