The Experts below are selected from a list of 756 Experts worldwide ranked by ideXlab platform
Zuohui Zhao - One of the best experts on this subject based on the ideXlab platform.
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hadha overexpression disrupts lipid metabolism and inhibits tumor growth in clear cell renal cell carcinoma
Experimental Cell Research, 2019Co-Authors: Fei Wu, Hongyi Qu, Juntao Ge, Dongbin Bi, Xufeng Zhang, Yue Xu, Hui Zhang, Zuohui ZhaoAbstract:Hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) is a key lipid metabolic enzyme with a novel role in carcinogenesis. We previously reported that HADHA, a prognostic marker, was downregulated in clear cell renal cell carcinoma (ccRCC). Herein, the tumor inhibitory role of HADHA overexpression in ccRCC was investigated further. The quantitative proteomic analysis displayed that a total of 1293 and 1293 proteins were identified in HADHA overexpressed 786-O-hadha and vector-transfected control 786-O-vc cells, respectively, and 206 proteins were found to be up- or downregulated. PANTHER, OmicsNet, STRING, and DAVID tools were utilized on the dysregulated proteins in order to elucidate multiple metabolic pathways (especial lipid metabolism) and lipid metabolism-related proteins (e.g. ACAT1, ACLY). The dysregulation of the lipid metabolic enzymes, ACAT1, ACLY, CYB5R3 and FASN, were confirmed by Western blotting. Further assays demonstrated that HADHA overexpression significantly inhibited cell growth, induced cell apoptosis, and decreased the formation of cytoplasmic lipid droplets (LDs); moreover, it also inhibited tumor growth and lessened the formation of LDs in xenografted mouse. Collectively, these data revealed that HADHA overexpression disrupted lipid metabolism and inhibited tumor growth, which shed light on HADHA as a potential therapeutic target for clinical intervention of ccRCC.
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The mRNA Expression Signature and Prognostic Analysis of Multiple Fatty Acid Metabolic Enzymes in Clear Cell Renal Cell Carcinoma.
Journal of Cancer, 2019Co-Authors: Zuohui Zhao, Yueran Liu, Qiang Liu, Xiaoli Liu, Yijiao Yuan, Hao WangAbstract:Renal cell carcinoma (RCC) is a metabolic disease, and accumulating evidences indicate significant alterations in the cellular metabolism, especial aerobic glycolysis and glutamine metabolism, in RCC. However, fatty acid (FA) metabolism has received less attention, and the mRNA expression pattern and prognostic role of FA metabolic enzymes in clear cell RCC (ccRCC) have not been carefully examined. In the current study, we first investigated the mRNA expression profiles of multiple FA metabolic enzymes, i.e., ACLY, ACC, FASN, SCD, CPT1A, HADHA, HADHB, and ACAT1, in 42 ccRCC and 33 normal kidney tissues using the Oncomine database, validated their mRNA expression profiles using GEPIA resource, then evaluated and validated the prognostic significance of these metabolic enzymes in 530 ccRCC patients using Kaplan-Meier plotter and GEPIA analyses respectively. The Oncomine and GEPIA confirmed higher ACLY, SCD, and lower ACAT1 mRNA expression in ccRCC than normal tissues (P
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prognostic significance of two lipid metabolism enzymes hadha and acat2 in clear cell renal cell carcinoma
Tumor Biology, 2016Co-Authors: Zuohui Zhao, Jiaju Lu, Xiaoqing WangAbstract:Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality in adults, but there is still no acknowledged biomarker for its prognostic evaluation. Our previous proteomic data had demonstrated the dysregulation of some lipid metabolism enzymes in clear cell RCC (ccRCC). In the present study, we elucidated the expression of two lipid metabolism enzymes, hydroxyl-coenzyme A dehydrogenase, alpha subunit (HADHA) and acetyl-coenzyme A acetyltransferase 2 (ACAT2), using Western blotting analysis, then assessed the prognostic potential of HADHA and ACAT2 using immunohistochemistry (IHC) on a tissue microarray of 145 ccRCC tissues. HADHA and ACAT2 were downregulated in ccRCC (P < 0.05); further IHC analysis revealed that HADHA expression was significantly associated with tumor grade, stage, size, metastasis, and cancer-specific survival (P = 0.004, P < 0.001, P < 0.001, P = 0.049, P < 0.001, respectively) and ACAT2 expression was significantly associated with tumor stage, size, and cancer-specific survival (P < 0.001, P = 0.001, P < 0.001, respectively). In addition, a strong correlation was found between HADHA and ACAT2 expression (R = 0.655, P < 0.001). Further univariate survival analysis demonstrated that high stage, big tumor size, metastasis, and HADHA and ACAT2 down-expression were associated with poorer prognosis on cancer-specific survival (P = 0.007, P = 0.005, P = 0.006, P < 0.001, P = 0.001, respectively), and multivariate analysis revealed that HADHA, stage, and metastasis were identified as independent prognostic factors for cancer-specific survival in patients with ccRCC (P = 0.018, P = 0.046, P = 0.001, respectively). Collectively, these findings indicated that HADHA could serve as a promising prognostic marker in ccRCC, which indicated lipid metabolism abnormality might be involved in ccRCC tumorigenesis.
