The Experts below are selected from a list of 13563 Experts worldwide ranked by ideXlab platform
Eran Eyal - One of the best experts on this subject based on the ideXlab platform.
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Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency
Journal of inherited metabolic disease, 2016Co-Authors: Carlo Dionisi-vici, Eyal Shteyer, Marcello Niceta, Cristiano Rizzo, Ben Pode-shakked, Giovanni Chillemi, Alessandro Bruselles, Michela Semeraro, Ortal Barel, Eran EyalAbstract:Transient infantile hypertriglyceridemia (HTGT1; OMIM #614480) is a rare autosomal recessive disorder, which manifests in early infancy with transient hypertriglyceridemia, Hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis. This rare clinical entity is caused by inactivating mutations in the GPD1 gene, which encodes the cytosolic isoform of glycerol-3-phosphate dehydrogenase. Here we report on four patients from three unrelated families of diverse ethnic origins, who presented with Hepatomegaly, liver steatosis, hypertriglyceridemia, with or without fasting ketotic hypoglycemia. Whole exome sequencing revealed the affected individuals to harbor deleterious biallelic mutations in the GPD1 gene, including the previously undescribed c.806G > A (p.Arg269Gln) and c.640T > C (p.Cys214Arg) mutations. The clinical features in three of our patients showed several differences compared to the original reports. One subject presented with recurrent episodes of fasting hypoglycemia along with Hepatomegaly, hypetriglyceridemia, and elevated liver enzymes; the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement; finally, the third presented persistent hypertriglyceridemia at the age of 30 years. These findings expand the current knowledge of this rare disorder, both with regard to the phenotype and molecular basis. The enlarged phenotypic spectrum of glycerol-3-phosphate dehydrogenase 1 deficiency can mimic other inborn errors of metabolism with liver involvement and should alert clinicians to recognize this entity by considering GPD1 mutations in appropriate clinical settings.
Carlo Dionisi-vici - One of the best experts on this subject based on the ideXlab platform.
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Expanding the molecular diversity and phenotypic spectrum of glycerol 3-phosphate dehydrogenase 1 deficiency
Journal of inherited metabolic disease, 2016Co-Authors: Carlo Dionisi-vici, Eyal Shteyer, Marcello Niceta, Cristiano Rizzo, Ben Pode-shakked, Giovanni Chillemi, Alessandro Bruselles, Michela Semeraro, Ortal Barel, Eran EyalAbstract:Transient infantile hypertriglyceridemia (HTGT1; OMIM #614480) is a rare autosomal recessive disorder, which manifests in early infancy with transient hypertriglyceridemia, Hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis. This rare clinical entity is caused by inactivating mutations in the GPD1 gene, which encodes the cytosolic isoform of glycerol-3-phosphate dehydrogenase. Here we report on four patients from three unrelated families of diverse ethnic origins, who presented with Hepatomegaly, liver steatosis, hypertriglyceridemia, with or without fasting ketotic hypoglycemia. Whole exome sequencing revealed the affected individuals to harbor deleterious biallelic mutations in the GPD1 gene, including the previously undescribed c.806G > A (p.Arg269Gln) and c.640T > C (p.Cys214Arg) mutations. The clinical features in three of our patients showed several differences compared to the original reports. One subject presented with recurrent episodes of fasting hypoglycemia along with Hepatomegaly, hypetriglyceridemia, and elevated liver enzymes; the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement; finally, the third presented persistent hypertriglyceridemia at the age of 30 years. These findings expand the current knowledge of this rare disorder, both with regard to the phenotype and molecular basis. The enlarged phenotypic spectrum of glycerol-3-phosphate dehydrogenase 1 deficiency can mimic other inborn errors of metabolism with liver involvement and should alert clinicians to recognize this entity by considering GPD1 mutations in appropriate clinical settings.
Yue Gao - One of the best experts on this subject based on the ideXlab platform.
