Abstract

Accumulation of fat in the liver, or hepatic steatosis, increases the risk to develop liver fibrosis, cirrhosis and is associated with different features of the metabolic syndrome. There is genetic basis for the susceptibility to develop hepatic steatosis but the genes or gene pathways involved are not fully identified. Here, we studied A/J and C57Bl/6 mice, which are, respectively, resistant and sensitive to diet-induced hepatosteatosis and obesity. 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. Resistance to steatosis in A/J mice was associated with: i) a coordinated up-regulation of 10 genes controlling peroxisome biogenesis and function, and increased peroxisomal beta-oxidation; ii) increased expression of the genes for the essential fatty acid modifying enzymes elongase Elovl5 and desaturases Fads1 and Fads2. In agreement with the transcriptomic data, lipidomic analysis showed increased concentrations of long chain fatty acid containing triglycerides, and also increased arachidonic acid-containing lysophosphatidylcholine, a marker of augmented peroxisome activity, and an increased production of the cannabinoid receptor agonist arachidonylglycerol. We found the mouse liver to preferentially expresses the anti-inflammatory cannabinoid receptor CB2, in particular in Kupffer cells. Increased levels of arachidonyl glycerol were correlated with lower expression of IL-1beta and G-CSF in A/J than in B6 mouse livers. Together, our data show that resistance to diet-induced hepatosteatosis, pro-inflammation and obesity are linked to activation of two hepatic lipid-modifying pathways.