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Prognostic significance of two lipid metabolism enzymes, HADHA and ACAT2, in clear cell renal cell carcinoma
Tumor Biology, 2015Co-Authors: Zuohui Zhao, Jiaju Lu, Xiaoqing WangAbstract:Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality in adults, but there is still no acknowledged biomarker for its prognostic evaluation. Our previous proteomic data had demonstrated the dysregulation of some lipid metabolism enzymes in clear cell RCC (ccRCC). In the present study, we elucidated the expression of two lipid metabolism enzymes, hydroxyl-coenzyme A dehydrogenase, alpha subunit (HADHA) and acetyl-coenzyme A acetyltransferase 2 (ACAT2), using Western blotting analysis, then assessed the prognostic potential of HADHA and ACAT2 using immunohistochemistry (IHC) on a tissue microarray of 145 ccRCC tissues. HADHA and ACAT2 were downregulated in ccRCC (P
Neil E G Marsh - One of the best experts on this subject based on the ideXlab platform.
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targeting viperin to the mitochondrion inhibits the thiolase activity of the trifunctional enzyme complex
Journal of Biological Chemistry, 2020Co-Authors: Arti B Dumbrepatil, Kelcie A Zegalia, Keerthi Sajja, Robert T Kennedy, Neil E G MarshAbstract:Understanding the mechanisms by which viruses evade host cell immune defenses is important for developing improved antiviral therapies. In an unusual twist, human cytomegalovirus co-opts the antiviral radical SAM enzyme viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) to enhance viral infectivity. This process involves translocation of viperin to the mitochondrion, where it binds the β-subunit (HADHB) of the mitochondrial trifunctional enzyme complex that catalyzes thiolysis of β-ketoacyl-CoA esters as part of fatty acid β-oxidation. Here we investigated how the interaction between these two enzymes alters their activities and affects cellular ATP levels. Experiments with purified enzymes indicated that viperin inhibits the thiolase activity of HADHB, but, unexpectedly, HADHB activates viperin, leading to synthesis of the antiviral nucleotide 3'-deoxy-3',4'-didehydro-CTP. Measurements of enzyme activities in lysates prepared from transfected HEK293T cells expressing these enzymes mirrored the findings obtained with purified enzymes. Thus, localizing viperin to mitochondria decreased thiolase activity, and coexpression of HADHB significantly increased viperin activity. Furthermore, targeting viperin to mitochondria also increased the rate at which HADHB is retrotranslocated out of mitochondria and degraded, providing an additional mechanism by which viperin reduces HADHB activity. Targeting viperin to mitochondria decreased cellular ATP levels by more than 50%, consistent with the enzyme disrupting fatty acid catabolism. These results provide biochemical insight into the mechanism by which human cytomegalovirus subverts viperin; they also provide a biochemical rationale for viperin's recently discovered role in regulating thermogenesis in adipose tissues.
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targeting viperin to the mitochondrion inhibits the thiolase activity of the trifunctional enzyme complex
Journal of Biological Chemistry, 2020Co-Authors: Arti B Dumbrepatil, Kelcie A Zegalia, Keerthi Sajja, Robert T Kennedy, Neil E G MarshAbstract:Understanding the mechanisms by which viruses evade host cell immune defenses is important for developing improved antiviral therapies. In an unusual twist, human cytomegalovirus co-opts the antiviral radical SAM enzyme viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) to enhance viral infectivity. This process involves translocation of viperin to the mitochondrion, where it binds the beta-subunit (HADHB) of the mitochondrial trifunctional enzyme complex that catalyzes thiolysis of beta-ketoacyl-CoA esters as part of fatty acid beta-oxidation. Here we investigated how the interaction between these two enzymes alters their activities and affects cellular ATP levels. Experiments with purified enzymes indicated that viperin inhibits the thiolase activity of HADHB, but, unexpectedly, HADHB activates viperin, leading to synthesis of the antiviral nucleotide 3'-deoxy-3',4'-didehydro-CTP. Measurements of enzyme activities in lysates prepared from transfected HEK293T cells expressing these enzymes mirrored the findings obtained with purified enzymes. Thus, localizing viperin to mitochondria decreased thiolase activity, and coexpression of HADHB significantly increased viperin activity. Furthermore, targeting viperin to mitochondria also increased the rate at which HADHB is retrotranslocated out of mitochondria and degraded, providing an additional mechanism by which viperin reduces HADHB activity. Targeting viperin to mitochondria decreased cellular ATP levels by more than 50%, consistent with the enzyme disrupting fatty acid catabolism. These results provide biochemical insight into the mechanism by which human cytomegalovirus subverts viperin; they also provide a biochemical rationale for viperin's recently discovered role in regulating thermogenesis in adipose tissues.
