The Experts below are selected from a list of 10242 Experts worldwide ranked by ideXlab platform
Anthony H. Barnett - One of the best experts on this subject based on the ideXlab platform.
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The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population
BMC medical genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, J. Paul O'hare, Sudhesh Kumar, Anthony H. Barnett, M. Ann KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.
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the promoter polymorphism 232c g of the PCK1 gene is associated with type 2 diabetes in a uk resident south asian population
BMC Medical Genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, Sudhesh Kumar, Anthony H. Barnett, Paul J Ohare, Ann M KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.
Srikanth Bellary - One of the best experts on this subject based on the ideXlab platform.
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The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population
BMC medical genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, J. Paul O'hare, Sudhesh Kumar, Anthony H. Barnett, M. Ann KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.
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the promoter polymorphism 232c g of the PCK1 gene is associated with type 2 diabetes in a uk resident south asian population
BMC Medical Genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, Sudhesh Kumar, Anthony H. Barnett, Paul J Ohare, Ann M KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.
Simon D. Rees - One of the best experts on this subject based on the ideXlab platform.
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The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population
BMC medical genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, J. Paul O'hare, Sudhesh Kumar, Anthony H. Barnett, M. Ann KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.
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the promoter polymorphism 232c g of the PCK1 gene is associated with type 2 diabetes in a uk resident south asian population
BMC Medical Genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, Sudhesh Kumar, Anthony H. Barnett, Paul J Ohare, Ann M KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.
Kai Wang - One of the best experts on this subject based on the ideXlab platform.
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Deficiency of gluconeogenic enzyme PCK1 promotes non-alcoholic steatohepatitis progression by activation of PI3K/AKT/PDGF axis
2021Co-Authors: Yi Liu, Guiji Zhang, Xuanming Pan, Chang Chen, Haijun Deng, Jiangao Fan, Qin Pan, Kai WangAbstract:AbstractBackground and AimsNonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. However, the pathomechanisms underlying NASH are incompletely explored. Phosphoenolpyruvate carboxykinase 1 (PCK1) catalyzes the first rate-limiting step of gluconeogenesis in the cytoplasm. This study was designed to determine the role of PCK1 in regulating NASH progression.MethodsLiver metabolism, hepatic steatosis, and fibrosis were evaluated at 24 weeks in liver-specific PCK1-knockout (L-KO) mice fed with NASH diet (high fat diet with ad libitum consumption of water containing glucose and fructose). AKT and RhoA inhibitors were evaluated for disease treatment in L-KO mice fed NASH diet.ResultsPCK1 is downregulated in patients with NASH and mouse models of NASH. L-KO mice displayed hepatic lipid disorder and liver injury fed with normal diet, while fibrosis and inflammation were aggravated when fed NASH diet. Mechanistically, transcriptome analysis revealed PCK1 deficiency upregulated genes involved in fatty acid transport and lipid droplet formation. Moreover, untargeted metabolomics analysis showed the accumulation of glycerol 3-phosphate, the substrate of triglyceride synthesis. Furthermore, the loss of PCK1 could activate the RhoA/PI3K/AKT pathway, which leads to increased secretion of PDGF-AA and promotes the activation of hepatic stellate cells. RhoA and AKT inhibitors alleviated NASH progression in L-KO mice fed NASH diet.ConclusionsPCK1 deficiency plays a key role in the development of hepatic steatosis and fibrosis by facilitating the RhoA/PI3K/AKT/PDGF-AA axis. These findings provide a novel insight into therapeutic approaches for the treatment of NASH.Lay summaryNon-alcoholic steatohepatitis (NASH) is currently the most common chronic liver disease, which is correlated with progressing chronic disorder of lipid metabolism and a persistent inflammatory response. In the present study, decreased PCK1 is observed in patients with NASH and mouse NASH models, and its loss aggravates steatohepatitis in NASH mice fed high-fat, high-fructose diet by stimulating expression of lipogenic genes and lipid synthesis. Inhibitors of proteins involved in the underlying molecular process alleviated the liver disease, highlighting a new therapeutic strategy for NASH.Graphical abstractHighlightsGluconeogenic enzyme PCK1 is downregulated in both human patients and NASH mice.PCK1 depletion promotes hepatic steatosis by dysregulating lipid metabolism and synthesis.PCK1 loss promotes hepatic fibrosis by activating RhoA/PI3K/AKT/PDGF-AA axis.Targeting RhoA/AKT alleviates NASH progression in liver-specific PCK1-knockout mice.
