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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The CYP7A1 gene encodes cholesterol 7aα-hydroxylase, catalyzing the first and major rate-limiting step in the classical, neutral pathway for bile acid biosynthesis. The CYP7B1 gene codes for a 7α-hydroxylase involved in metabolism of oxysterols, sex hormones, and neurosteroids. CYP7B1 shares 40% amino acid sequence identity with CYP7A1.
Use of Amnion Epithelial Cells in Metabolic Liver Disorders
Published in Ornella Parolini, Antonietta Silini, Placenta, 2016
Roberto Gramignoli, Fabio Marongiu, Strom Stephen C.
One month after differentiation, structural cytoskeleton elements such as cytokeratins 8, 18, and 19, in addition several metabolic and functional genes (A1AT, albumin, several forms of cytochrome P450) as well as nuclear factors pregnane-X and constitutive-androstane receptors were detected at levels similar to those observed in human fetal livers at midgestation (18–22 weeks) (Marongiu et al. 2011). Some hepatic genes are expressed preferentially during the fetal period and decline in expression after birth. A well-known example of this type of pattern can be found in alpha-fetoprotein (AFP) and albumin. Genes in the CYP3A family show a similar pattern to AFP/albumin: fetal liver expressed predominantly CYP3A7, whereas expression of CYP3A4 occurred after birth (Noreault et al. 2005; Schuetz et al. 1994; Yang et al. 1994). Cultured hAEC-derived hepatocyte-like cells also expressed both CYP3A7 and CYP3A4 (Marongiu et al. 2011; Miki et al. 2009). However, the ratio of CYP3A4/CYP3A7 suggested that hAECs are close to fetal hepatocytes progressing toward the adult phenotype. Notably, hAEC-derived hepatocyte-like cells possessed metabolic function typical of mature hepatocyte the ability to metabolize ammonia and 17-hydroxyprogesterone caproate (normally metabolized by CYP3A7), together with inducible cytochrome P450 and phase II enzymes (Marongiu et al. 2011). The coexpression of cytokeratin 19 and AFP is reminiscent of a stage in liver development during fetal life where bipotential progenitor cells can give rise to both hepatocytes and bile duct cells, and their expression suggests that hAECs may give rise to bile ducts as well as hepatocytes. One gene has been reported to be specific for definitive endoderm, CYP7A1 (Asahina et al. 2004), an enzyme involved in the conversion of cholesterol to bile acids in hepatocytes (Ellis et al. 1998). The detection of expression of CYP7A1 in amnion-derived hepatocyte-like cells indicates that the hAECs differentiate to definitive endoderm. CYP7A1 expression is specifically downregulated by bile acid exposure along with the bile salt export protein.
Effect of the Ileum and Colon on Liver Regeneration
Published in Journal of Investigative Surgery, 2021
Cláudia Nunes Oliveira, Ítalo Medeiros Azevedo, Keyla Borges Ferreira Rocha, Eryvaldo Sócrates Tabosa Egito, Aldo Cunha Medeiros
Ileal resection likely altered bile acid homeostasis, which was important for liver regeneration, in the 70% hepatectomy + ileal resection group. Zhang et al (2013) demonstrated that farnesoid X receptor (FXR) expressed in the liver and intestine activates the expression of fibroblast growth factor 15 (FGF15) in the ileum [13]. This contributes to suppressing CYP7a1 transcription, decreasing bile acid synthesis, and enhancing liver regeneration. It has been demonstrated that FGF15 released from the ileum has important effects on the enterohepatic cycle [14]. In addition to controlling bile acid synthesis, FXR stimulation activates pro-mitogenic mechanisms [15]. In the present study, we used ileal resection as a possible factor influencing liver regeneration, based on these mechanisms and other regulatory molecular factors of the enterohepatic cycle [16]. Qiu et al (2009) reported a change in functional liver mass, autophagy and apoptosis after small bowel resection in mice [12]. In our laboratory we have evaluated functional liver mass, using aspartate aminotransferase, alanine aminotransferase, gamaglutamiltransferase and biodistribution of pertechnetate labeled phytate (99 m-Tc-phytate), a radiocolloid used to validate the assessment of liver function in postoperative period of ileal resection in an animal model. We observed a significant reduction of functional liver capacity in rats subjected to 50 cm ileum resection [17].
Survival genes expression analysis following ionizing radiation to LiCl treated KG1a cells
Published in International Journal of Radiation Biology, 2020
Yogesh Kumar Verma, Ajay Kumar Singh, Gangenahalli Ugraiah Gurudutta
The analysis of interacting genes in largest cluster of coregulated gens exhibited differential regulation of CYP7A1, which is transcriptionally regulated by FOXA2 gene. CYP7A1 encodes a member of the cytochrome P450 superfamily of enzymes (monooxygenases), which catalyzes many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. During catabolism of cholesterol in liver, it is converted to bile acids. This reaction is a rate-limiting step and major site of regulation of bile acid synthesis, which is the primary mechanism for removal of cholesterol from the body (Chiang 2009). FOXA2 is a transcription activator for a number of liver genes such as α fetoprotein (AFP), albumin, tyrosine aminotransferase, PEPCK and CYP7A1, etc. It is involved in glucose homeostasis, regulates the expression of genes important for glucose sensing in pancreatic beta-cells, fat metabolism and glucose homeostasis (Bochkis et al. 2008).
Emerging drugs for the treatment of primary biliary cholangitis
Published in Expert Opinion on Emerging Drugs, 2020
Naw April Phaw, Jessica Katharine Dyson, David Jones
The accumulation of high concentrations of hydrophobic bile acids in cholestasis probably plays an important role in the progression of PBC as hydrophobic bile acids are significantly more cytotoxic than hydrophilic. Bile acid synthesis modulators and transporters in the gut-liver axis have been successful therapeutic targets, reducing disease activity. Farnesoid X Receptors (FXR) physiologically regulate the genes involved in bile acid synthesis, absorption, uptake, and transport [11]. Upon activation of the receptor, it inhibits bile acid synthesis by suppressing the transcription activity of genes encoding the enzyme cholesterol 7alpha-hydroxylase (CYP7A1) that initiates the bile acid production pathway [37]. It also downregulates the expression of bile acid transporters (Na+ -taurocholate cotransporting polypeptide, NTCP, and Apical sodium-dependent bile acid transporter (ASBT) in the liver and intestine) thereby regulating bile acid uptake and export [38]. FXR agonists are the novel agents in PBC that have progressed furthest to date and have entered clinical practice following provisional FDA and EMA approval.