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targeting viperin to the mitochondrion inhibits the thiolase activity of the trifunctional enzyme complex
bioRxiv, 2019Co-Authors: Arti B Dumbrepatil, Kelcie A Zegalia, Keerthi Sajja, Robert T Kennedy, Neil E G MarshAbstract:Abstract Understanding the mechanisms by which viruses evade host cell immune defenses is important for developing improved antiviral therapies. In an unusual twist, human cytomegalovirus (HCMV) co-opts the antiviral radical SAM enzyme, viperin (Virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible), to enhance viral infectivity. This process involves translocation of viperin to the mitochondrion where it binds the β-subunit (HADHB) of the mitochondrial trifunctional enzyme complex that catalyzes the thiolysis of β-ketoacyl-CoA esters as part of fatty acid β-oxidation. We have investigated how the interaction between these two enzymes alters their activities and their effect on cellular ATP levels. Studies with purified enzymes demonstrated that viperin inhibits the thiolase activity of HADHB, but, unexpectedly, HADHB activates viperin to synthesize the antiviral nucleotide 3’-deoxy-3’,4’-didehydro-CTP. Enzyme activities were also measured in lysates prepared from transfected HEK 293T cells transiently expressing these enzymes. Mirroring the studies on purified enzymes, localizing viperin to the mitochondria decreased thiolase activity whereas co-expression of HADHB significantly increased viperin activity. Furthermore, targeting viperin to mitochondria also increased the rate at which HADHB was retro-translocated out of mitochondria and degraded, providing an additional mechanism for reducing HADHB activity. Targeting viperin to the mitochondria decreased cellular ATP levels by over 50 %, consistent with the enzyme disrupting fatty acid catabolism. These results provide biochemical insight into the mechanism by which HCMV subjugates viperin; they also provide a biochemical rational for viperin’s recently discovered role in regulating thermogenesis in adipose tissues.
Guiping Zhao - One of the best experts on this subject based on the ideXlab platform.
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Uncovering the embryonic development-related proteome and metabolome signatures in breast muscle and intramuscular fat of fast-and slow-growing chickens
BMC Genomics, 2017Co-Authors: Hongyang Wang, Maiqing Zheng, Siyuan Xing, Qinghe Li, Jie Wang, Guiping ZhaoAbstract:Skeletal muscle development is closely linked to meat production and its quality. This study is the first to quantify the proteomes and metabolomes of breast muscle in two distinct chicken breeds at embryonic day 12 (ED 12), ED 17, post-hatch D 1 and D 14 using mass spectrometry-based approaches. Results found that intramuscular fat (IMF) accumulation increased from ED 17 to D 1 and that was exactly the opposite of when most obvious growth of muscle occurred (ED 12 - ED 17 and D 1 - D 14). For slow-growing Beijing-You chickens, Ingenuity Pathway Analysis of 77–99 differential abundance (DA) proteins and 63–72 metabolites, indicated significant enrichment of molecules and pathways related to protein processing and PPAR signaling. For fast-growing Cobb chickens, analysis of 68–95 DA proteins and 56–59 metabolites demonstrated that molecules and pathways related to ATP production were significantly enriched after ED12. For IMF, several rate-limiting enzymes for beta-oxidation of fatty acid (ACADL, ACAD9, HADHA and HADHB) were identified as candidate biomarkers for IMF deposition in both breeds. This study found that ED 17 - D 1 was the earliest period for IMF accumulation. Pathways related to protein processing and PPAR signaling were enriched to support high capacity of embryonic IMF accumulation in Beijing-You. Pathways related to ATP production were enriched to support the fast muscle growth in Cobb. The beta-oxidation of fatty acid is identified as the key pathway regulating chicken IMF deposition at early stages.
