TY  - JOUR
A1  - Wieneke, Nadine
A1  - Hirsch-Ernst, Karen I.
A1  - Kuna, Manuela
A1  - Kersten, Sander
A1  - Püschel, Gerhard Paul
T1  - PPARalpha-dependent induction of the energy homeostasis-regulating nuclear
N2  - A tight hormonal control of energy homeostasis is of pivotal relevance for animals. Recent evidence suggests an involvement of the nuclear receptor NR1i3 (CAR). Fasting induces CAR by largely unknown mechanisms and CAR-deficient mice are defective in fasting adaptation. In rat hepatocytes CAR was induced by WY14643, a PPARalpha-agonist. A DR1 motif in the CAR promoter was necessary and sufficient for this control. The PPARalpha-dependent increase in CAR potentiated the phenobarbital-induced transcription of the prototypical CAR-dependent gene CYP2B1. Since free fatty acids are natural ligands for PPARalpha, a fasting-induced increase in free fatty acids might induce CAR. In accordance with this hypothesis, CAR induction by fasting was abrogated in PPARalpha-deficient mice.
Y1  - 2007
UR  - http://www.sciencedirect.com/science/article/pii/S0014579307011556
SN  - 0014-5793
ER  - 
TY  - JOUR
A1  - Püschel, Gerhard Paul
T1  - Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves
N2  - More than any other organ, the liver contributes to maintaining metabolic equilibrium of the body, most importantly of glucose homeostasis. It can store or release large quantities of glucose according to changing demands. This homeostasis is controlled by circulating hormones and direct innervation of the liver by autonomous hepatic nerves. Sympathetic hepatic nerves can increase hepatic glucose output; they appear, however, to contribute little to the stimulation of hepatic glucose output under physiological conditions. Parasympathetic hepatic nerves potentiate the insulin-dependent hepatic glucose extraction when a portal glucose sensor detects prandial glucose delivery from the gut. In addition, they might coordinate the hepatic and extrahepatic glucose utilization to prevent hypoglycemia and, at the same time, warrant efficient disposal of excess glucose.
Y1  - 2004
UR  - http://www3.interscience.wiley.com/cgi-bin/abstract/109596173/ABSTRACT
ER  - 
TY  - JOUR
A1  - Pathe-Neuschäfer-Rube, Andrea
A1  - Neuschäfer-Rube, Frank
A1  - Püschel, Gerhard Paul
T1  - G protein coupling control by the ERC-motif in the proximal part of the second intracellular loop and the C- terminal domain of the human prostaglandin F-2A receptor (FP receptor)
Y1  - 2004
SN  - 0028-1298
ER  - 
TY  - JOUR
A1  - Neuschäfer-Rube, Frank
A1  - Hermosilla, Ricardo
A1  - Kuna, Manuela
A1  - Pathe-Neuschaefer-Rube, Andrea
A1  - Püschel, Gerhard Paul
T1  - Agonist-induced desensitization of rat prostaglandin EP3 receptor isoforms
Y1  - 2004
SN  - 0028-1298
ER  - 
TY  - JOUR
A1  - Camargo, Rodolfo Gonzalez
A1  - dos Reis Riccardi, Daniela Mendes
A1  - Teixeira Ribeiro, Henrique Quintas
A1  - Carnevali Junior, Luiz Carlos
A1  - de Matos-Neto, Emidio Marques
A1  - Enjiu, Lucas
A1  - Neves, Rodrigo Xavier
A1  - Carola Correia Lima, Joanna Darck
A1  - Figueredo, Raquel Galvao
A1  - Martins de Alcantara, Paulo Sergio
A1  - Maximiano, Linda
A1  - Otoch, Jose
A1  - Batista Jr., Miguel Luiz
A1  - Püschel, Gerhard Paul
A1  - Seelaender, Marilia
T1  - NF-kappa Bp65 and Expression of Its Pro-Inflammatory Target Genes Are Upregulated in the Subcutaneous Adipose Tissue of Cachectic Cancer Patients
JF  - Nutrients
N2  - Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro-inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-B). We have examined the gene expression of the subunits NF-Bp65 and NF-Bp50, as well as NF-Bp65 and NF-Bp50 binding, the gene expression of pro-inflammatory mediators under NF-B control (IL-1, IL-6, INF-, TNF-, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IB-). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-Bp65 and its target genes expression (TNF-, IL-1, MCP-1 and IB-) were significantly higher in cachectic cancer patients. Moreover, NF-Bp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-B pathway plays a role in the promotion of WAT inflammation during cachexia.
