A high-fat diet is not enough to cause short-term fatty liver disease. However, if this diet is combined with the intake of beverages sweetened with liquid fructose, the accumulation of fats in the liver accelerates and hypertriglyceridemia —a cardiovascular risk factor— can appear. This is explained in a study on a mouse experimental model, published in the journal Molecular Nutrition and Food Research and led by Professor Juan Carlos Laguna, from the Faculty of Pharmacy and Food Sciences, the Institute of Biomedicine of Barcelona (IBUB) and the Physiopathology of Obesity and Nutrition Networking Biomedical Research Centre (CIBEROBN).
The study counts on the collaboration of the researchers Aleix Sala-Vila and Iolanda Lázaro, from the Hospital del Mar Medical Research Institute (IMIM), and José Rodríguez-Morató, from IMIM-Hospital del Mar and MELIS-Pompeu Fabra University, among other experts.
Fructose and lipid metabolism
Fructose is one of the most common sweeteners in the food industry. This simple sugar (monosaccharide) is industrially obtained from corn syrup, a product derived from this gramineae. With a great sweetener power and low production costs, fructose is used by the food industry to sweeten beverages, sauces and processed foods, despite the scientific evidence that associates it with metabolic diseases which are risk factors of cardiovascular pathologies.
According to the new study, the effect caused by fructose in the increase in the synthesis of fatty acids in the liver is more decisive than the external introduction of fats through the diet.
In high-fat diets which are supplemented with liquid fructose, this monosaccharide is able to induce an increase in the de novo lipogenesis —that is, the formation of fats through sugar— and an inhibition of the lipid oxidation in the liver."
Professor Juan Carlos Laguna, Department of Pharmacology, Toxicology and Therapeutical Chemistry
"In particular, fructose intake affects directly the expression and activity of the nuclear factor ChREBP. Once activated, this factor causes an increase in the expression of enzymes that control the hepatic synthesis of fatty acids", he continues. "Parallelly, fructose intake reduces the activity of the nuclear receptor PPARalfa, which is the main responsible for the controlling of the expression of genes that code the enzymes involved in the fatty acid oxidation (mitochondrial and peroxisome) in the liver".
As stated in the preclinical study, the combination of the saturated fat from dietary origin and the induction of the endogen synthesis of fatty acids is what causes the emergence of the fatty liver. "Moreover, we are describing for the first time that fructose —unlike high-fat diets— increases the expression of the PNPLA3 protein, associated with the appearance of hypertriglyceridemia, a risk factor for cardiovascular diseases", notes Núria Roglans, co-author of the study and member of the mentioned Department.
Fatty liver disease in humans
Several epidemiologic studies related the consumption of drinks that are sweetened with fructose to the non-alcoholic fatty liver disease (NAFLD), a pathology for which there is no specific pharmacological therapy. In these patients, de novo lipogenesis contributes up to a 30% of the lipids accumulated in the liver, while in healthy people, this synthesis brings only the 5% of hepatic lipids.
The animal model characterized by the team will be of potential interest to study future drugs to treat the non-alcoholic fatty liver disease (NAFLD). "People with this pathology have a higher endogenous synthesis of lipids in the liver than healthy people. Therefore, the effects described in this study might appear in humans as well", note the experts.
"Unfortunately, —they continue— the fatty liver is the starting point for more serious pathologies, such as steatohepatitis and cirrhosis. It is a practically asymptomatic pathology, although in some cases, some mild unspecific digestive disorders can appear. Apart from following a healthy diet and physical activity, there is no efficient treatment against this pathology for now".
The effects described in the study are only observable if fructose is taken in its liquid form. "Regarding sweetened beverages, fructose is quickly absorbed and it reaches the liver massively, producing the described metabolic alterations. To find a comparison, we could talk about the appearance of a fructose overdose when this is taken in sweetened drinks", notes the team.
"However, when we eat fruit, the amount of taken fructose is a lot lower compared to a sweetened drink. Also, the process of chewing it and the presence of other elements in the fruit, such as fiber, slows down the absorption of fructose and its arrival to the liver", conclude the authors.
Velázquez, A.M., et al. (2022) ChREBP-driven DNL and PNPLA3 Expression Induced by Liquid Fructose are Essential in the Production of Fatty Liver and Hypertriglyceridemia in a High-Fat Diet-Fed Rat Model. Molecular Nutrition and Food Research. doi.org/10.1002/mnfr.202101115.