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deficiency of gluconeogenic enzyme PCK1 promotes non alcoholic steatohepatitis progression by activation of pi3k akt pdgf axis
bioRxiv, 2021Co-Authors: Yi Liu, Guiji Zhang, Xuanming Pan, Kai Wang, Chang Chen, Haijun Deng, Jiangao Fan, Qin Pan, Ailong Huang, Ni TangAbstract:Background and AimsNonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. However, the pathomechanisms underlying NASH are incompletely explored. Phosphoenolpyruvate carboxykinase 1 (PCK1) catalyzes the first rate-limiting step of gluconeogenesis in the cytoplasm. This study was designed to determine the role of PCK1 in regulating NASH progression. MethodsLiver metabolism, hepatic steatosis, and fibrosis were evaluated at 24 weeks in liver-specific PCK1-knockout (L-KO) mice fed with NASH diet (high fat diet with ad libitum consumption of water containing glucose and fructose). AKT and RhoA inhibitors were evaluated for disease treatment in L-KO mice fed NASH diet. ResultsPCK1 is downregulated in patients with NASH and mouse models of NASH. L-KO mice displayed hepatic lipid disorder and liver injury fed with normal diet, while fibrosis and inflammation were aggravated when fed NASH diet. Mechanistically, transcriptome analysis revealed PCK1 deficiency upregulated genes involved in fatty acid transport and lipid droplet formation. Moreover, untargeted metabolomics analysis showed the accumulation of glycerol 3-phosphate, the substrate of triglyceride synthesis. Furthermore, the loss of PCK1 could activate the RhoA/PI3K/AKT pathway, which leads to increased secretion of PDGF-AA and promotes the activation of hepatic stellate cells. RhoA and AKT inhibitors alleviated NASH progression in L-KO mice fed NASH diet. ConclusionsPCK1 deficiency plays a key role in the development of hepatic steatosis and fibrosis by facilitating the RhoA/PI3K/AKT/PDGF-AA axis. These findings provide a novel insight into therapeutic approaches for the treatment of NASH. Lay summaryNon-alcoholic steatohepatitis (NASH) is currently the most common chronic liver disease, which is correlated with progressing chronic disorder of lipid metabolism and a persistent inflammatory response. In the present study, decreased PCK1 is observed in patients with NASH and mouse NASH models, and its loss aggravates steatohepatitis in NASH mice fed high-fat, high-fructose diet by stimulating expression of lipogenic genes and lipid synthesis. Inhibitors of proteins involved in the underlying molecular process alleviated the liver disease, highlighting a new therapeutic strategy for NASH. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/426294v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1ac7a1aorg.highwire.dtl.DTLVardef@84523borg.highwire.dtl.DTLVardef@132c19aorg.highwire.dtl.DTLVardef@144a5ad_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights O_LIGluconeogenic enzyme PCK1 is downregulated in both human patients and NASH mice. C_LIO_LIPCK1 depletion promotes hepatic steatosis by dysregulating lipid metabolism and synthesis. C_LIO_LIPCK1 loss promotes hepatic fibrosis by activating RhoA/PI3K/AKT/PDGF-AA axis. C_LIO_LITargeting RhoA/AKT alleviates NASH progression in liver-specific PCK1-knockout mice. C_LI
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Transcriptomic changes associated with PCK1 overexpression in hepatocellular carcinoma cells detected by RNA-seq
Genes & diseases, 2019Co-Authors: Jin Xiang, Jie Xia, Li Liang, Lin Tuo, Ni Tang, Yuhong Zhang, Rui Liu, Dongmei Gou, Chang Chen, Kai WangAbstract:Abstract Phosphoenolpyruvate carboxykinase 1 (PCK1), a step limiting enzyme of gluconeogenesis, is downregulated in hepatocellular carcinoma (HCC). Overexpression of PCK1 has been shown to suppress hepatoma cell growth, but the underlying mechanism remains unclear. We used recombinant adenovirus overexpressing PCK1 or GFP in Huh7 cells, and the differentially expressed genes (DEGs) were identified by RNA-Seq. 180 were upregulated by PCK1 overexpression, whereas 316 were downregulated. Pathway analysis illustrated that PCK1 was closely correlated with Wnt signaling pathway and TGF-beta signaling pathway. Hence, Wnt signaling pathway and its downstream component, FZD2, FZD6, FZD7 and β-catenin were confirmed by qRT-PCR and Western blot. In vivo we also observed that PCK1 had restrained tumor growth as a result of decreasing expression of β-catenin. Whole-transcriptomic profile analysis discovered that overexpression of PCK1 downregulates several oncogenic signaling pathways in HCC, providing potential therapeutic targets for improving HCC therapy.
