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

Meghan Maguire1,2, Michele Campaigne Larsen2, Chad M Vezina3

  • 1Endocrinology and Reproductive Physiology Program, University of Wisconsin-Madison, Madison, WI.

Plos One
|February 7, 2020
PubMed

Insights

Cytochrome P450 1b1 (Cyp1b1) deletion and pregnancy retinol deficiency impact liver functions regulated by Srebp. Cyp1b1 and retinol influence postnatal Srebp activity through developing liver or systemic signaling.

Area of Science:

  • Biochemistry
  • Developmental Biology
  • Genetics

Background:

  • Cytochrome P450 1b1 (Cyp1b1) deletion and pregnancy retinol deficiency (GVAD) impact perinatal liver functions regulated by Sterol Regulatory Element-Binding Proteins (Srebp).
  • Cyp1b1 is not expressed in the perinatal liver but is present in the E9.5 embryo near retinoic acid (RA) signaling centers.

Purpose of the Study:

  • To investigate the parallel effects of Cyp1b1 and retinol on postnatal Srebp-regulated liver functions.
  • To determine if these effects originate from the developing liver or systemic signaling pathways.

Main Methods:

  • Clustering of postnatal hepatic gene expression changes related to GVAD or Cyp1b1 deletion.
  • Analysis of gene expression changes in relation to Srebp1 and Srebp2 targets.
  • Examination of E9.5 embryos for effects on RA homeostasis (Aldh1a2, Cyp26a1) and RA targets (Hoxb1, Pax6) using in situ hybridization.
  • Assessment of mice with combined Lrat and Rbp4 deficiency (DKO mice) to limit embryonic retinol supply.

Main Results:

  • GVAD and Cyp1b1 deletion at birth stimulate hepatic stellate cell (HSC) activation markers but suppress Hamp.
  • These interventions selectively inhibit the postnatal expression of genes involved in cholesterol synthesis, fatty acid synthesis, cholesterol transport, and retinoid synthesis.
  • Cyp1b1 is expressed in the septum transversum mesenchyme (STM) with Bco1, which generates retinaldehyde, and STM supports liver development.
  • RA-dependent gene expression (Hoxb1, Pax6) is unaffected by GVAD and Cyp1b1 deficiency, but RA-dependent Cyp26a1 is lost in DKO embryos, though Hoxb1 is sustained.

Conclusions:

  • Cyp1b1 deficiency suppresses Srebp-dependent genes, with distinct Srebp1 and Srebp2 mediation by GVAD.
  • Srebp regulation significantly overlaps in cholesterol and retinoid homeostasis.
  • A partnership between Bco1 and Cyp1b1 in the STM may contribute to later liver regulation.
Abstract

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