Fasting enriches liver triacylglycerol with n-3 polyunsaturated fatty acids: implications for understanding the adipose–liver axis in serum docosahexaenoic acid regulation

Abstract

We investigated the effect of short-term fasting on coordinate changes in the fatty acid composition of adipose triacylglycerol (TAG), serum non-esterified fatty acids (NEFA), liver TAG, and serum TAG and phospholipids in mice fed ad libitum or fasted for 16 h overnight. In contrast to previous reports under conditions of maximal lipolysis, adipose tissue TAG was not preferentially depleted of n-3 PUFA or any specific fatty acids, nor were there any striking changes in the serum NEFA composition. Short-term fasting did, however, increase the hepatic proportion of n-3 PUFA, and almost all individual species of n-3 PUFA showed relative and absolute increases. The relative proportion of n-6 PUFA in liver TAG also increased but to a lesser extent, resulting in a significant decrease in the n-6:n-3 PUFA ratio (from 14.3 ± 2.54 to 9.6 ± 1.20), while the proportion of MUFA decreased significantly and SFA proportion did not change. Examination of genes involved in PUFA synthesis suggested that hepatic changes in the elongation and desaturation of precursor lipids could not explain this effect. Rather, an increase in the expression of fatty acid transporters specific for 22:6n-3 and other long-chain n-3 and n-6 PUFA likely mediated the observed hepatic enrichment. Analysis of serum phospholipids indicated a specific increase in the concentration of 22:6n-3 and 16:0, suggesting increased specific synthesis of DHA-enriched phospholipid by the liver for recirculation. Given the importance of blood phospholipid in distributing DHA to neural tissue, these findings have implications for understanding the adipose-liver-brain axis in n-3 PUFA metabolism.

Acute Fasting Induces Expression of Acylglycerophosphate Acyltransferase (AGPAT) Enzymes in Murine Liver, Heart, and Brain

“…Among these changes, the largest effect was a 92-fold up-regulation of Agpat2, which is consistent with prior reports of a role for this enzyme specifically in triacylglycerol storage [13,14]. These data are therefore consistent with reports that hepatic TAG synthesis is increased [15], and hepatic TAG stores are enriched following an acute fast [16][17][18][19], and that the liver acts as the main site of phospholipid synthesis in the fasted state [20].…”

Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice

“…These differences are unlikely to reflect the FA composition of the diets, which delivered similar proportions of PUFA sand MUFA in HFD formulas and a greater proportion of PUFA in CD. After overnight fasting, HLC increased in the CD group, as expected [17][18][19]. This hepatic lipid deposition was accompanied by modifications of the unsaturation indices similar to those induced by an HFD (i.e., increase of PUFA and reduction of MUFA indices).…”

“…In addition, an early association between HFD feeding and hepatic insulin resistance has been reported [8,9,16]. Increased hepatic FA influx leading to lipid accumulation is also observed with prolonged fasting, on mobilization of adipose stores [17][18][19], but in this case hepatic insulin resistance is not present [18]. Thus, alterations in the hepatic lipid pool are a physiological response to increased circulating FA levels, and are not necessarily associated with changes in insulin sensitivity.…”

Starvation and refeeding in rats: effect on some parameters of energy metabolism and electrolytes and changes of hepatic tissue

“…Previous studies have reported that fasting and impaired glucose regulation can increase hepatic content of triacylglycerol and eventually result in the accumulation of lipid in the liver parenchyma (Lonardo et al 2015, Marks et al 2015. In the present experiment, tissue sections of rats revealed clear vacuoles, representing stored lipid droplets by starvation and also during refeeding.…”