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Regulation of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Further microarray studies in CYP2D6-humanized transgenic mice have shown that seven transcription factors, namely, activating transcription factor 5 (ATF5), early growth response 1 (EGR1), forkhead box protein A3 (FOXA3), JUNB, KLF9, KLF10, and REV-ERBα, are upregulated in mouse liver during pregnancy (Koh et al. 2014b). KLF9 itself is a weak transactivator of CYP2D6 promoter but significantly enhances CYP2D6 promoter transactivation by HNF-4α, a known transcriptional activator of CYP2D6 expression. The results from deletion and mutation analysis of CYP2D6 promoter activity have identified a KLF9 putative binding motif at the –22/-14 region to be critical in the potentiation of HNF-4α–induced transactivation of CYP2D6 (Koh et al. 2014b). KLF9, a member of the KLF transcription factor family of zinc finger DNA-binding proteins, can either activate or repress target gene expression in a promoter-specific context. KLF9 is involved in cell differentiation of B cells, keratinocytes, and neurons. Biologic actions of KLF9 are mediated either by its direct binding to the promoters of its target genes such as CYPIAI or by coactivation of other transcription factors (Kaczynski et al. 2002; Shields and Yang 1998; Zhang et al. 1998). KLF9 is also a key transcriptional regulator for uterine endometrial cell proliferation, adhesion, and differentiation, all factors that are essential during the process of pregnancy and are switched off during tumorigenesis (Pabona et al. 2012; Shimizu et al. 2010; Simmen et al. 2008, 2015). In endometrial cells, KLF9 binds to progesterone receptors and enhances transcriptional activation of the target genes (Zhang et al. 2003).
Mouse Knockout Models of Biliary Epithelial Cell Formation and Disease
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Smads are intracellular mediators of TGF-beta that are conserved through evolution. Recent genetic using combinatorial genetics have shown the key roles of Smad2 and Smad4 in gastrulation as well as endoderm formation and liver development.4 Similarly transcription factors Sox 17 (an Sry-related HMG box factor), Mixer (a homeobox protein) and Casanova have been shown to be key determinants of endoderm in Xenopus and zebrafish, with mammalian Sox 17 being crucial for gut endoderm.7 All are expressed in the fetal, adult liver, and other endoderm derived tissues and the fox proteins regulate virtually all liver-specific genes, as well as genes in the lung and the pancreas. 8,9Foxa2 (formerly Hnf3b) is expressed during gastrulation (6.5 days of embryonic gestation in the mouse; E6.5) in the primitive streak (an endoderm progenitor) and in the node (an endoderm and notochord progenitor, Foxa1 (Ηnf3α) expression initiates in the gut endoderm at E7- E8, before organogenesis, whereas Foxa3 (Hnf3c) expression begins in the gut endoderm at E8-E9 but is restricted to the midgut and hindgut regions.10,11 Homozygous mutants for Foxa2 result in embryonic lethality shortly after gastrulation, with defects in the primitive streak, node and notochord that impair neural tube development, and in foregut morphogenesis. 12–15 Homozygous mutation in Foxal leads to impaired pancreatic glucagon expression and consequent postnatal death, whereas homozygous mutation in Foxal appear normal, yet have a decrease in the transcription levels of a number of liver genes. These are seen in Figure 1.
