Impairment of hepatic Stat-3 activation and reduction of PPARα activity in fructose-fed rats

Abstract

Fructose makes up a significant proportion of energy intake in westernized diets; its increased consumption has paralleled the growing prevalence of obesity and metabolic syndrome over the past two decades. In the current study, we demonstrate that fructose administration (10% wt/vol) in the drinking water of rats reduces the trans-activating and trans-repressing activity of the hepatic peroxisome proliferator-activated receptor ␣ (PPAR␣). As a consequence, fructose decreases hepatic fatty oxidation and increases pro-inflammatory transcription factor nuclear factor B (NF-B) activity. These changes were not observed in glucose-administered rats (10% wt/ vol), although both carbohydrates produced similar changes in plasma adiponectin and in the hepatic expression of transcription factors and enzymes involved in fatty acid synthesis. Fructosefed, but not glucose-fed, rats were hyperleptinemic and exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) transcription factor, although they did not present a similar increase in the serine phosphorylation of nuclear STAT3. Thus, an impairment in the hepatic transduction of the leptin signal could be responsible for the observed alterations in PPAR␣ activity in fructose-fed rats. Because PPAR␣ activity is lower in human than in rodent liver, fructose ingestion in humans should cause even worse effects, which would partly explain the link between increased consumption of fructose and widening epidemics of obesity and metabolic syndrome. T he prevalence of metabolic syndrome and the risk for developing diabetes mellitus and cardiovascular disease is increasing worldwide. 1,2 Environmental factors (diet, physical activity), in tandem with predisposing genetic factors, may be responsible for this trend. Along with an increase in total energy consumption during recent decades, there has also been a shift in the types of nutrients, with an increased consumption of fructose, largely attributable to the greater intake of beverages containing high levels of fructose. 3 Once absorbed, dietary fructose is mainly taken up by the liver, promoting triacylglycerol synthesis and very low-density lipoprotein (VLDL) production. However, increases in liver fatty acid synthesis alone is not sufficient to account for such elevated triacylglycerol production. 4 Thus, those mechanisms underlying liver lipid metabolic derangements caused by high-fructose diets are not completely understood.The rat offers an effective model of human fructose metabolism. 5 A high-fructose diet in rats induces metabolic derangements similar to those found in the metabolic syndrome. 6 Nevertheless, although experimental designs using 50% to 60% of fructose in pelleted diets induce hypertriglyceridemia and a pronounced state of insulin resistance, 6,7 diets incorporating 10% wt/vol of fructose in drinking water induce hypertriglyceridemia and fatty liver without modifying plasma glucose and insulin levels. 8,9 Because high-carbohydrate diets and chronic hyperin...

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

“…38 Recently, it has been reported that fructose-fed rats show impairment of hepatic STAT-3 activation as well as reduction in PPARa mRNA expression and activity. 39 In our study, adiponectin-null mice also showed reduced STAT3 activity and PPARa mRNA expression during the early phase of liver regeneration. These results suggest that STAT3 and PPARa may take part to the regulation of the hepatic lipid accumulation during liver regeneration.…”

Plasma lipid levels and body weight altered by intrauterine growth restriction and postnatal fructose diet in adult rats

“…Our study indicates that high, long-term consumption of fructose does not induce weight gain, whereas it increases the amount of lipids in visceral, metabolically most deleterious adipose tissue in the body, making the effects of a fructose diet especially harmful. In one study, there was a decrease in peroxisome proliferator-activated receptor-α activity, and therefore, decreased fatty acid oxidation and increased lipid accumulation was induced by fructose feeding (25), which might be one mechanism to explain our results.…”

Fructose and metabolic diseases: New findings, new questions

“…In rodents, a high-fructose diet was shown to increase the expression of lipogenic genes, to suppress peroxisome proliferator activated receptor-alpha (PPAR-α)-dependent lipid oxidation genes, and to cause intrahepatic fat deposition and hypertriglyceridemia. In contrast, a high-glucose diet also stimulated lipogenic gene expression, but failed to suppress lipid oxidation genes or to produce hepatic steatosis or dyslipidemia [43]. In humans, it has been shown that fructose, when substituted for starch, increases plasma triglycerides [44].…”