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Transient hepatic overexpression of insulin-like growth factor 2 induces free cholesterol and lipid droplet formation

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Abstract
Although insulin-like growth factor 2 (IGF2) has been reported to be overexpressed in steatosis and steatohepatitis, a causal role of IGF2 in steatosis development remains elusive. Aim of our study was to decipher the role of IGF2 in steatosis development. Hydrodynamic gene delivery of an Igf2 plasmid used for transient Igf2 overexpression employing codon-optimized plasmid DNA resulted in a strong induction of hepatic Igf2 expression. The exogenously delivered Igf2 had no influence on endogenous Igf2 expression. The downstream kinase AKT was activated in Igf2 animals. Decreased ALT levels mirrored the cytoprotective effect of IGF2. Serum cholesterol was increased and sulfo-phospho-vanillin colorimetric assay confirmed lipid accumulation in Igf2-livers while no signs of inflammation were observed. Interestingly, hepatic cholesterol and phospholipids, determined by thin layer chromatography, and free cholesterol by filipin staining, were specifically increased. Lipid droplet (LD) size was not changed, but their number was significantly elevated. Furthermore, free cholesterol, which can be stored in LDs and has been reported to be critical for steatosis progression, was elevated in Igf2 overexpressing mice. Accordingly, Hmgcr/HmgCoAR was upregulated. To have a closer look at de novo lipid synthesis we investigated expression of the lipogenic transcription factor SREBF1 and its target genes. SREBF1 was induced and also SREBF1 target genes were slightly upregulated. Interestingly, the expression of Cpt1a, which is responsible for mitochondrial fatty acid oxidation, was induced. Hepatic IGF2 expression induces a fatty liver, characterized by increased cholesterol and phospholipids leading to accumulation of LDs. We therefore suggest a causal role for IGF2 in hepatic lipid accumulation.
Keywords
NONALCOHOLIC STEATOHEPATITIS, HEPATOCELLULAR-CARCINOMA, VIRUS CORE PROTEIN, HYDRODYNAMIC GENE DELIVERY, BINDING-PROTEIN P62/IGF2BP2-2, FATTY LIVER-DISEASE, lipid droplets, fatty liver, hydrodynamic gene delivery, NASH, insulin-like growth factor 2 (IGF2), OBESE CHILDREN, PLASMID DNA, OLIGONUCLEOTIDE MICROARRAY, ACID OXIDATION

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Citation

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Chicago
Kessler, Sonja M, Stephan Laggai, Elien Van Wonterghem, Katja Gemperlein, Rolf Müller, Johannes Haybaeck, Roosmarijn Vandenbroucke, Manfred Ogris, Claude Libert, and Alexandra K Kiemer. 2016. “Transient Hepatic Overexpression of Insulin-like Growth Factor 2 Induces Free Cholesterol and Lipid Droplet Formation.” Frontiers in Physiology 7.
APA
Kessler, S. M., Laggai, S., Van Wonterghem, E., Gemperlein, K., Müller, R., Haybaeck, J., Vandenbroucke, R., et al. (2016). Transient hepatic overexpression of insulin-like growth factor 2 induces free cholesterol and lipid droplet formation. FRONTIERS IN PHYSIOLOGY, 7.
Vancouver
1.
Kessler SM, Laggai S, Van Wonterghem E, Gemperlein K, Müller R, Haybaeck J, et al. Transient hepatic overexpression of insulin-like growth factor 2 induces free cholesterol and lipid droplet formation. FRONTIERS IN PHYSIOLOGY. 2016;7.
MLA
Kessler, Sonja M, Stephan Laggai, Elien Van Wonterghem, et al. “Transient Hepatic Overexpression of Insulin-like Growth Factor 2 Induces Free Cholesterol and Lipid Droplet Formation.” FRONTIERS IN PHYSIOLOGY 7 (2016): n. pag. Print.
@article{7236119,
  abstract     = {Although insulin-like growth factor 2 (IGF2) has been reported to be overexpressed in steatosis and steatohepatitis, a causal role of IGF2 in steatosis development remains elusive. Aim of our study was to decipher the role of IGF2 in steatosis development. Hydrodynamic gene delivery of an Igf2 plasmid used for transient Igf2 overexpression employing codon-optimized plasmid DNA resulted in a strong induction of hepatic Igf2 expression. The exogenously delivered Igf2 had no influence on endogenous Igf2 expression. The downstream kinase AKT was activated in Igf2 animals. Decreased ALT levels mirrored the cytoprotective effect of IGF2. Serum cholesterol was increased and sulfo-phospho-vanillin colorimetric assay confirmed lipid accumulation in Igf2-livers while no signs of inflammation were observed. Interestingly, hepatic cholesterol and phospholipids, determined by thin layer chromatography, and free cholesterol by filipin staining, were specifically increased. Lipid droplet (LD) size was not changed, but their number was significantly elevated. Furthermore, free cholesterol, which can be stored in LDs and has been reported to be critical for steatosis progression, was elevated in Igf2 overexpressing mice. Accordingly, Hmgcr/HmgCoAR was upregulated. To have a closer look at de novo lipid synthesis we investigated expression of the lipogenic transcription factor SREBF1 and its target genes. SREBF1 was induced and also SREBF1 target genes were slightly upregulated. Interestingly, the expression of Cpt1a, which is responsible for mitochondrial fatty acid oxidation, was induced. Hepatic IGF2 expression induces a fatty liver, characterized by increased cholesterol and phospholipids leading to accumulation of LDs. We therefore suggest a causal role for IGF2 in hepatic lipid accumulation.},
  articleno    = {147},
  author       = {Kessler, Sonja M and Laggai, Stephan and Van Wonterghem, Elien and Gemperlein, Katja and M{\"u}ller, Rolf and Haybaeck, Johannes and Vandenbroucke, Roosmarijn and Ogris, Manfred and Libert, Claude and Kiemer, Alexandra K},
  issn         = {1664-042X},
  journal      = {FRONTIERS IN PHYSIOLOGY},
  language     = {eng},
  pages        = {11},
  title        = {Transient hepatic overexpression of insulin-like growth factor 2 induces free cholesterol and lipid droplet formation},
  url          = {http://dx.doi.org/10.3389/fphys.2016.00147},
  volume       = {7},
  year         = {2016},
}

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