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Article ; Online: The effect of alcohol and hydrogen peroxide on liver hepcidin gene expression in mice lacking antioxidant enzymes, glutathione peroxidase-1 or catalase.

Harrison-Findik, Duygu Dee / Lu, Sizhao

2015 Volume 5, Issue 2, Page(s) 793–807

Abstract: This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1(-/-)) and catalase (catalase(-/-)) knockout mice. For alcohol studies, 10% ethanol was ... ...

Abstract	This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1(-/-)) and catalase (catalase(-/-)) knockout mice. For alcohol studies, 10% ethanol was administered in the drinking water for 7 days. Gpx-1(-/-) displayed significantly higher hepatic H2O2 levels than catalase(-/-) compared to wild-type mice, as measured by 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The basal level of liver hepcidin expression was attenuated in gpx-1(-/-) mice. Alcohol increased H2O2 production in catalase(-/-) and wild-type, but not gpx-1(-/-), mice. Hepcidin expression was inhibited in alcohol-fed catalase(-/-) and wild-type mice. In contrast, alcohol elevated hepcidin expression in gpx-1(-/-) mice. Gpx-1(-/-) mice also displayed higher level of basal liver CHOP protein expression than catalase(-/-) mice. Alcohol induced CHOP and to a lesser extent GRP78/BiP expression, but not XBP1 splicing or binding of CREBH to hepcidin gene promoter, in gpx-1(-/-) mice. The up-regulation of hepatic ATF4 mRNA levels, which was observed in gpx-1(-/-) mice, was attenuated by alcohol. In conclusion, our findings strongly suggest that H2O2 inhibits hepcidin expression in vivo. Synergistic induction of CHOP by alcohol and H2O2, in the absence of gpx-1, stimulates liver hepcidin gene expression by ER stress independent of CREBH.
MeSH term(s)	Animals ; Catalase/genetics ; Cells, Cultured ; Ethanol/toxicity ; Glutathione Peroxidase/deficiency ; Glutathione Peroxidase/genetics ; Hepcidins/genetics ; Hepcidins/metabolism ; Hydrogen Peroxide/toxicity ; Liver/drug effects ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Transcription Factor CHOP/genetics ; Transcription Factor CHOP/metabolism
Chemical Substances	Ddit3 protein, mouse ; Hepcidins ; Transcription Factor CHOP (147336-12-7) ; Ethanol (3K9958V90M) ; Hydrogen Peroxide (BBX060AN9V) ; Catalase (EC 1.11.1.6) ; Glutathione Peroxidase (EC 1.11.1.9)
Language	English
Publishing date	2015-05-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom5020793
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Article ; Online: Saturated fatty acids induce post-transcriptional regulation of HAMP mRNA via AU-rich element-binding protein, human antigen R (HuR).

Lu, Sizhao / Mott, Justin L / Harrison-Findik, Duygu Dee

The Journal of biological chemistry

2015 Volume 290, Issue 40, Page(s) 24178–24189

Abstract: Iron is implicated in fatty liver disease pathogenesis. The human hepcidin gene, HAMP, is the master switch of iron metabolism. The aim of this study is to investigate the regulation of HAMP expression by fatty acids in HepG2 cells. For these studies, ... ...

