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  - 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  - 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  - Henkel, Janin
A1  - Neuschaefer-Rube, Frank
A1  - Pathe-Neuschaefer-Rube, Andrea
A1  - Püschel, Gerhard Paul
T1  - Aggravation by prostaglandin e-2 of interleukin-6-dependent insulin resistance in hepatocytes
N2  - Hepatic insulin resistance is a major contributor to fasting hyperglycemia in patients with metabolic syndrome and type 2 diabetes. Circumstantial evidence suggests that cyclooxygenase products in addition to cytokines might contribute to insulin resistance. However, direct evidence for a role of prostaglandins in the development of hepatic insulin resistance is lacking. Therefore, the impact of prostaglandin E-2 (PGE(2)) alone and in combination with interleukin-6 (IL-6) on insulin signaling was studied in primary hepatocyte cultures. Rat hepatocytes were incubated with IL-6 and/or PGE(2) and subsequently with insulin. Glycogen synthesis was monitored by radiochemical analysis; the activation state of proteins of the insulin receptor signal chain was analyzed by western blot with phosphospecific antibodies. In hepatocytes, insulin-stimulated glycogen synthesis and insulin-dependent phosphorylation of Akt-kinase were attenuated synergistically by prior incubation with IL-6 and/or PGE(2) while insulin receptor autophosphorylation was barely affected. IL-6 but not PGE(2) induced suppressors of cytokine signaling (SOCS3). PGE(2) but not IL-6 activated extracellular signal-regulated kinase 1/2 (ERK1/2) persistently. Inhibition of ERK1/2 activation by PD98059 abolished the PGE(2)-dependent but not the IL-6-dependent attenuation of insulin signaling. In HepG2 cells expressing a recombinant EP3-receptor, PGE(2) pre-incubation activated ERK1/2, caused a serine phosphorylation of insulin receptor substrate 1 (IRS1), and reduced the insulin-dependent Akt-phosphorylation. Conclusion: PGE(2) might contribute to hepatic insulin resistance via an EP3-receptor-dependent ERK1/2 activation resulting in a serine phosphorylation of insulin receptor substrate, thereby preventing an insulin-dependent activation of Akt and glycogen synthesis. Since different molecular mechanisms appear to be employed, PGE(2) may synergize with IL-6, which interrupted the insulin receptor signal chain, principally by an induction of SOCS, namely SOCS3.
Y1  - 2009
UR  - http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291527-3350
U6  - https://doi.org/10.1002/Hep.23064
SN  - 0270-9139
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Klauder, Julia
A1  - Statz, Meike
A1  - Wohlenberg, Anne-Sophie
A1  - Kuipers, Sonja
A1  - Vahrenbrink, Madita
A1  - Püschel, Gerhard Paul
T1  - Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E-2
JF  - Biomedicines
N2  - Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E-2 (PGE(2)) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE(2) to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE(2) synthesis. PGE(2) in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE(2) in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.
KW  - macrophages
KW  - insulin
KW  - prostaglandin E-2
KW  - interleukin-8
KW  - inflammation
Y1  - 2021
U6  - https://doi.org/10.3390/biomedicines9050449
SN  - 2227-9059
VL  - 9
IS  - 5
PB  - MDPI
CY  - Basel
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  - 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  - 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  - 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  - 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  - Henkel, Janin
A1  - Coleman, Charles Dominic
A1  - Schraplau, Anne
A1  - Joehrens, 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.