KW  - cancer cachexia
KW  - inflammation
KW  - white adipose tissue
KW  - NF-B
KW  - IB
Y1  - 2015
U6  - https://doi.org/10.3390/nu7064465
SN  - 2072-6643
VL  - 7
IS  - 6
SP  - 4465
EP  - 4479
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Frede, Katja
A1  - Schanze, Nancy
A1  - Vogel, Heike
A1  - Schürmann, Annette
A1  - Spruß, Astrid
A1  - Bergheim, Ina
A1  - Püschel, Gerhard Paul
T1  - Stimulation of fat accumulation in hepatocytes by PGE(2)-dependent repression of hepatic lipolysis, beta-oxidation and VLDL-synthesis
JF  - Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology
N2  - Hepatic steatosis is recognized as hepatic presentation of the metabolic syndrome. Hyperinsulinaemia, which shifts fatty acid oxidation to de novo lipogenesis and lipid storage in the liver, appears to be a principal elicitor particularly in the early stages of disease development. The impact of PGE(2), which has previously been shown to attenuate insulin signaling and hence might reduce insulin-dependent lipid accumulation, on insulin-induced steatosis of hepatocytes was studied. The PGE(2)-generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE(2) attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE(2) enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE(2)-dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial beta-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1 alpha, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1 alpha completely blunted the PGE(2)-dependent fat accumulation. PGE(2) enhanced lipid accumulation synergistically with insulin, despite attenuating insulin signaling and might thus contribute to the development of hepatic steatosis. Induction of enzymes involved in PGE(2) synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH. Laboratory Investigation (2012) 92, 1597-1606; doi:10.1038/labinvest.2012.128; published online 10 September 2012
KW  - cyclooxygenase
KW  - hepatic steatosis
KW  - mPGES
KW  - NAFLD
KW  - NASH
KW  - type 2 diabetes (T2DM)
KW  - PGC1 alpha
Y1  - 2012
U6  - https://doi.org/10.1038/labinvest.2012.128
SN  - 0023-6837
VL  - 92
IS  - 11
SP  - 1597
EP  - 1606
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Neuschaefer-Rube, Frank
A1  - Schraplau, Anne
A1  - Schewe, Bettina
A1  - Lieske, Stefanie
A1  - Kruetzfeldt, Julia-Mignon
A1  - Ringel, Sebastian
A1  - Henkela, Janin
A1  - Birkenfeld, Andreas L.
A1  - Püschel, Gerhard Paul
T1  - Arylhydrocarbon receptor-dependent mIndy (SIc13a5) induction as possible contributor to benzo[a]pyrene-induced lipid accumulation in hepatocytes
JF  - Toxicology
N2  - Non-alcoholic fatty liver disease is a growing problem in industrialized and developing countries. Hepatic lipid accumulation is the result of an imbalance between fatty acid uptake, fatty acid de novo synthesis, beta-oxidation and secretion of triglyceride-rich lipoproteins from the hepatocyte. A central regulator of hepatic lipid metabolism is cytosolic citrate that can either be derived from the mitochondrium or be taken up from the blood via the plasma membrane sodium citrate transporter NaCT, the product of the mammalian INDY gene (SLC13A5). mINDY ablation protects against diet-induced steatosis whereas mINDY expression is increased in patients with hepatic steatosis. Diet-induced hepatic steatosis is also enhanced by activation of the arylhyrocarbon receptor (AhR) both in humans and animal models. Therefore, the hypothesis was tested whether the mINDY gene might be a target of the AhR. In accordance with such a hypothesis, the AhR activator benzo[a]pyrene induced the mINDY expression in primary cultures of rat hepatocytes in an AhR-dependent manner. This induction resulted in an increased citrate uptake and citrate incorporation into lipids which probably was further enhanced by the benzo[a]pyrene-dependent induction of key enzymes of fatty acid synthesis. A potential AhR binding site was identified in the mINDY promoter that appears to be conserved in the human promoter. Elimination or mutation of this site largely abolished the activation of the mINDY promoter by benzo[a]pyrene. This study thus identified the mINDY as an AhR target gene. AhR-dependent induction of the mINDY gene might contribute to the development of hepatic steatosis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
KW  - SLC13A5
KW  - Non-alcoholic fatty liver disease
KW  - NAFLD
Y1  - 2015
U6  - https://doi.org/10.1016/j.tox.2015.08.007
SN  - 0300-483X
VL  - 337
SP  - 1
EP  - 9
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Hesse, Deike
A1  - Jaschke, Alexander
