Abstract
Fructose, especially industrial fructose (sucrose and high fructose corn syrup) is commonly used in all kinds of beverages and processed foods. Liver is the primary organ for fructose metabolism, recent studies suggest that excessive fructose intake is a driving force in non-alcoholic fatty liver disease (NAFLD). Dietary fructose metabolism begins at the intestine, along with its metabolites, may influence gut barrier and microbiota community, and contribute to increased nutrient absorption and lipogenic substrates overflow to the liver. Overwhelming fructose and the gut microbiota-derived fructose metabolites (e.g., acetate, butyric acid, butyrate and propionate) trigger the de novo lipogenesis in the liver, and result in lipid accumulation and hepatic steatosis. Fructose also reprograms the metabolic phenotype of liver cells (hepatocytes, macrophages, NK cells, etc.), and induces the occurrence of inflammation in the liver. Besides, there is endogenous fructose production that expands the fructose pool. Considering the close association of fructose metabolism and NAFLD, the drug development that focuses on blocking the absorption and metabolism of fructose might be promising strategies for NAFLD. Here we provide a systematic discussion of the underlying mechanisms of dietary fructose in contributing to the development and progression of NAFLD, and suggest the possible targets to prevent the pathogenetic process.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by an excessive fat build-up in the liver without clear other causes, e.g., alcohol addiction, virus infection, and drug induction
Fructose dose as low as 0.33 g·kgBM−1 is sufficient to stimulate de novo lipogenesis (DNL) in mice (Tran et al, 2010), while fructose
In lipopolysaccharide (LPS)-stressed macrophages, high concentrations of fructose alter the mode of energy supply, with impaired glycolysis and enhanced oxidative phosphorylation, along with glutaminolysis and oxidative stress, which result in the secretion of inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, IL-8, IL-10, and TNF (Jones et al, 2021) (Figure 2)
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized by an excessive fat build-up in the liver without clear other causes, e.g., alcohol addiction, virus infection, and drug induction. Fructose consumption is found to be positively correlated with obesity, diabetes, cardiovascular disease, NAFLD, hypertension, and cancer (Ouyang et al, 2008; Shapiro et al, 2011; White, 2013; DiNicolantonio et al, 2018). Excessive fructose-contained drinks intake is strongly related to the childhood obesity and pediatric NAFLD (Forshee and Storey, 2003). Overconsumption of fructose can assemble most metabolic features that associated with NAFLD patients, such as insulin resistance, hyperlipidemia, visceral obesity and hyperuricemia (Sánchez-Lozada et al, 2008), suggesting that fructose is a noticeable factor that drives the process of NAFLD. We will review the recent studies that focus on the contribution of dietary fructose to NAFLD development and progression, and highlight the metabolic risks and possible drug targets
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