Y1  - 2018
U6  - https://doi.org/10.1038/s41598-018-34633-y
SN  - 2045-2322
VL  - 8
PB  - Nature Publ. Group
CY  - London
ER  - 
TY  - GEN
A1  - Henkel, Janin
A1  - Buchheim-Dieckow, Katja
A1  - Castro, José Pedro
A1  - Laeger, Thomas
A1  - Wardelmann, Kristina
A1  - Kleinridders, André
A1  - Jöhrens, Korinna
A1  - Püschel, Gerhard Paul
T1  - Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 807 
KW  - NAFLD
KW  - NASH
KW  - endurance exercise
KW  - FGF21
KW  - glucose intolerance
KW  - cholesterol
KW  - oxidative stress
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-442384
SN  - 1866-8372
IS  - 807
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Buchheim-Dieckow, Katja
A1  - Castro, José Pedro
A1  - Laeger, Thomas
A1  - Wardelmann, Kristina
A1  - Kleinridders, André
A1  - Jöhrens, Korinna
A1  - Püschel, Gerhard Paul
T1  - Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH
JF  - Nutrients
N2  - Non-alcoholic fatty liver diseases (NAFLD) including the severe form with steatohepatitis (NASH) are highly prevalent ailments to which no approved pharmacological treatment exists. Dietary intervention aiming at 10% weight reduction is efficient but fails due to low compliance. Increase in physical activity is an alternative that improved NAFLD even in the absence of weight reduction. The underlying mechanisms are unclear and cannot be studied in humans. Here, a rat NAFLD model was developed that reproduces many facets of the diet-induced NAFLD in humans. The impact of endurance exercise was studied in this model. Male Wistar rats received control chow or a NASH-inducing diet rich in fat, cholesterol, and fructose. Both diet groups were subdivided into a sedentary and an endurance exercise group. Animals receiving the NASH-inducing diet gained more body weight, got glucose intolerant and developed a liver pathology with steatosis, hepatocyte hypertrophy, inflammation and fibrosis typical of NAFLD or NASH. Contrary to expectations, endurance exercise did not improve the NASH activity score and even enhanced hepatic inflammation. However, endurance exercise attenuated the hepatic cholesterol overload and the ensuing severe oxidative stress. In addition, exercise improved glucose tolerance possibly in part by induction of hepatic FGF21 production.
KW  - NAFLD
KW  - NASH
KW  - endurance exercise
KW  - FGF21
KW  - glucose intolerance
KW  - cholesterol
KW  - oxidative stress
Y1  - 2019
U6  - https://doi.org/10.3390/nu11112709
SN  - 2072-6643
VL  - 11
IS  - 11
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Henkel, Janin
A1  - Alfine, Eugenia
A1  - Saín, Juliana
A1  - Jöhrens, Korinna
A1  - Weber, Daniela
A1  - Castro, José Pedro
A1  - König, Jeannette
A1  - Stuhlmann, Christin
A1  - Vahrenbrink, Madita
A1  - Jonas, Wenke
A1  - Kleinridders, André
A1  - Püschel, Gerhard Paul
T1  - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol
JF  - Nutrients
N2  - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.
KW  - non-alcoholic fatty liver disease (NAFLD)
KW  - NASH
KW  - cholesterol
KW  - PUFA
KW  - inflammation
KW  - oxidative stress
Y1  - 2018
U6  - https://doi.org/10.3390/nu10091326
SN  - 2072-6643
VL  - 10
IS  - 9
SP  - 1
EP  - 17
PB  - Molecular Diversity Preservation International (MDPI)
CY  - Basel
ER  - 
TY  - GEN
A1  - Henkel, Janin
A1  - Alfine, Eugenia
A1  - Saín, Juliana
A1  - Jöhrens, Korinna
A1  - Weber, Daniela
A1  - Castro, José Pedro
A1  - König, Jeannette
A1  - Stuhlmann, Christin
A1  - Vahrenbrink, Madita
A1  - Jonas, Wenke
A1  - Kleinridders, André
A1  - Püschel, Gerhard Paul
T1  - Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol
T2  - Nutrients
N2  - While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 479 
KW  - non-alcoholic fatty liver disease (NAFLD)
KW  - NASH
KW  - cholesterol
KW  - PUFA
KW  - inflammation
KW  - oxidative stress
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-419773
ER  - 
TY  - JOUR
A1  - Fayyaz, Susann
A1  - Henkel, Janin
A1  - Japtok, Lukasz
A1  - Krämer, Stephanie
A1  - Damm, Georg
A1  - Seehofer, Daniel
A1  - Püschel, Gerhard Paul
A1  - Kleuser, Burkhard
T1  - Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P(2) receptor subtype
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.
 The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.
 Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P(2) receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P(2), was not able to inhibit insulin signalling.
 These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P(2) receptor to impair insulin signalling. In particular, S1P(2) inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.
KW  - FTY720
KW  - Insulin signalling
KW  - Palmitate
KW  - S1P receptors
KW  - Sphingolipids
KW  - Sphingosine 1-phosphate
Y1  - 2014
U6  - https://doi.org/10.1007/s00125-013-3123-6
SN  - 0012-186X
SN  - 1432-0428
VL  - 57
IS  - 2
SP  - 373
EP  - 382
PB  - Springer
CY  - New York
ER  -