A1  - Kanzleiter, Timo
A1  - Witte, Nicole
A1  - Augustin, Robert
A1  - Hommel, Angela
A1  - Püschel, Gerhard Paul
A1  - Petzke, Klaus-Jürgen
A1  - Joost, Hans-Georg
A1  - Schupp, Michael
A1  - Schürmann, Annette
T1  - GTPase ARFRP1 is essential for normal hepatic glycogen storage and insulin-like growth factor 1 secretion
JF  - Molecular and cellular biology
N2  - The GTPase ADP-ribosylation factor-related protein 1 (ARFRP1) is located at the trans-Golgi compartment and regulates the recruitment of Arf-like 1 (ARL1) and its effector golgin-245 to this compartment. Here, we show that liver-specific knockout of Arfrp1 in the mouse (Arfrp1(liv-/-)) resulted in early growth retardation, which was associated with reduced hepatic insulin-like growth factor 1 (IGF1) secretion. Accordingly, suppression of Arfrp1 in primary hepatocytes resulted in a significant reduction of IGF1 release. However, the hepatic secretion of IGF-binding protein 2 (IGFBP2) was not affected in the absence of ARFRP1. In addition, Arfrp1(liv-/-) mice exhibited decreased glucose transport into the liver, leading to a 50% reduction of glycogen stores as well as a marked retardation of glycogen storage after fasting and refeeding. These abnormalities in glucose metabolism were attributable to reduced protein levels and intracellular retention of the glucose transporter GLUT2 in Arfrp1(liv-/-) livers. As a consequence of impaired glucose uptake into the liver, the expression levels of carbohydrate response element binding protein (ChREBP), a transcription factor regulated by glucose concentration, and its target genes (glucokinase and pyruvate kinase) were markedly reduced. Our data indicate that ARFRP1 in the liver is involved in the regulation of IGF1 secretion and GLUT2 sorting and is thereby essential for normal growth and glycogen storage.
Y1  - 2012
U6  - https://doi.org/10.1128/MCB.00522-12
SN  - 0270-7306
VL  - 32
IS  - 21
SP  - 4363
EP  - 4374
PB  - American Society for Microbiology
CY  - Washington
ER  - 
TY  - JOUR
A1  - Spruss, Astrid
A1  - Henkel, Janin
A1  - Kanuri, Giridhar
A1  - Blank, Daniela
A1  - Püschel, Gerhard Paul
A1  - Bischoff, Stephan C.
A1  - Bergheim, Ina
T1  - Female mice are more susceptible to nonalcoholic fatty liver disease  sex-specific regulation of the hepatic AMP-Activated protein Kinase-Plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response
JF  - Molecular medicine
N2  - As significant differences between sexes were found in the susceptibility to alcoholic liver disease in human and animal models, it was the aim of the present study to investigate whether female mice also are more susceptible to the development of nonalcoholic fatty liver disease (NAFLD). Male and female C57BL/6J mice were fed either water or 30% fructose solution ad libitum for 16 wks. Liver damage was evaluated by histological scoring. Portal endotoxin levels and markers of Kupffer cell activation and insulin resistance, plasminogen activator inhibitor 1 (PAI-1) and phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) were measured in the liver. Adiponectin mRNA expression was determined in adipose tissue. Hepatic steatosis was almost similar between male and female mice; however, inflammation was markedly more pronounced in livers of female mice. Portal endotoxin levels, hepatic levels of myeloid differentiation primary response gene (88) (MyD88) protein and of 4-hydroxynonenal protein adducts were elevated in animals with NAFLD regardless of sex. Expression of insulin receptor substrate 1 and 2 was decreased to a similar extent in livers of male and female mice with NAFLD. The less pronounced susceptibility to liver damage in male mice was associated with a superinduction of hepatic pAMPK in these mice whereas, in livers of female mice with NAFLD, PAI-1 was markedly induced. Expression of adiponectin in visceral fat was significantly lower in female mice with NAFLD but unchanged in male mice compared with respective controls. In conclusion, our data suggest that the sex-specific differences in the susceptibility to NAFLD are associated with differences in the regulation of the adiponectin-AMPK-PAI-1 signaling cascade. Online address: http://www.molmed.Org doi: 10.2119/molmed.2012.00223
Y1  - 2012
U6  - https://doi.org/10.2119/molmed.2012.00223
SN  - 1076-1551
VL  - 18
IS  - 9
SP  - 1346
EP  - 1355
PB  - Feinstein Inst. for Medical Research
CY  - Manhasset
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Gärtner, Daniela
A1  - Dorn, Christoph
A1  - Hellerbrand, Claus
A1  - Schanze, Nancy
A1  - Elz, Sheila R.