Micronutrients in Prevention and Improvement of the Standard Therapy in Diabetes
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Several studies on changes in the expression of microRNAs and their corresponding target proteins play a significant role in the pathogenesis of diabetes. A few selected investigations in human and animal diabetes are presented in Table 6.2. In women with gestational diabetes (GDM), the expression of miR-222 was elevated in omentalsdipode tissue from GDM compared with pregnant women with normal glucose tolerance. The expression of miR-222 was also upregulated in 3T3-L-1 adipocytes in the presence of high concentration of 17β-estrodiol, while the levels of estrogen receptor (ER) protein-α and glucose transporter 4 (GLUT4) protein decreased. These results suggest that miR-222 could be considered a potential regulator of ER-alpha levels in estrogen-induced insulin resistance in GDM.79 Islet-specific miR-375 was upregulated and downregulated its target protein myotrophin (Mtpn) leading to the suppression of glucose-induced insulin secretion in pancreatic endocrine cells. Inhibition of Mtpn synthesis by a small interfering (siRNA) mimicked the effects of miR-375, suggesting that this microRNA regulated the secretion of insulin.80 In patients with type 2 diabetes, decreased expression of miR-19-3p increased the levels of its target protein suppressor of cytokine signaling 3 (SOCS3), and these changes were associated with high concentrations of blood glucose in type 2 diabetes. Transfection of β-cells with miR-19-3p enhanced the proliferation and insulin secretion. Additionally. Inhibition of the synthesis of SOCS3 protein by siRNA increased cell proliferation and insulin secretion.81 Overexpression of miR-124a and downregulation of its target proteins Mptn (myotrophin) and FOXa3 (forkhead box protein A3) in MIN6 pseudoislets (insulin-secreting MIN6 cells grown as islet-like clusters), and these changes were associated with reduced glucose-induced insulin secretion.82
Targeting endoplasmic reticulum stress—the responder to lipotoxicity and modulator of non-alcoholic fatty liver diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Yu Luo, Qiangqiang Jiao, Yuping Chen
As a key effector of IRE1α, sXBP1 coordinates hepatic metabolic activities in different nutritional states [58]. Accordingly, XBP1 promotes hepatosteatosis in NAFLD and is often highly expressed in livers of obese NAFLD patients [33]. In high carbohydrate-fed mice, sXBP1 was found to stay at and activate the promoters of many lipogenic enzyme genes, like ACC2, fatty acid synthase (FAS), diacylglycerol acyltransferase (DGAT2) and SCD1, and its liver-specific deletion alleviated ob/ob- or HFD-induced hepatosteatosis[1,5]. Notably, XBP1 acted as a transactivator of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and mediated the upregulation of HMGCR and cholesterol biosynthesis in cancer cells [59]. As a target of sXBP1, forkhead box A3 (FOXA3) directly regulated Period1 (PER1) transcription, which in turn promoted the expression of SREBP1c and lipogenesis [60]. In obese mice and NAFLD patients, the hepatic levels of FOXA3, PER1 and SREBP1c went up identically, indicating that this pathway may drive NAFLD development [60]. In addition, sirtuin 6 was seen to alleviate ER stress and hepatosteatosis via deacetylating the Lys257 and Lys297 at the transactivation domain of sXBP1 and hastening its degradation [61], while the acetylation extent of sXBP1 in NAFLD patient livers was correlated positively with NAFLD activity score but negatively with sirtuin 6 level [61], further highlighting the pro-steatotic activity for sXBP1.
Indirect regulation of CYP2C19 gene expression via DNA methylation
Published in Xenobiotica, 2018
Kathryn Elisa Burns, Phillip Shepherd, Graeme Finlay, Malcolm Drummond Tingle, Nuala Ann Helsby
5-Aza-2′-deoxycytidine (5azaDC), a methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylase, are often used in in vitro models to identify genes which are regulated by these mechanisms. However, genes that are actively transcribed in somatic cells typically have CpG islands that are unmethylated and these areas are generally characterised by nucleosome depletion. In these cases, gene expression can be controlled by the availability and binding of transcription factors (TFs) (Jones, 2012). Transcription factors such as ERα, FOXA3 (HNF–3γ), GATA–4, CAR, and GR have been shown to bind response elements in the promoter region of CYP2C19 (Figure 1) and alter gene expression in cell culture models (Reviewed in Helsby & Burns, 2012).
Role of the mucins in pathogenesis of COPD: implications for therapy
Published in Expert Review of Respiratory Medicine, 2020
Federica Lo Bello, Antonio Ieni, Philip M. Hansbro, Paolo Ruggeri, Antonino Di Stefano, Francesco Nucera, Irene Coppolino, Francesco Monaco, Giovanni Tuccari, Ian M. Adcock, Gaetano Caramori
These changes were associated with increased expression of FOXA3, a transcription factor expressed in mucin-secreting cells at baseline (p < 0.001) as well as after RV infection in COPD cells (p = 0.008). In contrast, the basal mRNA expression of FOXA2, a transcription factor that negatively regulates mucin-secreting cell differentiation, and FOXJ1, which promotes ciliated cell differentiation, were relatively lower in COPD compared to normal cell cultures [33].