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Uncovering the embryonic development-related proteome and metabolome signatures in breast muscle and intramuscular fat of fast-and slow-growing chickens
BMC, 2017Co-Authors: Ranran Liu, Maiqing Zheng, Siyuan Xing, Hongyang Wang, Jie Wang, Jie Liu, Xiaodong Tan, Huanxian Cui, Guiping ZhaoAbstract:Abstract Background Skeletal muscle development is closely linked to meat production and its quality. This study is the first to quantify the proteomes and metabolomes of breast muscle in two distinct chicken breeds at embryonic day 12 (ED 12), ED 17, post-hatch D 1 and D 14 using mass spectrometry-based approaches. Results Results found that intramuscular fat (IMF) accumulation increased from ED 17 to D 1 and that was exactly the opposite of when most obvious growth of muscle occurred (ED 12 - ED 17 and D 1 - D 14). For slow-growing Beijing-You chickens, Ingenuity Pathway Analysis of 77–99 differential abundance (DA) proteins and 63–72 metabolites, indicated significant enrichment of molecules and pathways related to protein processing and PPAR signaling. For fast-growing Cobb chickens, analysis of 68–95 DA proteins and 56–59 metabolites demonstrated that molecules and pathways related to ATP production were significantly enriched after ED12. For IMF, several rate-limiting enzymes for beta-oxidation of fatty acid (ACADL, ACAD9, HADHA and HADHB) were identified as candidate biomarkers for IMF deposition in both breeds. Conclusions This study found that ED 17 - D 1 was the earliest period for IMF accumulation. Pathways related to protein processing and PPAR signaling were enriched to support high capacity of embryonic IMF accumulation in Beijing-You. Pathways related to ATP production were enriched to support the fast muscle growth in Cobb. The beta-oxidation of fatty acid is identified as the key pathway regulating chicken IMF deposition at early stages
Xiaoqing Wang - One of the best experts on this subject based on the ideXlab platform.
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prognostic significance of two lipid metabolism enzymes hadha and acat2 in clear cell renal cell carcinoma
Tumor Biology, 2016Co-Authors: Zuohui Zhao, Jiaju Lu, Xiaoqing WangAbstract:Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality in adults, but there is still no acknowledged biomarker for its prognostic evaluation. Our previous proteomic data had demonstrated the dysregulation of some lipid metabolism enzymes in clear cell RCC (ccRCC). In the present study, we elucidated the expression of two lipid metabolism enzymes, hydroxyl-coenzyme A dehydrogenase, alpha subunit (HADHA) and acetyl-coenzyme A acetyltransferase 2 (ACAT2), using Western blotting analysis, then assessed the prognostic potential of HADHA and ACAT2 using immunohistochemistry (IHC) on a tissue microarray of 145 ccRCC tissues. HADHA and ACAT2 were downregulated in ccRCC (P < 0.05); further IHC analysis revealed that HADHA expression was significantly associated with tumor grade, stage, size, metastasis, and cancer-specific survival (P = 0.004, P < 0.001, P < 0.001, P = 0.049, P < 0.001, respectively) and ACAT2 expression was significantly associated with tumor stage, size, and cancer-specific survival (P < 0.001, P = 0.001, P < 0.001, respectively). In addition, a strong correlation was found between HADHA and ACAT2 expression (R = 0.655, P < 0.001). Further univariate survival analysis demonstrated that high stage, big tumor size, metastasis, and HADHA and ACAT2 down-expression were associated with poorer prognosis on cancer-specific survival (P = 0.007, P = 0.005, P = 0.006, P < 0.001, P = 0.001, respectively), and multivariate analysis revealed that HADHA, stage, and metastasis were identified as independent prognostic factors for cancer-specific survival in patients with ccRCC (P = 0.018, P = 0.046, P = 0.001, respectively). Collectively, these findings indicated that HADHA could serve as a promising prognostic marker in ccRCC, which indicated lipid metabolism abnormality might be involved in ccRCC tumorigenesis.
