Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development

Abstract

Cyp1b1 deletion and gestational vitamin A deficiency (GVAD) redirect adult liver gene expression. A matched sufficient pre- and post-natal diet, which has high carbohydrate and normal iron content (LF12), increased inflammatory gene expression markers in adult livers that were suppressed by GVAD and Cyp1b1 deletion. At birth on the LF12 diet, Cyp1b1 deletion and GVAD each suppress liver expression of the iron suppressor, hepcidin (Hepc), while increasing stellate cell activation markers and suppressing post-natal increases in lipogenesis. Hepc was less suppressed in Cyp1b1−/− pups with a standard breeder diet, but was restored by iron supplementation of the LF12 diet. Conclusions The LF12 diet delivered low post-natal iron and attenuated Hepc. Hepc decreases in Cyp1b1−/− and GVAD mice resulted in stellate activation and lipogenesis suppression. Endothelial BMP6, a Hepc stimulant, is a potential coordinator and Cyp1b1 target. These neonatal changes in Cyp1b1−/− mice link to diminished adult obesity and liver inflammation.

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

“…Cytochrome P450 1b1 (Cyp1b1) has a major influence on obesity and genes that have been linked to Type 2 diabetes [1][2][3]. Such changes may be initiated during pregnancy [4,5]. Cyp1b1 exhibits diverse expression in mouse embryo mesenchymal progenitor cells [6][7][8] and vascular cells [9,10].…”

“…A functional link between Cyp1b1 and dietary retinol has been discovered from shared perinatal effects on hepatic gene regulation provided by gestational vitamin A deficiency (GVAD) and Cyp1b1 deletion. Each deliver coordinated, but distinct suppression of genes in two pathways that convert acetate to, respectively, oleoyl-CoA and cholesterol [4,5]. One possibility is that these effects arise through earlier events in liver development.…”

Cytochrome P450 1B1: role in health and disease and effect of nutrition on its expression

“…These neonatal change in CYP1B1 decient mice were lined to attenuated adult obesity and liver inammation. 73 Last year, Falero-Perez and colleagues evaluated the impact of CYP1B1 expression on LSEC (liver sinusoidal endothelial cells) properties. Concluding their ndings, it was stated that CYP1B1 expression had a signicant impact on LSEC angiogenic and inammatory functions.…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…Raldh2-deficient mouse embryos died around E9.0 and displayed severe defects in heart development (Niederreither, Subbarayan, Dollé, & Chambon, 1999;K. Besides RALDH1-3, CYP1B1 can contribute to RA production and the effect of CYP1B1 deletion on liver lipid metabolism is exacerbated by vitamin A-depletion (Chambers, Wilson, Maden, & Lumsden, 2007;Maguire, Larsen, Foong, Tanumihardjo, & Jefcoate, 2017). RALDH3 is found in the embryonic retina, nasal region as well as skeletal muscle.…”

“…On the other hand, lack of Raldh1, which is expressed in the brain, retina and cardiac valves, did not cause embryonic death, possibly because of compensation by the other embryonic RALDHs. Besides RALDH1-3, CYP1B1 can contribute to RA production and the effect of CYP1B1 deletion on liver lipid metabolism is exacerbated by vitamin A-depletion (Chambers, Wilson, Maden, & Lumsden, 2007;Maguire, Larsen, Foong, Tanumihardjo, & Jefcoate, 2017). Mutations in CYP1B1 are associated with glaucoma, while deletion of Cyp1b1 in mice also causes dysgenesis of eye drainage structure (Schlemm's canal) in mice (Bejjani et al, 2000;Libby et al, 2003).…”