Thyroid hormone differentially regulates rat intestinal brush border enzyme gene expression

Hodin, Richard A.; Chamberlain, Sherman; Upton, Melissa P.

doi:10.1016/0016-5085(92)91174-3

Cited by 47 publications

(31 citation statements)

References 33 publications

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“…For example, the thyroid hormone exerts a positive effect on gut mucosal maturation (5) and enterocyte differentiation (6,7). Members of the nuclear hormone receptor superfamily are activated by metabolically transformed lipids that are absorbed by intestinal epithelial cells (IEC) 4 before interacting with their receptors and associated gene targets (8).…”

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confidence: 99%

Nuclear Receptor Co-repressor Is Required to Maintain Proliferation of Normal Intestinal Epithelial Cells in Culture and Down-modulates the Expression of Pigment Epithelium-derived Factor

Doyon

St-Jean

Darsigny

et al. 2009

Journal of Biological Chemistry

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Stem cells of the gut epithelium constantly produce precursors that progressively undergo a succession of molecular changes resulting in growth arrest and commitment to a specific differentiation program. Few transcriptional repressors have been identified that maintain the normal intestinal epithelial cell (IEC) proliferation state. Herein, we show that the nuclear receptor co-repressor (NCoR1) is differentially expressed during the proliferation-to-differentiation IEC transition. Silencing of NCoR1 expression in proliferating cells of crypt origin resulted in a rapid growth arrest without associated cell death. A genechip profiling analysis identified several candidate genes to be up-regulated in NCoR1-deficient IEC. Pigment epitheliumderived factor (PEDF, also known as serpinf1), a suspected tumor suppressor gene that plays a key role in the inhibition of epithelial tissue growth, was significantly up-regulated in these cells. Chromatin immunoprecipitation experiments showed that the PEDF gene promoter was occupied by NCoR1 in proliferating epithelial cells. Multiple retinoid X receptor (RXR) heterodimers interacting sites of the PEDF promoter were confirmed to interact with RXR and retinoid acid receptor (RAR). Cotransfection assays showed that RXR and RAR were able to transactivate the PEDF promoter and that NCoR1 was repressing this effect. Finally, forced expression of PEDF in IEC resulted in a slower rate of proliferation. These observations suggest that NCoR1 expression is required to maintain IEC in a proliferative state and identify PEDF as a novel transcriptional target for NCoR1 repressive action.The intestinal epithelium consists of a cell monolayer organized in crypts and villi. This epithelium is under constant and rapid renewal, which is assured by constant division of the stem cells located at the base of the crypts (1). The descendant progenitor cells are progressively instructed to differentiate to exert their functional role during their journey along the villus compartment (2). The proliferation-to-differentiation transition of single progenitor cell is tightly regulated by morphogens, growth factors and hormones that impact on intracellular signaling pathways. Molecular alterations of specific components from these different classes of molecules are suspected to be important during the development of intestinal cancer (3).In vivo studies have demonstrated the role of steroid hormones and ligands during intestinal epithelial development and homeostasis (4). For example, the thyroid hormone exerts a positive effect on gut mucosal maturation (5) and enterocyte differentiation (6, 7). Members of the nuclear hormone receptor superfamily are activated by metabolically transformed lipids that are absorbed by intestinal epithelial cells (IEC) 4 before interacting with their receptors and associated gene targets (8). Peroxisome proliferator-activated receptors (PPARs) are welldescribed examples of lipophilic ligand binding transcription factors that can influence intestinal epithelial proliferati...

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confidence: 99%

Nuclear Receptor Co-repressor Is Required to Maintain Proliferation of Normal Intestinal Epithelial Cells in Culture and Down-modulates the Expression of Pigment Epithelium-derived Factor

Doyon

St-Jean

Darsigny

et al. 2009

Journal of Biological Chemistry

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“…Previously, using both in vitro and in vivo models, we have demonstrated that the IAP gene is a direct target for two transcription factors, the thyroid hormone receptor (12,14) and the gut-enriched KLF4 (or GKLF) (10). We have localized the major KLF4RE to a segment of the IAP gene between Ϫ224 and Ϫ114 bp upstream from the translational start site (10), and the TRE response element between Ϫ632 and Ϫ612 (23).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of intestinal alkaline phosphatase gene expression by Cdx1 and Cdx2