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Prognostic significance of two lipid metabolism enzymes, HADHA and ACAT2, in clear cell renal cell carcinoma
Tumor Biology, 2015Co-Authors: Zuohui Zhao, Jiaju Lu, Xiaoqing WangAbstract:Renal cell carcinoma (RCC) is one of the leading causes of cancer mortality in adults, but there is still no acknowledged biomarker for its prognostic evaluation. Our previous proteomic data had demonstrated the dysregulation of some lipid metabolism enzymes in clear cell RCC (ccRCC). In the present study, we elucidated the expression of two lipid metabolism enzymes, hydroxyl-coenzyme A dehydrogenase, alpha subunit (HADHA) and acetyl-coenzyme A acetyltransferase 2 (ACAT2), using Western blotting analysis, then assessed the prognostic potential of HADHA and ACAT2 using immunohistochemistry (IHC) on a tissue microarray of 145 ccRCC tissues. HADHA and ACAT2 were downregulated in ccRCC (P
Brian J. Morris - One of the best experts on this subject based on the ideXlab platform.
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cAMP controls human renin mRNA stability via specific RNA-binding proteins.
Acta physiologica Scandinavica, 2004Co-Authors: Brian J. Morris, David J. Adams, Dianne J. Beveridge, Helena Mangs, L. Van Der Weyden, Peter J. LeedmanAbstract:It is now recognized that post-transcriptional mechanisms are pivotal to renin production. These involve factors that modulate renin mRNA stability. In 2003 new data has emerged from work in Australia and Germany that has identified several of the, as many as, 20 or so proteins involved. These include CP1 (hnRNP E1), HuR, HADHB, dynamin, nucleolin, YP-1, hnRNP K and MINT-homologous protein. Cyclic AMP (cAMP) is a crucial regulator of renin secretion as well as transcriptional and post-transcriptional control of expression. Many of the RNA-binding proteins that were identified responded to forskolin, increasing in amount by two to 10-fold. The cAMP mechanisms that regulate renin mRNA target, at least in large part, other genes that presumably encode some of these proteins. The increase in the expression of these then facilitates, sequentially, renin mRNA stabilization and destabilization. Our data, using a battery of different techniques, confirm that CP1 and HuR stabilize renin mRNA, whereas HADHB causes destabilization. These proteins target cis-acting C-rich sequences (in the case of CP1) and AU-rich sequences (HuR) in the distal region of the 3'-untranslated region of renin mRNA. We found HADHB was enriched in juxtaglomerular cells and that that within Calu-6 cells HADHB, HuR and CP1 all localized in nuclear subregions, as well as cytoplasm (HADHB and CP1) and mitochondria (HADHB) commensurate with the role each plays in control of renin mRNA stability. The specific proteins that bind to human renin mRNA have begun to be revealed. Cyclic AMP upregulates the binding of several of these proteins, which in turn affect renin mRNA stability and thus overall expression of renin.
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HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression.
The Journal of biological chemistry, 2003Co-Authors: David J. Adams, Dianne J. Beveridge, Louise Van Der Weyden, Helena Mangs, Peter J. Leedman, Brian J. MorrisAbstract:Abstract Production of renin is critically dependent on modulation of REN mRNA stability. Here we sought to elucidate the molecular mechanisms involved. Transfections of renin-expressing Calu-6 cells with reporter constructs showed that a cis-acting 34-nucleotide AU-rich “renin stability regulatory element” in the REN 3′-untranslated region (3′-UTR) contributes to basal REN mRNA instability. Yeast three-hybrid screening with the REN 3′-UTR as bait isolated HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein) β-subunit) as a novel REN mRNA-binding protein. Recombinant HADHB bound specifically to the 3′-UTR of REN mRNA, as did the known mRNA stabilizers HuR and CP1 (poly(C)-binding protein-1). This required the renin stability regulatory element. Forskolin, which augments REN mRNA stability in Calu-6 cells, increased binding of several proteins, including HuR and CP1, to the REN 3′-UTR, whereas 4-bromocrotonic acid, a specific thiolase inhibitor, decreased binding and elevated renin protein levels. Upon decreasing HADHB mRNA with RNA interference, renin protein and mRNA stability increased, whereas RNA interference against HuR caused these to decrease. Immunoprecipitation and reverse transcription-PCR of Calu-6 extracts confirmed that HADHB, HuR, and CP1 each associate with REN mRNA in vivo. Intracellular imaging revealed distinct localization of HADHB to mitochondria, HuR to nuclei, and CP1 throughout the cell. Immunohistochemistry demonstrated enrichment of HADHB in renin-producing renal juxtaglomerular cells. In conclusion, HADHB, HuR, and CP1 are novel REN mRNA-binding proteins that target a cis-element in the 3′-UTR of REN mRNA and regulate renin production. cAMP-mediated increased REN mRNA stability may involve stimulation of HuR and CP1, whereas REN mRNA decay may involve thiolase-dependent pathways.