Abstract	Iron is implicated in fatty liver disease pathogenesis. The human hepcidin gene, HAMP, is the master switch of iron metabolism. The aim of this study is to investigate the regulation of HAMP expression by fatty acids in HepG2 cells. For these studies, both saturated fatty acids (palmitic acid (PA) and stearic acid (SA)) and unsaturated fatty acid (oleic acid (OA)) were used. PA and, to a lesser extent, SA, but not OA, up-regulated HAMP mRNA levels, as determined by real-time PCR. To understand whether PA regulates HAMP mRNA at the transcriptional or post-transcriptional level, the transcription inhibitor actinomycin D was employed. PA-mediated induction of HAMP mRNA expression was not blocked by actinomycin D. Furthermore, PA activated HAMP 3'-UTR, but not promoter, activity, as shown by reporter assays. HAMP 3'-UTR harbors a single AU-rich element (ARE). Mutation of this ARE abolished the effect of PA, suggesting the involvement of ARE-binding proteins. The ARE-binding protein human antigen R (HuR) stabilizes mRNA through direct interaction with AREs on 3'-UTR. HuR is regulated by phosphorylation-mediated nucleo-cytoplasmic shuttling. PA activated this process. The binding of HuR to HAMP mRNA was also induced by PA in HepG2 cells. Silencing of HuR by siRNA abolished PA-mediated up-regulation of HAMP mRNA levels. PKC is known to phosphorylate HuR. Staurosporine, a broad-spectrum PKC inhibitor, inhibited both PA-mediated translocation of HuR and induction of HAMP expression. Similarly, rottlerin, a novel class PKC inhibitor, abrogated PA-mediated up-regulation of HAMP expression. In conclusion, lipids mediate post-transcriptional regulation of HAMP throughPKC- and HuR-dependent mechanisms.
MeSH term(s)	3' Untranslated Regions ; Animals ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; ELAV-Like Protein 1/metabolism ; Fatty Acids/chemistry ; Fatty Liver/metabolism ; Hep G2 Cells ; Hepcidins/genetics ; Hepcidins/metabolism ; Humans ; Iron/chemistry ; Mice ; Mutagenesis ; Mutation ; Palmitic Acid/chemistry ; Phosphorylation ; Protein Binding ; Protein Transport ; RNA Processing, Post-Transcriptional ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Signal Transduction
Chemical Substances	3' Untranslated Regions ; ELAV-Like Protein 1 ; ELAVL1 protein, human ; Fatty Acids ; HAMP protein, human ; Hepcidins ; RNA, Messenger ; RNA, Small Interfering ; Palmitic Acid (2V16EO95H1) ; Iron (E1UOL152H7)
Language	English
Publishing date	2015-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.648212
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Article ; Online: Is the iron regulatory hormone hepcidin a risk factor for alcoholic liver disease?

Harrison-Findik, Duygu Dee

World journal of gastroenterology

2008 Volume 15, Issue 10, Page(s) 1186–1193

Abstract: Despite heavy consumption over a long period of time, only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors, besides alcohol, may be involved in the progression of the disease. Over the ... ...

Abstract	Despite heavy consumption over a long period of time, only a small number of alcoholics develop alcoholic liver disease. This alludes to the possibility that other factors, besides alcohol, may be involved in the progression of the disease. Over the years, many such factors have indeed been identified, including iron. Despite being crucial for various important biological processes, iron can also be harmful due to its ability to catalyze Fenton chemistry. Alcohol and iron have been shown to interact synergistically to cause liver injury. Iron-mediated cell signaling has been reported to be involved in the pathogenesis of experimental alcoholic liver disease. Hepcidin is an iron-regulatory hormone synthesized by the liver, which plays a pivotal role in iron homeostasis. Both acute and chronic alcohol exposure suppress hepcidin expression in the liver. The sera of patients with alcoholic liver disease, particularly those exhibiting higher serum iron indices, have also been reported to display reduced prohepcidin levels. Alcohol-mediated oxidative stress is involved in the inhibition of hepcidin promoter activity and transcription in the liver. This in turn leads to an increase in intestinal iron transport and liver iron storage. Hepcidin is expressed primarily in hepatocytes. It is noteworthy that both hepatocytes and Kupffer cells are involved in the progression of alcoholic liver disease. However, the activation of Kupffer cells and TNF-alpha signaling has been reported not to be involved in the down-regulation of hepcidin expression by alcohol in the liver. Alcohol acts within the parenchymal cells of the liver to suppress the synthesis of hepcidin. Due to its crucial role in the regulation of body iron stores, hepcidin may act as a secondary risk factor in the progression of alcoholic liver disease. The clarification of the mechanisms by which alcohol disrupts iron homeostasis will allow for further understanding of the pathogenesis of alcoholic liver disease.
MeSH term(s)	Antimicrobial Cationic Peptides/drug effects ; Antimicrobial Cationic Peptides/genetics ; Down-Regulation ; Ethanol/toxicity ; Hepcidins ; Homeostasis ; Iron/metabolism ; Kupffer Cells/drug effects ; Kupffer Cells/physiology ; Liver Diseases, Alcoholic/epidemiology ; Liver Diseases, Alcoholic/genetics ; Promoter Regions, Genetic/drug effects ; Risk Factors ; Transcription, Genetic/drug effects
Chemical Substances	Antimicrobial Cationic Peptides ; Hepcidins ; Ethanol (3K9958V90M) ; Iron (E1UOL152H7)
Language	English
Publishing date	2008-02-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.15.1186
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Article: Role of alcohol in the regulation of iron metabolism.

