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− | + | The nuclear receptor pregnane X receptor (PXR; NR1I2), initially isolated as a xenobiotic receptor, is extremely expressed in the liver, and plays a major part in drug metabolism and elimination through its regulation from the expression of cytochrome P450 enzymes [19]. A number of recent research recommended that PXR can also be involved in hepatic lipid homeostasis. Activation of PXR perturbs lipid homeostasis in mice by decreasing b-oxidation, rising no cost acid uptake and lipogenesis, which outcomes in hepatic steatosis in mice [20,21,22,23]. Activation of PXR also decreases the expression of carnitine palmitoyltransferase 1A (CPT1A), which controls the entry of activated long-chain fatty acids in to the mitochondria, and mitochondrial 3-hydroxy-3methyl-glutarate-CoA synthase two (Hmgcs2), the rate-limiting enzyme of ketogenesis. PXR regulates CPT1A and HmgcsSCD1 Contributes to the Lipogenic Impact by PXRexpression by means of its crosstalk together with the insulin-responsive forkhead issue A2 (FoxA2) [21]. A further study showed that in VPhPXR transgenic mice, the expression of various genes involved in fatty acid b-oxidation, like PPARa and thiolase, was suppressed [23]. The fatty acid translocase CD36 was established as a direct target gene of PXR. PXR binds to a DR3 sort PXRE within the CD36 gene promoter and induces the expression of CD36, increasing the fatty acid uptake in liver [23]. In human hepatocytes (HHPC), PXR [http://www.ncbi.nlm.nih.gov/pubmed/1315463 1315463] activation by rifampicin, a well-known hPXR agonist, stimulates de novo lipogenesis by way of the activation of S14, a smaller acidic protein that plays an important part inside the induction of lipogenic enzymes [20]. Stearoyl-CoA desaturase-1 (SCD1) is the rate-limiting enzyme that converts palmitoyl- and stearoyl-coenzyme A to palmitoleoyland oleoyl-coenzyme A, respectively [24]. The monounsaturated products of SCD1 are preferred substrates for the synthesis of triglycerides, cholesterol esters, and phospholipids [24]. The expression of SCD1 is regulated by a variety of dietary, physiological and hormonal things such as insulin, fructose, glucose, cholesterol and polyunsaturated fatty acids [25]. Activation of numerous nuclear receptors, which include LXRs [26], TR [27] and PPARa [28], can induce SCD1 gene expression. SCD1 has been reported as a direct target gene of LXRa and SREBP-1c [29]. In mouse models, activation of PXR induced SCD1 gene expression in the liver. Nonetheless, irrespective of whether SCD1 is [http://www.medchemexpress.com/McMMAF.html mc-MMAF custom synthesis] up-regulated upon PXR activation in human hepatocytes and whether or not the human SCD1 is usually a direct PXR target gene are nonetheless unknown. Within this study, we showed that activation of PXR in the human hepatoma HepG2 cells induced the expression of SCD1. We also showed that SCD1 is often a direct PXR target gene.Components and Procedures ReagentsRifampicin, Oil Red O, Isopropanol, 49,6-diamidino-2-phenylindole (DAPI), TO901317, penicillin and streptomycin were bought from Sigma (St. Louis, MO). Dimethyl sulfoxide (DMSO) was purchased from Merck (Darmstadt, Germany). Trizol, Dulbecco's modified Eagle's medium (DMEM) and fetal bovine serum (FBS) have been purchased from Gibco-BRL (Grand Island, NY). BCA-100 protein quantitative analysis kit was from Pierce (Rockford, IL). Rabbit polyclonal anti-PXR (H-160, sc25381), rabbit polyclonal anti-SCD1 (H-300, sc-30081), rabbit anti-b-actin (sc-1618), goat anti-rabbit IgG-HRP (ZB-2308) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). |
Версія за 20:07, 19 липня 2017
The nuclear receptor pregnane X receptor (PXR; NR1I2), initially isolated as a xenobiotic receptor, is extremely expressed in the liver, and plays a major part in drug metabolism and elimination through its regulation from the expression of cytochrome P450 enzymes [19]. A number of recent research recommended that PXR can also be involved in hepatic lipid homeostasis. Activation of PXR perturbs lipid homeostasis in mice by decreasing b-oxidation, rising no cost acid uptake and lipogenesis, which outcomes in hepatic steatosis in mice [20,21,22,23]. Activation of PXR also decreases the expression of carnitine palmitoyltransferase 1A (CPT1A), which controls the entry of activated long-chain fatty acids in to the mitochondria, and mitochondrial 3-hydroxy-3methyl-glutarate-CoA synthase two (Hmgcs2), the rate-limiting enzyme of ketogenesis. PXR regulates CPT1A and HmgcsSCD1 Contributes to the Lipogenic Impact by PXRexpression by means of its crosstalk together with the insulin-responsive forkhead issue A2 (FoxA2) [21]. A further study showed that in VPhPXR transgenic mice, the expression of various genes involved in fatty acid b-oxidation, like PPARa and thiolase, was suppressed [23]. The fatty acid translocase CD36 was established as a direct target gene of PXR. PXR binds to a DR3 sort PXRE within the CD36 gene promoter and induces the expression of CD36, increasing the fatty acid uptake in liver [23]. In human hepatocytes (HHPC), PXR 1315463 activation by rifampicin, a well-known hPXR agonist, stimulates de novo lipogenesis by way of the activation of S14, a smaller acidic protein that plays an important part inside the induction of lipogenic enzymes [20]. Stearoyl-CoA desaturase-1 (SCD1) is the rate-limiting enzyme that converts palmitoyl- and stearoyl-coenzyme A to palmitoleoyland oleoyl-coenzyme A, respectively [24]. The monounsaturated products of SCD1 are preferred substrates for the synthesis of triglycerides, cholesterol esters, and phospholipids [24]. The expression of SCD1 is regulated by a variety of dietary, physiological and hormonal things such as insulin, fructose, glucose, cholesterol and polyunsaturated fatty acids [25]. Activation of numerous nuclear receptors, which include LXRs [26], TR [27] and PPARa [28], can induce SCD1 gene expression. SCD1 has been reported as a direct target gene of LXRa and SREBP-1c [29]. In mouse models, activation of PXR induced SCD1 gene expression in the liver. Nonetheless, irrespective of whether SCD1 is mc-MMAF custom synthesis up-regulated upon PXR activation in human hepatocytes and whether or not the human SCD1 is usually a direct PXR target gene are nonetheless unknown. Within this study, we showed that activation of PXR in the human hepatoma HepG2 cells induced the expression of SCD1. We also showed that SCD1 is often a direct PXR target gene.Components and Procedures ReagentsRifampicin, Oil Red O, Isopropanol, 49,6-diamidino-2-phenylindole (DAPI), TO901317, penicillin and streptomycin were bought from Sigma (St. Louis, MO). Dimethyl sulfoxide (DMSO) was purchased from Merck (Darmstadt, Germany). Trizol, Dulbecco's modified Eagle's medium (DMEM) and fetal bovine serum (FBS) have been purchased from Gibco-BRL (Grand Island, NY). BCA-100 protein quantitative analysis kit was from Pierce (Rockford, IL). Rabbit polyclonal anti-PXR (H-160, sc25381), rabbit polyclonal anti-SCD1 (H-300, sc-30081), rabbit anti-b-actin (sc-1618), goat anti-rabbit IgG-HRP (ZB-2308) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).