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 - 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 -