Harrison-Findik, Duygu Dee

World journal of gastroenterology

2007 Volume 13, Issue 37, Page(s) 4925–4930

Abstract: Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown ... ...

Abstract	Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.
MeSH term(s)	Alcohol Drinking/metabolism ; Antimicrobial Cationic Peptides/physiology ; Ethanol/metabolism ; Hepcidins ; Humans ; Iron/metabolism ; Iron Overload/metabolism ; Iron Overload/physiopathology ; Liver Diseases, Alcoholic/metabolism ; Liver Diseases, Alcoholic/physiopathology
Chemical Substances	Antimicrobial Cationic Peptides ; HAMP protein, human ; Hepcidins ; Ethanol (3K9958V90M) ; Iron (E1UOL152H7)
Language	English
Publishing date	2007-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.v13.i37.4925
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Article ; Online: TLR4 signaling and the inhibition of liver hepcidin expression by alcohol.

Zmijewski, Emily / Lu, Sizhao / Harrison-Findik, Duygu Dee

World journal of gastroenterology

2014 Volume 20, Issue 34, Page(s) 12161–12170

Abstract: Aim: To understand the role of toll-like receptor 4 (TLR4) signaling in the regulation of iron-regulatory hormone, hepcidin by chronic alcohol consumption.: Methods: For chronic alcohol intake studies, TLR4 mutant mice on C3H/HeJ background and ... ...

Abstract	Aim: To understand the role of toll-like receptor 4 (TLR4) signaling in the regulation of iron-regulatory hormone, hepcidin by chronic alcohol consumption. Methods: For chronic alcohol intake studies, TLR4 mutant mice on C3H/HeJ background and wildtype counterpart on C3H/HeOuJ background were pair-fed with regular (control) and ethanol-containing Lieber De Carli liquids diets. Gene expression was determined by real-time quantitative PCR. Protein-protein interactions and protein expression were determined by co-immunoprecipitation and western blotting. The occupancy of hepcidin gene promoter was determined by chromatin immunoprecipitation assays. Results: Chronic alcohol intake suppressed hepcidin mRNA expression in the livers of wildtype, but not TLR4 mutant, mice. The phosphorylation and nuclear translocation of nuclear factor (NF)-κB p65 subunit protein was observed in alcohol-fed wildtype, but not in alcohol-fed TLR4 mutant, mice. Similarly, alcohol induced the binding of NF-κB p50 subunit protein to hepcidin gene promoter in wildtype, but not in TLR4 mutant, mice. In contrast, the phosphorylation of Stat3 in the liver was stronger in alcohol-treated TLR4 mutant mice compared to alcohol-treated wildtype mice. The occupancy of hepcidin gene promoter by Stat3 was observed in alcohol-fed mutant, but not in wildtype, mice. An interaction between NF-κB p65 subunit protein and small heterodimer partner protein (SHP) was observed in the livers of both wildtype and TLR4 mutant mice fed with the control diet, as shown by co-immunoprecipitation studies. Alcohol intake elevated cytosolic SHP expression but attenuated its interaction with NF-κB in the liver, which was more prominent in the livers of wildtype compared to TLR4 mutant mice. Conclusion: Activation of TLR4 signaling and NF-кB are involved in the suppression of hepcidin gene transcription by alcohol in the presence of inflammation in the liver.
MeSH term(s)	Animals ; Binding Sites ; Disease Models, Animal ; Down-Regulation ; Ethanol ; Hepcidins/genetics ; Hepcidins/metabolism ; Liver/metabolism ; Liver Diseases, Alcoholic/etiology ; Liver Diseases, Alcoholic/genetics ; Liver Diseases, Alcoholic/metabolism ; Male ; Mice, Inbred C3H ; Mice, Mutant Strains ; Mutation ; Phosphorylation ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/metabolism ; Transcription Factor RelA/metabolism ; Transcription, Genetic
Chemical Substances	Hamp protein, mouse ; Hepcidins ; RNA, Messenger ; Rela protein, mouse ; STAT3 Transcription Factor ; Stat3 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 4 ; Transcription Factor RelA ; Ethanol (3K9958V90M)
Language	English
Publishing date	2014-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2185929-2
ISSN	2219-2840 ; 1007-9327
ISSN (online)	2219-2840
ISSN	1007-9327
DOI	10.3748/wjg.v20.i34.12161
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Article ; Online: The Effect of Alcohol and Hydrogen Peroxide on Liver Hepcidin Gene Expression in Mice Lacking Antioxidant Enzymes, Glutathione Peroxidase-1 or Catalase

Duygu Dee Harrison-Findik / Sizhao Lu

Biomolecules, Vol 5, Iss 2, Pp 793-

2015 Volume 807

Abstract: This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1−/−) and catalase (catalase−/−) knockout mice. For alcohol studies, 10% ethanol was ... ...

