Stimulation of fat accumulation in hepatocytes by PGE(2)-dependent repression of hepatic lipolysis, beta-oxidation and VLDL-synthesis
- 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)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…
Verfasserangaben: | Janin HenkelORCiDGND, Katja Frede, Nancy Schanze, Heike VogelORCiDGND, Annette SchürmannORCiDGND, Astrid Spruß, Ina Bergheim, Gerhard Paul PüschelORCiDGND |
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DOI: | https://doi.org/10.1038/labinvest.2012.128 |
ISSN: | 0023-6837 |
Titel des übergeordneten Werks (Englisch): | Laboratory investigation : the basic and translational pathology research journal ; an official journal of the United States and Canadian Academy of Pathology |
Verlag: | Nature Publ. Group |
Verlagsort: | New York |
Publikationstyp: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Jahr der Erstveröffentlichung: | 2012 |
Erscheinungsjahr: | 2012 |
Datum der Freischaltung: | 26.03.2017 |
Freies Schlagwort / Tag: | NAFLD; NASH; PGC1 alpha; cyclooxygenase; hepatic steatosis; mPGES; type 2 diabetes (T2DM) |
Band: | 92 |
Ausgabe: | 11 |
Seitenanzahl: | 10 |
Erste Seite: | 1597 |
Letzte Seite: | 1606 |
Fördernde Institution: | Studienstiftung des Deutschen Volkes, Fellowship |
Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft |
Peer Review: | Referiert |