Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state

Diane Hall, Carine Poussin, Vidya Velagapudi, Christophe Empsen, Magali Joffraud, Jacques Beckmann, Albert E. Geerts, Yann Ravussin, Mark Ibberson, Matej Orešič, Bernard Thorens (Corresponding Author)

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Abstract

Accumulation of fat in the liver increases the risk to develop fibrosis and cirrhosis and is associated with development of the metabolic syndrome. Here, to identify genes or gene pathways that may underlie the genetic susceptibility to fat accumulation in liver, we studied A/J and C57Bl/6 mice that are resistant and sensitive to diet-induced hepatosteatosis and obesity, respectively. We performed comparative transcriptomic and lipidomic analysis of the livers of both strains of mice fed a high fat diet for 2, 10, and 30 days. We found that resistance to steatosis in A/J mice was associated with the following: (i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and β-oxidation; (ii) an increased expression of the elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with these observations, peroxisomal β-oxidation was increased in livers of A/J mice, and lipidomic analysis showed increased concentrations of long chain fatty acid-containing triglycerides, arachidonic acid-containing lysophosphatidylcholine, and 2-arachidonylglycerol, a cannabinoid receptor agonist. We found that the anti-inflammatory CB2 receptor was the main hepatic cannabinoid receptor, which was highly expressed in Kupffer cells. We further found that A/J mice had a lower pro-inflammatory state as determined by lower plasma levels and IL-1β and granulocyte-CSF and reduced hepatic expression of their mRNAs, which were found only in Kupffer cells. This suggests that increased 2-arachidonylglycerol production may limit Kupffer cell activity. Collectively, our data suggest that genetic variations in the expression of peroxisomal β-oxidation genes and of genes controlling the production of an anti-inflammatory lipid may underlie the differential susceptibility to diet-induced hepatic steatosis and pro-inflammatory state.
Original languageEnglish
Pages (from-to)31011-31023
JournalJournal of Biological Chemistry
Volume285
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

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Hall, D., Poussin, C., Velagapudi, V., Empsen, C., Joffraud, M., Beckmann, J., Geerts, A. E., Ravussin, Y., Ibberson, M., Orešič, M., & Thorens, B. (2010). Peroxisomal and microsomal lipid pathways associated with resistance to hepatic steatosis and reduced pro-inflammatory state. Journal of Biological Chemistry, 285, 31011-31023. https://doi.org/10.1074/jbc.M110.127159