Diet-dependent retinoid effects on liver gene expression include stellate and inflammation markers and parallel effects of the nuclear repressor Shp

Abstract

For mice, a maternal vitamin A (VA) deficient diet initiated from mid-gestation (GVAD) produces serum retinol deficiency in mature offspring. We hypothesize that the effects of GVAD arise from pre-weaning developmental changes. We compare the effect of this GVAD protocol in combination with a post-weaning high fat diet (HFD) or high carbohydrate diet (LF12). Each is compared to an equivalent VA sufficient combination. GVAD extensively decreased serum retinol and liver retinol, retinyl esters, and retinoid homeostasis genes (Lrat, Cyp26b1, and Cyp26a1). These suppressions were each more effective with LF12 than with HFD. Post-weaning initiation of VA deficiency with LF12 depleted liver retinoids, but serum retinol was unaffected. Liver retinoid depletion, therefore, precedes serum attenuation. Maternal LF12 decreased the obesity response to the HFD, which was further decreased by GVAD. LF12 fed to the mother and offspring extensively stimulated genes marking stellate activation (Col1a1, Timp2, and Cyp1b1) and novel inflammation markers (Ly6d, Trem2, Nupr1). The GVAD with LF12 diet combination suppressed these responses. GVAD in combination with the HFD increased these same clusters. A further set of expression differences on the HFD when compared to a high carbohydrate diet were prevented when GVAD was combined with HFD. Most of these GVAD gene changes match published effects from deletion of Nr0b2/Shp, a retinoid-responsive, nuclear co-repressor that modulates metabolic homeostasis. The stellate and inflammatory increases seen with the high carbohydrate, LF12 diet may represent postprandial responses. They depend on retinol and Shp, but the regulation reverses with a HFD.

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

“…These genes are mostly inflammation markers that are also suppressed by deletion of Shp/Nr0b2 (Kim et al, 2014) (Supplementary Figure 1). We have shown that the response changes in Cyp1b1−/− mice compared to WT mice correlate remarkably with the changes reported in Shp−/− mice (Maguire et al, 2017). Shp redirects postprandial metabolism from glycogen synthesis to glycolysis and lipogenesis (Garruti et al, 2012) (Figure 5B).…”

“…This basal diet (LF12) is similar to the low fat, post-weaning, control diet (LFD), sharing 20 percent refined protein content and approximately 70 percent kcal from carbohydrate (Supplementary Table 1). The combination of LF12 maternal diet with the HFD post-weaning (LF12-HFD) produced few liver gene expression differences when compared to the standard breeder diet combination (BD-HFD) (Maguire et al, 2017). Nevertheless, body weight and adipose were significantly decreased (Figure 1D).…”

“…This stellate cluster is then accompanied by the cluster of inflammatory markers that link to Shp and Ppp1r3g (Table 2) (Maguire et al, 2017). The stellate activation by GVAD may derive from the retinoid depletion (Supplementary Figure 1) (Wallace et al, 2015), but occurs without retinoid depletion in Cyp1b1−/− pups (Figure 2F).…”

“…Here, we show that the growth hormone- and leptin-associated liver responses to Cyp1b1 deletion were largely unaffected by GVAD. We have recently shown that administration of the LF12 diet in gestation to the mother and post-weaning to the progeny produces major increases in a set of inflammatory markers (Maguire et al, 2017). This appears to be a postprandial response to high dietary carbohydrate that is suppressed by GVAD treatment.…”

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].…”