Way back for fructose and liver metabolism: bench side to molecular insights

Abstract

The World Health Organization recommends that the daily intake of added sugars should make up no more than 10% of total energy. The consumption of sugar-sweetened beverages is the main source of added sugars. Fructose, together with glucose, as a component of high fructose corn syrups or as a component of the sucrose molecule, is one of the main sweeteners present in this kind of beverages. Data from prospective and intervention studies clearly point to high fructose consumption, mainly in the form of sweetened beverages, as a risk factor for several metabolic diseases in humans. The incidence of hypertension, nonalcoholic fatty liver disease (NAFLD), dyslipidemia (mainly hypertriglyceridemia), insulin resistance, type 2 diabetes mellitus, obesity, and the cluster of many of these pathologies in the form of metabolic syndrome is higher in human population segments that show high intake of fructose. Adolescent and young adults from low-income families are especially at risk. We recently reviewed evidence from experimental animals and human data that confirms the deleterious effect of fructose on lipid and glucose metabolism. In this present review we update the information generated in the past 2 years about high consumption of fructose-enriched beverages and the occurrence of metabolic disturbances, especially NAFLD, type 2 diabetes mellitus, and metabolic syndrome. We have explored recent data from observational and experimental human studies, as well as experimental data from animal and cell models. Finally, using information generated in our laboratory and others, we provide a view of the molecular mechanisms that may be specifically involved in the development of liver lipid and glucose metabolic alterations after fructose consumption in liquid form.

Keywords: Clinical studies; Dyslipidemia; Experimental studies; Hypertension; Metabolic syndrome; Nonalcoholic fatty liver disease; Obesity; Sweetened beverages.

Figure 1

X-box-binding protein-1, an endoplasmic reticulum stress transcription factor, plays an essential role in maintaining plasma glucose concentration and glucose tolerance. Indeed, in the liver samples from the fructose-fed rats used in the study, there was a marked increase in the spliced form of X-box-binding protein (XBP)-1 mRNA and nuclear protein, in accordance with the increased activity of mammalian target of rapamycin (mTOR) activity and mitogen-activated protein kinase (p38-MAPK). Thus, although the decreased expression of insulin receptor substrate-2 in liver represents an impairment of insulin signaling, the increased expression and activity of XBP-1 could compensate for this deficit and maintain appropriate gluconeogenesis. PEPCK G6Pc: Phosphoenolpyruvate carboxykinase and glucose-6-phosphatase; FoxO1: Forkhead box protein O1.