Exploring the impact of caloric restriction on molecular mechanisms of liver damage induced by sucrose intake in the drinking water

Abstract

A positive association has been demonstrated between consumption of sucrose-sweetened beverages and the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Since the administration of 30% sucrose in the drinking water (SRD) to rats has proven to be a good model of systemic insulin resistance, the aim of our study was to analyze the effect of caloric restriction applied on SRD-treated rats by switching back to a standard diet, on liver morphology, function, and metabolism.Consumption of a SRD causes a metabolic shift towards gluconeogenesis and fatty acid synthesis leading to an increase in triacilglyceride (TAG) levels in plasma and in the liver that were associated with a decrease in insulin sensitivity. Moreover, our results show that animals fed a SRD develop steatohepatitis characterized by the generation of oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis. Although no histological changes were observed after a two-week caloric restriction, key pathways associated with the progression of MASLD as inflammation, ER stress and apoptosis were slowed down. Notably, this two-week intervention also increased liver insulin sensitivity (evaluated by AKT activity in this tissue) and drove the lipid metabolic profile towards oxidation, thus lowering circulating TAG levels.In summary, the present study uncovers underlying mechanisms affected, and their metabolic consequences, during the first stages of the phenotypic reversal of steatohepatitis by switching back to a standard diet after receiving sucrose-sweetened water for several weeks.