title: The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis.
abstract: Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease.
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Department of Pharmacy, Pharmaceutical, Saarland University, Saarbrücken, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Laggai
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Department of Pharmacy, Pharmaceutical, Saarland University, Saarbrücken, Germany Medicinal Chemistry, Saarland University, Saarbrücken, Germany Laboratory of Hepato-gastroenterology, Institut de Recherche expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Kessler
authors.affiliation: Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boettcher
authors.affiliation: Laboratory of Hepato-gastroenterology, Institut de Recherche expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lebrun
authors.affiliation: Department of Pharmacy, Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Gemperlein
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Lederer
authors.affiliation: Laboratory of Hepato-gastroenterology, Institut de Recherche expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Isabelle A
authors.initials: IA
authors.lastname: Leclercq
authors.affiliation: Department of Pharmacy, Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Mueller
authors.affiliation: Medicinal Chemistry, Saarland University, Saarbrücken, Germany Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Department of Pharmacy, Pharmaceutical, Saarland University, Saarbrücken, Germany.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Kiemer
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C000630955:ELOVL6 protein, human; C000630968:Elovl6 protein, mouse; D005227:Fatty Acids; C513121:IGF2 protein, mouse; C559768:IGF2BP2 protein, mouse; D016601:RNA-Binding Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D007335:Insulin-Like Growth Factor II; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases
keywords: fatty acid elongase 6; hepatic steatosis; insulin-like growth factor 2 signalling; sterol regulatory element binding transcription factor 1
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