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yap tead mediates peroxisome proliferator activated receptor α induced Hepatomegaly and liver regeneration in mice
Hepatology, 2021Co-Authors: Shicheng Fan, Xinpeng Yao, Yiming Jiang, Xiao Yang, Yue Gao, Shuguang Zhu, Jianing Tian, Guomin Xie, Tomoki Yagai, Ruimin WangAbstract:Background & aims Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces Hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. Approach & results In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically-modified mice. PPARα activation by the specific agonist WY-14643 significantly induced Hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Pparα-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (CTGF, CYR61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced Hepatomegaly, and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce Hepatomegaly in AAV-Yap shRNA-treated mice and liver-specific Yap-deficient (YapΔHep ) mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Conclusions This study revealed a novel function of PPARα in regulating liver size and liver regeneration via activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
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pxr mediates mifepristone induced Hepatomegaly in mice
Acta Pharmacologica Sinica, 2021Co-Authors: Xinpeng Yao, Tingying Jiao, Yiming Jiang, Shicheng Fan, Yingyuan Zhao, Xiao Yang, Yue Gao, Yanying Zhou, Panpan Chen, Min HuangAbstract:Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce Hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce Hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced Hepatomegaly in C57BL/6 mice and Pxr-knockout mice. The results demonstrated that high-dose Mif (100 mg · kg−1 · d−1, i.p.) treatment for 5 days significantly induced Hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg−1 · d−1, i.p.) cannot induce Hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg−1 · d−1, i.p.) failed to induce Hepatomegaly in Pxr-knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced Hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced Hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced Hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
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constitutive androstane receptor induced Hepatomegaly and liver regeneration is partially via yes associated protein activation
Acta Pharmaceutica Sinica B, 2021Co-Authors: Yue Gao, Xinpeng Yao, Yiming Jiang, Shicheng Fan, Xiao Yang, Shuguang Zhu, Ruimin Wang, Jianing Tian, Frank J Gonzalez, Min HuangAbstract:Abstract The constitutive androstane receptor (CAR, NR3I1) belongs to nuclear receptor superfamily. It was reported that CAR agonist TCPOBOP induces Hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein (YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced Hepatomegaly and liver regeneration. TCPOBOP-induced CAR activation on Hepatomegaly and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice. Hepatocytes enlargement around central vein (CV) area was observed, meanwhile hepatocytes proliferation was promoted as evidenced by the increased number of KI67+ cells around portal vein (PV) area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential protein–protein interaction of CAR and YAP. However, CAR activation-induced Hepatomegaly can still be observed in liver-specific YAP-deficient (Yap–/–) mice. In summary, CAR activation promotes Hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.
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constitutive androstane receptor promoted Hepatomegaly and liver regeneration is partially via yes associated protein activation
Authorea Preprints, 2020Co-Authors: B I Huichang, Xinpeng Yao, Yiming Jiang, Shicheng Fan, Xiao Yang, Yue Gao, Shuguang Zhu, Ruimin Wang, Jianing Tian, Frank J GonzalezAbstract:Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to Hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted Hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced Hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes Hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.
Shicheng Fan - One of the best experts on this subject based on the ideXlab platform.
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yap tead mediates peroxisome proliferator activated receptor α induced Hepatomegaly and liver regeneration in mice
Hepatology, 2021Co-Authors: Shicheng Fan, Xinpeng Yao, Yiming Jiang, Xiao Yang, Yue Gao, Shuguang Zhu, Jianing Tian, Guomin Xie, Tomoki Yagai, Ruimin WangAbstract:Background & aims Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces Hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear. Approach & results In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically-modified mice. PPARα activation by the specific agonist WY-14643 significantly induced Hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Pparα-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (CTGF, CYR61 and ANKRD1) as well as proliferation-related proteins (CCNA1, CCND1 and CCNE1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced Hepatomegaly, and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce Hepatomegaly in AAV-Yap shRNA-treated mice and liver-specific Yap-deficient (YapΔHep ) mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Conclusions This study revealed a novel function of PPARα in regulating liver size and liver regeneration via activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
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pxr mediates mifepristone induced Hepatomegaly in mice
Acta Pharmacologica Sinica, 2021Co-Authors: Xinpeng Yao, Tingying Jiao, Yiming Jiang, Shicheng Fan, Yingyuan Zhao, Xiao Yang, Yue Gao, Yanying Zhou, Panpan Chen, Min HuangAbstract:Mifepristone (Mif), an effective synthetic steroidal antiprogesterone drug, is widely used for medical abortion and pregnancy prevention. Due to its anti-glucocorticoid effect, high-dose Mif is also used to treat Cushing’s syndrome. Mif was reported to active pregnane X receptor (PXR) in vitro and PXR can induce Hepatomegaly via activation and interaction with yes-associated protein (YAP) pathway. High-dose Mif was reported to induce Hepatomegaly in rats and mice, but the underlying mechanism remains unclear. Here, the role of PXR was studied in Mif-induced Hepatomegaly in C57BL/6 mice and Pxr-knockout mice. The results demonstrated that high-dose Mif (100 mg · kg−1 · d−1, i.p.) treatment for 5 days significantly induced Hepatomegaly with enlarged hepatocytes and promoted proliferation, but low dose of Mif (5 mg · kg−1 · d−1, i.p.) cannot induce Hepatomegaly. The dual-luciferase reporter gene assays showed that Mif can activate human PXR in a concentration-dependent manner. In addition, Mif could promote nuclear translocation of PXR and YAP, and significantly induced the expression of PXR, YAP, and their target proteins such as CYP3A11, CYP2B10, UGT1A1, ANKRD, and CTGF. However, Mif (100 mg · kg−1 · d−1, i.p.) failed to induce Hepatomegaly in Pxr-knockout mice, as well as hepatocyte enlargement and proliferation, further indicating that Mif-induced Hepatomegaly is PXR-dependent. In summary, this study demonstrated that PXR-mediated Mif-induced Hepatomegaly in mice probably via activation of YAP pathway. This study provides new insights in Mif-induced Hepatomegaly, and provides novel evidence on the crucial function of PXR in liver enlargement and regeneration.
