High dietary n-6 PUFA and low dietary n-3 PUFA intake has been suggested to promote the pathogenesis of several diseases, including cardiovascular disease, inflammatory and http://www.selleckchem.com/products/BI6727-Volasertib.html autoimmune disease [11], [12]. Moreover, a lower intake in dietary sources of n-3 PUFA was suggested to be associated with non-alcoholic fatty liver disease [13], [14]. In fact, patients with hepatic steatosis present a lower n-3/n-6 PUFA ratio in liver tissue biopsies, namely in phospholipids subfractions, and in red blood cells [15], [16]. In accordance with this observation, rats and mice presenting a depletion of n-3 PUFA for two generations display several features of metabolic syndrome including hepatic steatosis [17], [18]. However, the biochemical mechanisms explaining the hepatic alterations occurring upon n-3 PUFA depletion remain unclear.

Therefore, in the present study, we have investigated, in mice, the effect of n-3 PUFA depletion established for 3-months on hepatic lipid composition and metabolism using molecular and integrative physiological approaches in vitro and in vivo. We observed a stimulation of the hepatic lipogenic pathway, most likely induced by the increased expression and activity of SREBP-1c. Results Mice fed with a diet depleted in n-3 PUFA exhibit a decrease in n-3 PUFA in hepatic phospholipid fractions and changes in hepatic endocannabinoid content DEF mice exhibited a large drop in n-3 PUFA content in hepatic phospholipids (PLs), thereby confirming the tissue depletion (Table 1). Despite a qualitative change in n-6 PUFA in favour of arachidonic acid (C20:4 n-6), the total amount of n-6 PUFA in hepatic PLs was similar between both groups.

The other modification observed in DEF mice was a 51% increase in the content of monounsaturated fatty acid (MUFA) and especially of oleic acid (C18:1) compared to CT mice (Table 1). In accordance with the changes in arachidonic and oleic acid, we found a higher level of bioactive lipids belonging to the endocannabinoid system and known to control lipogenesis, namely 2-arachidonoylglycerol (2-AG) and N-oleoylethanolamine, in the liver of DEF mice than in CT mice. However, for N-oleoylethanolamine it was not significant (Table S1). Table 1 Fatty acids pattern in liver phospholipids (PLs) fractions of CT and DEF mice.

n-3 PUFA depletion decreases fatty acid oxidation and promotes hepatic lipid synthesis, storage and secretion Histological analysis GSK-3 revealed a higher number and size of lipid droplets in the livers of DEF mice compared to CT mice (Figure 1A). These observations were confirmed by the biochemical analysis showing that lipid accumulation in the liver of DEF mice was due to an increased hepatic content of triglycerides (TG) and esterified cholesterol (Figure 1B). Figure 1 Accumulation of lipids in the livers of n-3 PUFA depleted mice.