A1  - Püschel, Gerhard Paul
T1  - Oncostatin M produced in Kupffer cells in response to PGE(2) possible contributor to hepatic insulin resistance and steatosis
JF  - Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology
N2  - Hepatic insulin resistance is a major contributor to hyperglycemia in metabolic syndrome and type II diabetes. It is caused in part by the low-grade inflammation that accompanies both diseases, leading to elevated local and circulating levels of cytokines and cyclooxygenase (COX) products such as prostaglandin E-2 (PGE(2)). In a recent study, PGE(2) produced in Kupffer cells attenuated insulin-dependent glucose utilization by interrupting the intracellular signal chain downstream of the insulin receptor in hepatocytes. In addition to directly affecting insulin signaling in hepatocytes, PGE(2) in the liver might affect insulin resistance by modulating cytokine production in non-parenchymal cells. In accordance with this hypothesis, PGE(2) stimulated oncostatin M (OSM) production by Kupffer cells. OSM in turn attenuated insulin-dependent Akt activation and, as a downstream target, glucokinase induction in hepatocytes, most likely by inducing suppressor of cytokine signaling 3 (SOCS3). In addition, it inhibited the expression of key enzymes of hepatic lipid metabolism. COX-2 and OSM mRNA were induced early in the course of the development of non-alcoholic steatohepatitis (NASH) in mice. Thus, induction of OSM production in Kupffer cells by an autocrine PGE(2)-dependent feed-forward loop may be an additional, thus far unrecognized, mechanism contributing to hepatic insulin resistance and the development of NASH.
KW  - cyclooxygenase
KW  - cytokine
KW  - hepatic steatosis
KW  - NASH
KW  - suppressor of cytokine signaling (SOCS)
KW  - type II diabetes (T2DM)
Y1  - 2011
U6  - https://doi.org/10.1038/labinvest.2011.47
SN  - 0023-6837
VL  - 91
IS  - 7
SP  - 1107
EP  - 1117
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Neuschaefer-Rube, Frank
A1  - Lieske, Stefanie
A1  - Kuna, Manuela
A1  - Henkel, Janin
A1  - Perry, Rachel J.
A1  - Erion, Derek M.
A1  - Pesta, Dominik
A1  - Willmes, Diana M.
A1  - Brachs, Sebastian
A1  - von Loeffelholz, Christian
A1  - Tolkachov, Alexander
A1  - Schupp, Michael
A1  - Pathe-Neuschaefer-Rube, Andrea
A1  - Pfeiffer, Andreas F. H.
A1  - Shulman, Gerald I.
A1  - Püschel, Gerhard Paul
A1  - Birkenfeld, Andreas L.
T1  - The mammalian INDY homolog is induced by CREB in a rat model of type 2 diabetes
JF  - Diabetes : a journal of the American Diabetes Association
Y1  - 2014
SN  - 0012-1797
SN  - 1939-327X
VL  - 63
IS  - 3
SP  - 1048
EP  - 1057
PB  - American Diabetes Association
CY  - Alexandria
ER  - 
TY  - CHAP
A1  - Henkel, Janine
A1  - Camargo, Rodolfo Gonzalez
A1  - Schanze, Nancy
A1  - Püschel, Gerhard Paul
T1  - The vicious circle of prostaglandin- and cytokine-dependent hepatic insulin resistance: a key role of prostaglandin E2
T2  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
Y1  - 2014
SN  - 0012-186X
SN  - 1432-0428
VL  - 57
SP  - S241
EP  - S242
PB  - Springer
CY  - New York
ER  - 
TY  - GEN
A1  - Henkel, Janin
A1  - Coleman Mac Gregor of Inneregny, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weiss, Thomas Siegfried
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 483 
KW  - suppress VLDL secretion
KW  - mice lacking
KW  - nonalcoholic steatohepatthis
KW  - insulin-resistance
KW  - rat hepatocytes
KW  - kupffer cells
KW  - E-2
KW  - disease
KW  - expression
KW  - accumulation
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-420879
SN  - 1866-8372
IS  - 483
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Haumann, Hannah
A1  - Rahnenführer, Jan
A1  - Reichetzeder, Christoph
A1  - Kalk, Philipp
A1  - Pfab, Thiemo
A1  - Tsuprykov, Oleg
A1  - Winter, Stefan
A1  - Hofmann, Ute
A1  - Li, Jian
A1  - Püschel, Gerhard Paul
A1  - Lang, Florian
A1  - Schuppan, Detlef
A1  - Schwab, Matthias
A1  - Schaeffeler, Elke
T1  - Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner
JF  - Epigenetics : the official journal of the DNA Methylation Society
N2  - Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.