Alkhoury¹,

Malo²,

Mozumder³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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-We have examined the role that the caudal-related homeobox transcription factors Cdx1 and Cdx2 play in activating the enterocyte differentiation marker gene intestinal alkaline phosphatase (IAP). Human colon cancer Caco-2 cells were transiently transfected with Cdx1 and/or Cdx2, and semiquantitative RT-PCR was used to study the effects on IAP mRNA expression. Transfections with a variety of IAP-luciferase reporter constructs were used to identify a Cdx response element located within the human IAP gene promoter. Protein-DNA interactions were examined by EMSA. Results showed that Cdx1 markedly induced IAP mRNA expression, whereas Cdx2 did not, and, in fact, inhibited the Cdx1 effects. Functional analysis revealed that Cdx1 transactivates (fourfold, P Ͻ 0.05) the IAP promoter through a novel Cdx response element (GTTTAGA) located between Ϫ2369 and Ϫ2375 upstream of the translational start site. EMSA showed that both Cdx1 and Cdx2 could bind to the cis element, but in cotransfection experiments, Cdx2 inhibited the Cdx1 effects by ϳ50%. Thus we have identified a previously unrecognized interaction between two important gut transcription factors, Cdx1 and Cdx2, in the context of IAP gene regulation. Cdx1 activates the IAP gene via a novel cis element, whereas Cdx2 inhibits the Cdx1 effects. cell cycle; enterocyte differentiation; gene regulation; gut development; homeostasis; intestinal alkaline phosphatase; tumorigenesis INTESTINAL ALKALINE PHOSPHATASE (IAP) is one of four alkaline phosphatase (AP) isoenzymes. In humans, three of the four AP isozyme are tissue specific, i.e., the intestinal AP (IAP), placental AP, and germ cell AP, while the fourth AP gene is the tissue-nonspecific AP present in bone, liver, and kidney (9). IAP is exclusively expressed in villus enterocytes and hence serves as an excellent marker of crypt-villus differentiation (11). IAP represents a major component of the surfactant-like particles seen after fat feeding (19), and Narisawa et al. (24) recently described the phenotype of the IAP knockout mice, indicating that IAP functions to limit fat absorption during high-fat feeding.IAP expression is dramatically regulated by a variety of dietary, developmental, and hormonal factors, e.g., it is induced at the time of postnatal weaning, whereas fasting in the adult rat causes a dramatic decrease in IAP levels. These alterations in IAP levels likely have important physiological consequences regarding the absorption of dietary fat, and we have, therefore, been interested in elucidating the molecular mechanisms that govern IAP gene regulation. Among the known transcriptional regulators of IAP expression are the thyroid hormone receptor and the gut-enriched Kruppel-like factor (KLF4) (10, 23).Cdx1 and Cdx2 are members of the caudal-related homeobox family and appear to play critical roles in gut differentiation, proliferation, and neoplasia. The Cdx proteins are involved in the regulation of intestine-specific genes, such as sucrase-isomaltase, intestinal phospholipase A/lysophospholipase, lactase-p...

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“…Thyroxine regulates lactase ontogeny by posttranslational mechanisms that include altered processing and increased degradation of the lactase enzyme [42]. Hodin et al [43] noted that T3 therapy in adult rats decreased lactase mRNA levels by approximately 75%. Therefore, it is possible that in the HLD rats, where growth depends on the ability to ingest lactose as the only carbohydrate source, a decrease in active thyroid hormone levels is adaptive.…”

Section: Discussionmentioning

confidence: 99%

Metabolic effects of dietary lactose in adult female rats

et al. 2003

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-As an outgrowth of our interest in the potential toxicity of dietary galactose, we investigated the metabolic effects of high lactose diets in Long-Evans female rats. Seventy-five LongEvans female rats (25-day-old) were randomized to receive one of 3 diets for 7 months: glucose diet (CON); low lactose diet (10.5%, LLD); or a high lactose diet (41.9%, HLD). Necropsy was performed seven months after randomization. HLD animals had significantly lower body weights than controls (P < 0.01). These animals continued to grow, however at a retarded rate compared to the CON group. The HLD group also had significantly lower triglyceride and non-esterified fatty acid levels than the CON group (P < 0.01 and P < 0.05). Serum glucose concentrations were lower in the HLD group compared to CON animals (P < 0.05), while serum insulin levels were lower than both the LLD and CON animals (P < 0.01 and P < 0.05). Leptin exhibited a similar trend. Thyroid studies revealed no difference in TSH between groups. Free T4 was significantly higher in HLD rats compared to LLD and CON rats while free T3 was lower in the HLD group (P < 0.05). This indicates a possible impairment in T4 to T3 conversion. Our data suggests that a long-term high lactose diet is associated with a decrease in insulin and leptin levels, and an increase in the insulin to glucose ratio. However, these changes are seen in the presence of a decreased body mass. A significant effect on thyroid hormone metabolism is also seen, and may be an adaptive mechanism in lactose-fed rats.lactose / galactose / rat / thyroxine / thyroid metabolism

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Thyroid hormone differentially regulates rat intestinal brush border enzyme gene expression

Cited by 47 publications

References 33 publications

Nuclear Receptor Co-repressor Is Required to Maintain Proliferation of Normal Intestinal Epithelial Cells in Culture and Down-modulates the Expression of Pigment Epithelium-derived Factor

Nuclear Receptor Co-repressor Is Required to Maintain Proliferation of Normal Intestinal Epithelial Cells in Culture and Down-modulates the Expression of Pigment Epithelium-derived Factor

Differential regulation of intestinal alkaline phosphatase gene expression by Cdx1 and Cdx2

Metabolic effects of dietary lactose in adult female rats

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