The Disruption of Cyp7b1 Controls IGFBP2 and Prediabetes Exerted Through Different Hydroxycholesterol Metabolites
Cytochrome P450, family 7, subfamily b, polypeptide 1 (CYP7B1) is a widely expressed enzyme involved in the hydroxylation of sterols. Generated by transposon technology in zygotes, male rats lacking <i>Cyp7b1</i> expression in homozygosis showed an absence of <i>Cyp7b1</i> mRNA expression in the liver, small intestine, adipose tissue, and muscle. Elevated levels of 25-hydroxycholesterol were found in the liver of mutant rats. After overnight fasting, plasma triglyceride (TG) levels were increased in the homozygous rats. In agreement with this, increased hepatic secretion of very-low-density lipoprotein-TG (VLDL) in fasting rats treated with tyloxapol and decreased low-density receptor protein (LDLr) on the hepatocyte plasma membranes were observed. The decrease in LDLr was not due to decreased mRNA expression but to increased expressions of its proteases (<i>Psck9</i> and <i>Mylip</i>). RNA sequencing identified <i>Fasn</i>, <i>Igfbp2</i>, and <i>Pcsk9</i> as targets of the <i>Cyp7b1</i> absence. However, the hepatic protein contents of IGFBP2 were increased in <i>Cyp7b1</i>-deficient rats, accompanied by a normal glucose tolerance test. HepG2 cells lacking <i>CYP7B1</i> showed increased expressions of <i>FASN</i> and <i>IGFBP2</i>. These results suggest a role of CYP7B1 in the control of hepatic IGFBP2 and VLDL-TG secretion as a prediabetes sign exerted through 25-hydroxycholesterol and transcriptional or translational mechanisms depending on the species.
Authors
- María Á. Navarro (ORCID: https://orcid.org/0000-0002-0108-1004)
- Jesús Osada (ORCID: https://orcid.org/0000-0002-8251-8457)
- Celia Domeño (ORCID: https://orcid.org/0000-0001-8893-0963)
- Aron M. Geurts (ORCID: https://orcid.org/0000-0002-4347-2505)
- Luis V. Herrera‐Marcos (ORCID: https://orcid.org/0000-0002-4665-9674)
- Martín Laclaustra (ORCID: https://orcid.org/0000-0003-3963-0846)
- Cristina Nerı́n (ORCID: https://orcid.org/0000-0003-2685-5739)
- Cristina Barranquero (ORCID: https://orcid.org/0000-0002-8442-8041)
- Natalía Guillén (ORCID: https://orcid.org/0000-0001-6627-298X)
- Joaquín C. Surra (ORCID: https://orcid.org/0000-0002-5841-0462)
- María Jesús Rodriguez‐Yoldi (ORCID: https://orcid.org/0000-0002-3595-7668)
- Isabel Mendiara (ORCID: https://orcid.org/0000-0001-8830-6554)
- Javier Sánchez-Marco (ORCID: https://orcid.org/0000-0002-9023-741X)
- Roberto Martínez‐Beamonte (ORCID: https://orcid.org/0000-0002-8100-5596)
- Carmen Arnal (ORCID: https://orcid.org/0000-0003-1197-4276)
- Juan José Puente‐Lanzarote (ORCID: https://orcid.org/0000-0002-7213-7095)
Institutions
- Medical College of Wisconsin (US)
- Universidad de Zaragoza (ES)
- Instituto de Salud Carlos III (ES)
- Centro de Investigación y Tecnología Agroalimentaria de Aragón (ES)
- Hospital Clínico Universitario Lozano Blesa (ES)
- Instituto de Investigación Sanitaria Aragón (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-12-12
- DOI
- https://doi.org/10.3390/ijms262411994
- Primary Topic
- Cholesterol and Lipid Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Ministerio de Ciencia e Innovación
- Gobierno de Aragón
- Instituto de Salud Carlos III
- European Regional Development Fund