KW  - Epigenetics
KW  - eNOS
KW  - Fetal programming
KW  - fatty liver
KW  - metabolism
Y1  - 2016
U6  - https://doi.org/10.1080/15592294.2016.1184800
SN  - 1559-2294
SN  - 1559-2308
VL  - 11
SP  - 539
EP  - 552
PB  - Routledge, Taylor & Francis Group
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Coleman Mac Gregor of Inneregny, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weiss, Thomas Siegfried
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
JF  - Scientific Reports
N2  - In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
KW  - suppress VLDL secretion
KW  - mice lacking
KW  - nonalcoholic steatohepatthis
KW  - insulin-resistance
KW  - rat hepatocytes
KW  - kupffer cells
KW  - E-2
KW  - disease
KW  - expression
KW  - accumulation
Y1  - 2018
U6  - https://doi.org/10.1038/s41598-018-34633-y
SN  - 2045-2322
IS  - 8
SP  - 1
EP  - 11
PB  - Nature Research
CY  - London
ER  - 
TY  - JOUR
A1  - Manowsky, Julia
A1  - Camargo, Rodolfo Gonzalez
A1  - Kipp, Anna Patricia
A1  - Henkel, Janin
A1  - Püschel, Gerhard Paul
T1  - Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes
JF  - American journal of physiology : Endocrinology and metabolism
N2  - Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the beta-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1 beta, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1 beta was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-kappa B. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKK beta, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues.
KW  - metabolic syndrome
KW  - type 2 diabetes
KW  - inflammation
KW  - macrophage
KW  - insulin
KW  - cytokines
Y1  - 2016
U6  - https://doi.org/10.1152/ajpendo.00427.2015
SN  - 0193-1849
SN  - 1522-1555
VL  - 310
SP  - E938
EP  - E946
PB  - American Chemical Society
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Schenke, Maren
A1  - Schjeide, Brit-Maren
A1  - Püschel, Gerhard Paul
A1  - Seeger, Bettina
T1  - Analysis of motor neurons differentiated from human induced pluripotent stem cells for the use in cell-based Botulinum neurotoxin activity assays
JF  - Toxins
N2  - Botulinum neurotoxins (BoNTs) are potent neurotoxins produced by bacteria, which inhibit neurotransmitter release, specifically in their physiological target known as motor neurons (MNs). For the potency assessment of BoNTs produced for treatment in traditional and aesthetic medicine, the mouse lethality assay is still used by the majority of manufacturers, which is ethically questionable in terms of the 3Rs principle. In this study, MNs were differentiated from human induced pluripotent stem cells based on three published protocols. The resulting cell populations were analyzed for their MN yield and their suitability for the potency assessment of BoNTs. MNs produce specific gangliosides and synaptic proteins, which are bound by BoNTs in order to be taken up by receptor-mediated endocytosis, which is followed by cleavage of specific soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) proteins required for neurotransmitter release. The presence of receptors and substrates for all BoNT serotypes was demonstrated in MNs generated in vitro. In particular, the MN differentiation protocol based on Du et al. yielded high numbers of MNs in a short amount of time with high expression of BoNT receptors and targets. The resulting cells are more sensitive to BoNT/A1 than the commonly used neuroblastoma cell line SiMa. MNs are, therefore, an ideal tool for being combined with already established detection methods.
