Fructose-induced alterations of hepatic lipid metabolism are modulated by chronic stress in male rats

Abstract

Overconsumption of fructoseenriched beverages and everyday stress are both involved in the pathogenesis of metabolic disorders through their effects on hepatic lipid metabolism. The aim of this study was to investigate whether highfructose diet and chronic stress synergistically perturbs lipid metabolism in rat liver. Therefore, we analyzed the effects of 9-week 20% liquid fructose diet and 4-week chronic unpredictable stress, separately and in combination, on dyslipidemia, VLDL-TG kinetics, intrahepatic triglycerides (IHTG), liver de novo palmitate (DNPalm) content and fatty acid (FA) composition. In parallel, hepatic fractional de novo lipogenesis (fDNL) by stable isotope tracer protocol, as well as expression of lipid metabolism regulators were also analyzed. Results showed that highfructose diet led to hypertriglyceridemia, increased plasma VLDL-TGs and free FA (FFA), and increased visceral adiposity. Fructose diet also augmented the level of palmitate, palmitoleate and oleate in the liver, the latter being result of increased desaturase activity. In addition, newly synthesized palmitate (DNPalm content) was increased in the liver of fructose-fed animals, most likely as a result of stimulated fDNL. Chronic stress alone did not exert such effects, but when combined with fructose, stress decreased FFA level, ameliorated fructose-induced TG accumulation, and augmented the release of VLDL-TGs. Stress also enhanced the effects of high-fructose diet on fDNL, which was accompanied with increased expression of key regulators of lipid metabolism, that resulting in stimulated export of newly synthesized palmitate in the form of VLDL-TGs. These results imply that high-fructose diet affects hepatic lipid metabolism by stimulating fDNL and increasing de novo synthesized palmitate, which is partially accumulated in the liver and in part released into circulation in the form of VLDLTGs. On the other hand, stress in combination with high-fructose diet potentiated hepatic fDNL, but it decreased temporary TG storage and redirected newly synthesized palmitate into VLDL-TGs. Thus, the combination of high-fructose diet and chronic stress, as hallmarks of modern lifestyle, exerts more detrimental influence on lipid homeostasis than the individual factors, judged by stimulated fDNL and increased export of VLDL-TGs to non-hepatic tissues.