Abstract	This study investigates the regulation of hepcidin, the key iron-regulatory molecule, by alcohol and hydrogen peroxide (H2O2) in glutathione peroxidase-1 (gpx-1−/−) and catalase (catalase−/−) knockout mice. For alcohol studies, 10% ethanol was administered in the drinking water for 7 days. Gpx-1−/− displayed significantly higher hepatic H2O2 levels than catalase−/− compared to wild-type mice, as measured by 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The basal level of liver hepcidin expression was attenuated in gpx-1−/− mice. Alcohol increased H2O2 production in catalase−/− and wild-type, but not gpx-1−/−, mice. Hepcidin expression was inhibited in alcohol-fed catalase−/− and wild-type mice. In contrast, alcohol elevated hepcidin expression in gpx-1−/− mice. Gpx-1−/− mice also displayed higher level of basal liver CHOP protein expression than catalase−/− mice. Alcohol induced CHOP and to a lesser extent GRP78/BiP expression, but not XBP1 splicing or binding of CREBH to hepcidin gene promoter, in gpx-1−/− mice. The up-regulation of hepatic ATF4 mRNA levels, which was observed in gpx-1−/− mice, was attenuated by alcohol. In conclusion, our findings strongly suggest that H2O2 inhibits hepcidin expression in vivo. Synergistic induction of CHOP by alcohol and H2O2, in the absence of gpx-1, stimulates liver hepcidin gene expression by ER stress independent of CREBH.
Keywords	alcoholic liver disease ; CHOP ; endoplasmic reticulum stress ; Hamp ; hepatocyte ; iron ; oxidative stress ; Biology (General) ; QH301-705.5 ; Science ; Q
Language	English
Publishing date	2015-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: Autophagy and cancer.

Lu, Si-Zhao / Harrison-Findik, Duygu Dee

World journal of biological chemistry

2013 Volume 4, Issue 3, Page(s) 64–70

Abstract: Autophagy is a homeostatic and evolutionarily conserved mechanism of self-digestion by which the cells degrade and recycle long-lived proteins and excess or damaged organelles. Autophagy is activated in response to both physiological and pathological ... ...

Abstract	Autophagy is a homeostatic and evolutionarily conserved mechanism of self-digestion by which the cells degrade and recycle long-lived proteins and excess or damaged organelles. Autophagy is activated in response to both physiological and pathological stimuli including growth factor depletion, energy deficiency or the upregulation of Bcl-2 protein expression. A novel role of autophagy in various cancers has been proposed. Interestingly, evidence that supports both a positive and negative role of autophagy in the pathogenesis of cancer has been reported. As a tumor suppression mechanism, autophagy maintains genome stability, induces senescence and possibly autophagic cell death. On the other hand, autophagy participates in tumor growth and maintenance by supplying metabolic substrate, limiting oxidative stress, and maintaining cancer stem cell population. It has been proposed that the differential roles of autophagy in cancer are disease type and stage specific. In addition, substrate selectivity might be involved in carrying out the specific effect of autophagy in cancer, and represents one of the potential directions for future studies.
Language	English
Publishing date	2013-08-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2564793-3
ISSN	1949-8454
ISSN	1949-8454
DOI	10.4331/wjbc.v4.i3.64
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Article: Lack of hepcidin expression attenuates steatosis and causes fibrosis in the liver.

Lu, Sizhao / Bennett, Robert G / Kharbanda, Kusum K / Harrison-Findik, Duygu Dee

World journal of hepatology

2016 Volume 8, Issue 4, Page(s) 211–225

Abstract: Aim: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD).: Methods: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control ... ...