KW  - Botulinum neurotoxin
KW  - motor neurons
KW  - cell-based in vitro assay
KW  - potency
KW  - assessment
KW  - induced pluripotent stem cells
Y1  - 2020
U6  - https://doi.org/10.3390/toxins12050276
SN  - 2072-6651
VL  - 12
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Coleman, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weber, Daniela
A1  - Castro, Jose Pedro
A1  - Hugo, Martin
A1  - Schulz, Tim Julius
A1  - Krämer, Stephanie
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol
JF  - Molecular medicine
N2  - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
KW  - Nonalcoholic Steatohepatitis (NASH)
KW  - Typical Western Diet
KW  - Nonalcoholic Fatty Liver Disease (NAFLD)
KW  - Dietary Cholesterol
KW  - Kupffer Cells
Y1  - 2017
U6  - https://doi.org/10.2119/molmed.2016.00203
SN  - 1076-1551
SN  - 1528-3658
VL  - 23
SP  - 70
EP  - 82
PB  - Feinstein Inst. for Medical Research
CY  - Manhasset
ER  - 
TY  - JOUR
A1  - Knebel, Constanze
A1  - Neeb, Jannika
A1  - Zahn, Elisabeth
A1  - Schmidt, Flavia
A1  - Carazo, Alejandro
A1  - Holas, Ondej
A1  - Pavek, Petr
A1  - Püschel, Gerhard Paul
A1  - Zanger, Ulrich M.
A1  - Süssmuth, Roderich
A1  - Lampen, Alfonso
A1  - Marx-Stoelting, Philip
A1  - Braeuning, Albert
T1  - Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells
JF  - Toxicological sciences
N2  - Analyzing mixture toxicity requires an in-depth understanding of the mechanisms of action of its individual components. Substances with the same target organ, same toxic effect and same mode of action (MoA) are believed to cause additive effects, whereas substances with different MoAs are assumed to act independently. Here, we tested 2 triazole fungicides, propiconazole, and tebuconazole (Te), for individual and combined effects on liver toxicity-related endpoints. Both triazoles are proposed to belong to the same cumulative assessment group and are therefore thought to display similar and additive behavior. Our data show that Te is an antagonist of the constitutive androstane receptor (CAR) in rats and humans, while propiconazole is an agonist of this receptor. Both substances activate the pregnane X-receptor (PXR) and further induce mRNA expression of CYP3A4. CYP3A4 enzyme activity, however, is inhibited by propiconazole. For common targets of PXR and CAR, the activation of PXR by Te overrides CAR inhibition. In summary, propiconazole and Te affect different hepatotoxicity-relevant cellular targets and, depending on the individual endpoint analyzed, act via similar or dissimilar mechanisms. The use of molecular data based on research in human cell systems extends the picture to refine cumulative assessment group grouping and substantially contributes to the understanding of mixture effects of chemicals in biological systems.
KW  - triazole fungicides
KW  - constitutive androstane receptor
KW  - pregnane X-receptor
KW  - enzyme induction
KW  - liver toxicity
KW  - mixtures
Y1  - 2018
U6  - https://doi.org/10.1093/toxsci/kfy026
SN  - 1096-6080
SN  - 1096-0929
VL  - 163
IS  - 1
SP  - 170
EP  - 181
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Neuschäfer-Rube, Frank
A1  - Pathe-Neuschäfer-Rube, Andrea
A1  - Püschel, Gerhard Paul
T1  - Discrimination of the activity of low-affinity wild-type and high-affinity mutant recombinant BoNT/B by a SIMA cell-based reporter release assay
JF  - Toxins
N2  - Botulinum neurotoxin (BoNT) is used for the treatment of a number of ailments. The activity of the toxin that is isolated from bacterial cultures is frequently tested in the mouse lethality assay. Apart from the ethical concerns inherent to this assay, species-specific differences in the affinity for different BoNT serotypes give rise to activity results that differ from the activity in humans. Thus, BoNT/B is more active in mice than in humans. The current study shows that the stimulus-dependent release of a luciferase from a differentiated human neuroblastoma–based reporter cell line (SIMA-hPOMC1-26-Gluc) was inhibited by clostridial and recombinant BoNT/A to the same extent, whereas both clostridial and recombinant BoNT/B inhibited the release to a lesser extent and only at much higher concentrations, reflecting the low activity of BoNT/B in humans. By contrast, the genetically modified BoNT/B-MY, which has increased affinity for human synaptotagmin, and the BoNT/B protein receptor inhibited luciferase release effectively and with an EC50 comparable to recombinant BoNT/A. This was due to an enhanced uptake into the reporter cells of BoNT/B-MY in comparison to the recombinant wild-type toxin. Thus, the SIMA-hPOMC1-26-Gluc cell assay is a versatile tool to determine the activity of different BoNT serotypes providing human-relevant dose-response data.
KW  - cell-based assay
KW  - genetically modified BoNT
KW  - BoNT/B uptake
Y1  - 2022
U6  - https://doi.org/10.3390/toxins14010065
SN  - 2072-6651
VL  - 14
SP  - 1
EP  - 11
PB  - MDPI
CY  - Basel, Schweiz
ET  - 1
ER  -