title: Stimulation of fat accumulation in hepatocytes by PGE₂-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis.
abstract: 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 PGE₂, 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 PGE₂-generating capacity was enhanced in various obese mouse models by the induction of cyclooxygenase 2 and microsomal prostaglandin E-synthases (mPGES1, mPGES2). PGE₂ attenuated the insulin-dependent induction of SREBP-1c and its target genes glucokinase and fatty acid synthase. Nevertheless, PGE₂ enhanced incorporation of glucose into hepatic triglycerides synergistically with insulin. This was most likely due to a combination of a PGE₂-dependent repression of (1) the key lipolytic enzyme adipose triglyceride lipase, (2) carnitine-palmitoyltransferase 1, a key regulator of mitochondrial β-oxidation, and (3) microsomal transfer protein, as well as (4) apolipoprotein B, key components of the VLDL synthesis. Repression of PGC1α, a common upstream regulator of these genes, was identified as a possible cause. In support of this hypothesis, overexpression of PGC1α completely blunted the PGE₂-dependent fat accumulation. PGE₂ 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 PGE₂ synthesis in in vivo models of obesity imply a potential role of prostanoids in the development of NAFLD and NASH.
authors.affiliation: Department of Nutritional Biochemistry, University of Potsdam, Nuthetal, Germany.
authors.forename: Janin
authors.initials: J
authors.lastname: Henkel
authors.forename: Katja
authors.initials: K
authors.lastname: Frede
authors.forename: Nancy
authors.initials: N
authors.lastname: Schanze
authors.forename: Heike
authors.initials: H
authors.lastname: Vogel
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.forename: Astrid
authors.initials: A
authors.lastname: Spruss
authors.forename: Ina
authors.initials: I
authors.lastname: Bergheim
authors.forename: Gerhard P
authors.initials: GP
authors.lastname: Püschel
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008066:Lipolysis; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001055:Apolipoproteins B; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D007328:Insulin; D008079:Lipoproteins, VLDL; C106092:microsomal triglyceride transfer protein; D005947:Glucose; D015232:Dinoprostone