| First Author | Labrie M | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 6 | Pages | e0130230 |
| PubMed ID | 26083030 | Mgi Jnum | J:237806 |
| Mgi Id | MGI:5816810 | Doi | 10.1371/journal.pone.0130230 |
| Citation | Labrie M, et al. (2015) Apolipoprotein D Transgenic Mice Develop Hepatic Steatosis through Activation of PPARgamma and Fatty Acid Uptake. PLoS One 10(6):e0130230 |
| abstractText | Transgenic mice (Tg) overexpressing human apolipoprotein D (H-apoD) in the brain are resistant to neurodegeneration. Despite the use of a neuron-specific promoter to generate the Tg mice, they expressed significant levels of H-apoD in both plasma and liver and they slowly develop hepatic steatosis and insulin resistance. We show here that hepatic PPARgamma expression in Tg mice is increased by 2-fold compared to wild type (WT) mice. Consequently, PPARgamma target genes Plin2 and Cide A/C are overexpressed, leading to increased lipid droplets formation. Expression of the fatty acid transporter CD36, another PPARgamma target, is also increased in Tg mice associated with elevated fatty acid uptake as measured in primary hepatocytes. Elevated expression of AMPK in the liver of Tg leads to phosphorylation of acetyl CoA carboxylase, indicating a decreased activity of the enzyme. Fatty acid synthase expression is also induced but the hepatic lipogenesis measured in vivo is not significantly different between WT and Tg mice. In addition, expression of carnitine palmitoyl transferase 1, the rate-limiting enzyme of beta-oxidation, is slightly upregulated. Finally, we show that overexpressing H-apoD in HepG2 cells in presence of arachidonic acid (AA), the main apoD ligand, increases the transcriptional activity of PPARgamma. Supporting the role of apoD in AA transport, we observed enrichment in hepatic AA and a decrease in plasmatic AA concentration. Taken together, our results demonstrate that the hepatic steatosis observed in apoD Tg mice is a consequence of increased PPARgamma transcriptional activity by AA leading to increased fatty acid uptake by the liver. |