Abstract	Aim: To investigate the role of key iron-regulatory protein, hepcidin in non-alcoholic fatty liver disease (NAFLD). Methods: Hepcidin (Hamp1) knockout and floxed control mice were administered a high fat and high sucrose (HFS) or a regular control diet for 3 or 7 mo. Steatosis, triglycerides, fibrosis, protein and gene expression in mice livers were determined by histological and biochemical techniques, western blotting and real-time polymerase chain reaction. Results: Knockout mice exhibited hepatic iron accumulation. Despite similar weight gains, HFS feeding induced hepatomegaly in floxed, but not knockout, mice. The livers of floxed mice exhibited higher levels of steatosis, triglycerides and c-Jun N-terminal kinase (JNK) phosphorylation than knockout mice. In contrast, a significant increase in fibrosis was observed in knockout mice livers within 3 mo of HFS administration. The hepatic gene expression levels of sterol regulatory element-binding protein-1c and fat-specific protein-27, but not peroxisome proliferator-activated receptor-alpha or microsomal triglyceride transfer protein, were attenuated in HFS-fed knockout mice. Knockout mice fed with regular diet displayed increased carnitine palmitoyltransferase-1a and phosphoenolpyruvate carboxykinase-1 but decreased glucose-6-phosphatase expression in the liver. In summary, attenuated steatosis correlated with decreased expression of lipogenic and lipid storage genes, and JNK phosphorylation. Deletion of Hamp1 alleles per se modulated hepatic expression of beta-oxidation and gluconeogenic genes. Conclusion: Lack of hepcidin expression inhibits hepatic lipid accumulation and induces early development of fibrosis following high fat intake. Hepcidin and iron may play a role in the regulation of metabolic pathways in the liver, which has implications for NAFLD pathogenesis.
Language	English
Publishing date	2016-02-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2573703-X
ISSN	1948-5182
ISSN	1948-5182
DOI	10.4254/wjh.v8.i4.211
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Article: Apoptosis induced by Fas signaling does not alter hepatic hepcidin expression.

Lu, Sizhao / Zmijewski, Emily / Gollan, John / Harrison-Findik, Duygu Dee

World journal of biological chemistry

2014 Volume 5, Issue 3, Page(s) 387–397

Abstract: Aim: To determine the regulation of human hepcidin (HAMP) and mouse hepcidin (hepcidin-1 and hepcidin-2) gene expression in the liver by apoptosis using in vivo and in vitro experimental models.: Methods: For the induction of the extrinsic apoptotic ... ...

Abstract	Aim: To determine the regulation of human hepcidin (HAMP) and mouse hepcidin (hepcidin-1 and hepcidin-2) gene expression in the liver by apoptosis using in vivo and in vitro experimental models. Methods: For the induction of the extrinsic apoptotic pathway, HepG2 cells were treated with various concentrations of CH11, an activating antibody for human Fas receptor, for 12 h. Male C57BL/6NCR and C57BL/6J strains of mice were injected intraperitoneally with sublethal doses of an activating antibody for mouse Fas receptor, Jo2. The mice were anesthetized and sacrificed 1 or 6 h after the injection. The level of apoptosis was quantified by caspase-3 activity assay. Liver injury was assessed by measuring the levels of ALT/AST enzymes in the serum. The acute phase reaction in the liver was examined by determining the expression levels of IL-6 and SAA3 genes by SYBR green quantitative real-time PCR (qPCR). The phosphorylation of transcription factors, Stat3, Smad4 and NF-κB was determined by western blotting. Hepcidin gene expression was determined by Taqman qPCR. The binding of transcription factors to hepcidin-1 promoter was studied using chromatin immunoprecipitation (ChIP) assays. Results: The treatment of HepG2 cells with CH11 induced apoptosis, as shown by the significant activation of caspase-3 (P < 0.001), but did not cause any significant changes in HAMP expression. Short-term (1 h) Jo2 treatment (0.2 μg/g b.w.) neither induced apoptosis and acute phase reaction nor altered mRNA expression of mouse hepcidin-1 in the livers of C57BL/6NCR mice. In contrast, 6 h after Jo2 injection, the livers of C57BL/6NCR mice exhibited a significant level of apoptosis (P < 0.001) and an increase in SAA3 (P < 0.023) and IL-6 (P < 0.005) expression in the liver. However, mRNA expression of hepcidin-1 in the liver was not significantly altered. Despite the Jo2-induced phosphorylation of Stat3, no occupancy of hepcidin-1 promoter by Stat3 was observed, as shown by ChIP assays. Compared to C57BL/6NCR mice, Jo2 treatment (0.2 μg/g b.w.) of C57BL/6J strain mice for 6 h induced a more prominent activation of apoptosis, liver injury and acute phase reaction. Similar to C57BL/6NCR mice, the level of liver hepcidin-1 mRNA expression in the livers of C57BL/6J mice injected with a sublethal dose of Jo2 (0.2 μg/g b.w.) remained unchanged. The injection of C57BL/6J mice with a higher dose of Jo2 (0.32 μg/g b.w.) did not also alter hepatic hepcidin expression. Conclusion: Our findings suggest that human or mouse hepcidin gene expression is not regulated by apoptosis induced via Fas receptor activation in the liver.
Language	English
Publishing date	2014-04-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2564793-3
ISSN	1949-8454
ISSN	1949-8454
DOI	10.4331/wjbc.v5.i3.387
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Article ; Online: Ceramide Induces Human Hepcidin Gene Transcription through JAK/STAT3 Pathway.

