Effects of fructose on lipid metabolism in hepatocytes

Abstract

Dietary carbohydrate, especially fructose, causes hyper-triglyceridaemia in humans and laboratory animals. The potency of fructose in this respect is attributed to the ease of its conversion in the liver to the precursors of triacylglycerol, i.e. sn-glycerol 3 phosphate and fatty acids. This thesis investigates the short-term effects of fructose on lipid metabolism in isolated hepatocytes. Incorporation of fructose into triacylglycerol was much greater than from glucose. The majority of the radioactivity was associated with the glycerol moiety in each case, although there was a significant incorporation into fatty acids with fructose. The extensive incorporation of fructose into the glycerol moiety is the result of the ease of its conversion to triose phosphate and of the increase in sn-glycerol 3 phosphate content of the hepatocytes incubated with fructose. The latter effect occurs without a change in the cytoplasmic NADH/NAD ratio. Thus the incorporation of fructose into triacylglycerol is a good measure of triacylglycerol synthesis; it does not suffer from the disadvantage of the change in cytosolic redox potential observed with glycerol. Increasing fructose concentration caused a stimulation of lipid synthesis from endogenous acyl CoA, an effect also observed when exogenous oleate was added to the hepatocyte which resulted in a much higher level of triacylglycerol synthesis. Oleate also stimulated glucose incorporation into total lipid but, in contrast to fructose, more phospholipid than triacylglycerol synthesis occurred. This suggested a specific stimulatory effect on triacylglycerol synthesis which was confirmed using oleate as a precursor. The stimulation was attributed to the effect of the ketose on the cytoplasmic sn-glycerol 3-phosphate content of the cells. Glucagon was found to inhibit the fructose plus oleate stimulation of triacylglycerol synthesis. Physiological concentrations of fructose also caused increased pogenes is from lactate and acetate, but fatty acid synthesis was substantially inhibited at concentrations of the ketose above 2mM. It is concluded that the hyper-triglyceridaemic effect of fructose is the result of the specific stimulation of hepatic triacylglycerol synthesis and lipogenesis.