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  - 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  - 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  -