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constitutive androstane receptor induced Hepatomegaly and liver regeneration is partially via yes associated protein activation
Acta Pharmaceutica Sinica B, 2021Co-Authors: Yue Gao, Xinpeng Yao, Yiming Jiang, Shicheng Fan, Xiao Yang, Shuguang Zhu, Ruimin Wang, Jianing Tian, Frank J Gonzalez, Min HuangAbstract:Abstract The constitutive androstane receptor (CAR, NR3I1) belongs to nuclear receptor superfamily. It was reported that CAR agonist TCPOBOP induces Hepatomegaly but the underlying mechanism remains largely unknown. Yes-associated protein (YAP) is a potent regulator of organ size. The aim of this study is to explore the role of YAP in CAR activation-induced Hepatomegaly and liver regeneration. TCPOBOP-induced CAR activation on Hepatomegaly and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. The results demonstrate that TCPOBOP can increase the liver-to-body weight ratio in wild-type mice and PHx mice. Hepatocytes enlargement around central vein (CV) area was observed, meanwhile hepatocytes proliferation was promoted as evidenced by the increased number of KI67+ cells around portal vein (PV) area. The protein levels of YAP and its downstream targets were upregulated in TCPOBOP-treated mice and YAP translocation can be induced by CAR activation. Co-immunoprecipitation results suggested a potential protein–protein interaction of CAR and YAP. However, CAR activation-induced Hepatomegaly can still be observed in liver-specific YAP-deficient (Yap–/–) mice. In summary, CAR activation promotes Hepatomegaly and liver regeneration partially by inducing YAP translocation and interaction with YAP signaling pathway, which provides new insights to further understand the physiological functions of CAR.
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constitutive androstane receptor promoted Hepatomegaly and liver regeneration is partially via yes associated protein activation
Authorea Preprints, 2020Co-Authors: B I Huichang, Xinpeng Yao, Yiming Jiang, Shicheng Fan, Xiao Yang, Yue Gao, Shuguang Zhu, Ruimin Wang, Jianing Tian, Frank J GonzalezAbstract:Background & Purpose: The constitutive androstane receptor (CAR) belongs to nuclear receptor superfamily. The administration of CAR agonist TCPOBOP to mice leads to Hepatomegaly but the mechanism is unclear. Yes-associated protein (YAP) is a downstream factor of Hippo signaling pathway, which is a potent regulator of organ size and tissue homeostasis. This study examined the role of YAP in CAR-promoted Hepatomegaly and liver regeneration. Experimental Approach: The effect of CAR on liver enlargement and liver regeneration was evaluated in wild-type (WT) mice, liver-specific YAP-deficient mice, and partial hepatectomy (PHx) mice. KI67 and CTNNB1 staining were performed to evaluate the proliferation response and hepatocytes size. The protein levels of YAP and its downstream targets were measured and Co-IP was conducted to explore the protein-protein interaction between CAR and YAP. Key Results: The results suggested TCPOBOP increases the liver/body weight ratio in WT mice and PHx mice. Hepatocytes enlargement occurred around the central vein area, while the number of KI67+ cells increased around portal vein area. The translocation of YAP was induced and its downstream targets were upregulated after CAR activation via TCPOBOP. Co-IP results revealed a potential protein-protein interaction between CAR and YAP. However, CAR-induced Hepatomegaly was still observed in Yap-/- mice. Conclusion and Implications: CAR activation promotes Hepatomegaly and liver regeneration in part by inducing nuclear translocation of YAP and interaction with YAP pathway, which provides new insights for understanding the physiological functions of CAR, and suggests the potential for manipulation of liver size.
Stephen D Turley - One of the best experts on this subject based on the ideXlab platform.
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hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase deficient mice
American Journal of Physiology-gastrointestinal and Liver Physiology, 2014Co-Authors: Amal Aqul, Adam M Lopez, Kenneth S Posey, Anna M Taylor, Joyce J Repa, Dennis K Burns, Stephen D TurleyAbstract:Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). Hepatomegaly and deposition of esterified cholesterol (E...