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PCK1 negatively regulates cell cycle progression and hepatoma cell proliferation via the ampk p27 kip1 axis
Journal of Experimental & Clinical Cancer Research, 2019Co-Authors: Lin Tuo, Jie Xia, Li Liang, Jin Xiang, Xuanming Pan, Kai Wang, Hua Tang, Wenlu Zhang, Ailong Huang, Ni TangAbstract:Background Altered glucose metabolism endows tumor cells with metabolic flexibility for biosynthesis requirements. Phosphoenolpyruvate carboxykinase 1 (PCK1), a key enzyme in the gluconeogenesis pathway, is downregulated in hepatocellular carcinoma (HCC) and predicts poor prognosis. Overexpression of PCK1 has been shown to suppress liver tumor growth, but the underlying mechanism remains unclear.
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PCK1 Downregulation Promotes TXNRD1 Expression and Hepatoma Cell Growth via the Nrf2/Keap1 Pathway.
Frontiers in Oncology, 2018Co-Authors: Lin Tuo, Qingzhu Gao, Guiji Zhang, Yi Yang, Jie Xia, Li Liang, Jin Xiang, Xuanming Pan, Kai Wang, Ni TangAbstract:Gluconeogenesis, generates glucose from small carbohydrate substrates, and drives the metabolic flux in parallel but opposite to glycolysis. The cytoplasmic isoform of phosphoenolpyruvate carboxykinase (PCK1 or PEPCK-C), a rate-limiting enzyme in gluconeogenesis, initiates the gluconeogenesis process and is reportedly dysregulated in multiple types of cancer. Gluconeogenesis mainly occurs in the liver during fasting, and previous studies have demonstrated that PCK1 acts as a tumor suppressor in hepatocellular carcinoma (HCC); however, the role of PCK1 in cancer progression remains incompletely understood. In the current study, we found that PCK1 expression was decreased in HCC as compared to adjacent normal liver tissues, and low PCK1 expression correlated with poor patient prognosis. Furthermore, overexpression of PCK1 suppressed reactive oxygen species (ROS) production and nuclear translocation of Nrf2 in hepatoma cells. In addition, thioredoxin reductase 1 (TXNRD1), an antioxidant enzyme regulated by the Nrf2/Keap1 pathway, was downregulated upon overexpression of PCK1 in HCC cell lines. Furthermore, we verified this axis using nude mouse xenograft model. Finally, we found that auranofin, a TXNRD1 inhibitor, enhanced the sensitivity of PCK1-knockout hepatoma cells to sorafenib-induced apoptosis. Taken together, our findings suggest that PCK1 deficiency promotes hepatoma cell proliferation via the induction of oxidative stress and the activation of transcription factor Nrf2, and that targeting the TXNRD1 antioxidant pathway sensitizes PCK1-knockout hepatoma cells to sorafenib treatment in vitro.
M. Ann Kelly - One of the best experts on this subject based on the ideXlab platform.
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The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population
BMC medical genetics, 2009Co-Authors: Simon D. Rees, Abigail C Britten, Srikanth Bellary, J. Paul O'hare, Sudhesh Kumar, Anthony H. Barnett, M. Ann KellyAbstract:Background - The PCK1 gene, encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCKC), has previously been implicated as a candidate gene for type 2 diabetes (T2D) susceptibility. Rodent models demonstrate that over-expression of PCK1 can result in T2D development and a single nucleotide polymorphism (SNP) in the promoter region of human PCK1 (-232C/G) has exhibited significant association with the disease in several cohorts. Within the UK-resident South Asian population, T2D is 4 to 6 times more common than in indigenous white Caucasians. Despite this, few studies have reported on the genetic susceptibility to T2D in this ethnic group and none of these has investigated the possible effect of PCK1 variants. We therefore aimed to investigate the association between common variants of the PCK1 gene and T2D in a UK-resident South Asian population of Punjabi ancestry, originating predominantly from the Mirpur area of Azad Kashmir, Pakistan. Methods - We used TaqMan assays to genotype five tagSNPs covering the PCK1 gene, including the -232C/G variant, in 903 subjects with T2D and 471 normoglycaemic controls. Results - Of the variants studied, only the minor allele (G) of the -232C/G SNP demonstrated a significant association with T2D, displaying an OR of 1.21 (95% CI: 1.03 - 1.42, p = 0.019). Conclusion - This study is the first to investigate the association between variants of the PCK1 gene and T2D in South Asians. Our results suggest that the -232C/G promoter polymorphism confers susceptibility to T2D in this ethnic group.