Lu, Sizhao / Natarajan, Sathish Kumar / Mott, Justin L / Kharbanda, Kusum K / Harrison-Findik, Duygu Dee

PloS one

2016 Volume 11, Issue 1, Page(s) e0147474

Abstract: Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of ...

Abstract	Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of lipid and iron metabolism is largely unknown. We investigated the role of lipid intermediate, ceramide in the regulation of human hepcidin gene, HAMP. Human hepatoma HepG2 cells were treated with cell-permeable ceramide analogs. Ceramide induced significant up-regulation of HAMP mRNA expression in HepG2 cells. The effect of ceramide on HAMP expression was mediated through transcriptional mechanisms because it was completely blocked with actinomycin D treatment. Reporter assays also confirmed the activation of 0.6 kb HAMP promoter by ceramide. HepG2 cells treated with ceramide displayed increased phosphorylation of STAT3, JNK, and NF-κB proteins. However, ceramide induced the binding of STAT3, but not NF-κB or c-Jun, to HAMP promoter, as shown by the chromatin immunoprecipitation assays. The mutation of STAT3 response element within 0.6 kb HAMP promoter region significantly inhibited the stimulatory effect of ceramide on HAMP promoter activity. Similarly, the inhibition of STAT3 with a pan-JAK kinase inhibitor and STAT3 siRNA pool also diminished the induction of both HAMP promoter activity and mRNA expression by ceramide. In conclusion, we have shown a direct role for ceramide in the activation of hepatic HAMP transcription via STAT3. Our findings suggest a crosstalk between lipid and iron metabolism in the liver, which may contribute to the pathogenesis of obesity-related fatty liver disease.
MeSH term(s)	Anthracenes/pharmacology ; Ceramides/pharmacology ; Chromatin Immunoprecipitation ; Dactinomycin/pharmacology ; Hep G2 Cells ; Hepcidins/biosynthesis ; Hepcidins/genetics ; Humans ; Iron/metabolism ; Janus Kinases/physiology ; Liver/metabolism ; Mutagenesis, Site-Directed ; NF-kappa B/metabolism ; Non-alcoholic Fatty Liver Disease/epidemiology ; Non-alcoholic Fatty Liver Disease/etiology ; Non-alcoholic Fatty Liver Disease/metabolism ; Obesity/complications ; Obesity/metabolism ; Phosphorylation/drug effects ; Prevalence ; Promoter Regions, Genetic/drug effects ; Promoter Regions, Genetic/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Processing, Post-Translational/drug effects ; RNA Interference ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Response Elements ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/physiology ; Signal Transduction/drug effects ; Transcription, Genetic/drug effects
Chemical Substances	Anthracenes ; Ceramides ; HAMP protein, human ; Hepcidins ; NF-kappa B ; Protein Kinase Inhibitors ; RNA, Messenger ; RNA, Small Interfering ; Recombinant Fusion Proteins ; STAT3 Transcription Factor ; STAT3 protein, human ; Dactinomycin (1CC1JFE158) ; pyrazolanthrone (1TW30Y2766) ; Iron (E1UOL152H7) ; Janus Kinases (EC 2.7.10.2)
Language	English
Publishing date	2016-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0147474
Database	MEDical Literature Analysis and Retrieval System OnLINE

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