The severity of rat liver injury by fructose and high fat depends on the degree of respiratory dysfunction and oxidative stress induced in mitochondria

Abstract

Background High fat or fructose induces non-alcoholic fatty liver disease (NAFLD) accompanied of mitochondrial dysfunction and oxidative stress. Controversy remains about whether fructose or fat is more deleterious for NAFLD development. To get more insights about this issue and to determine if the severity of liver disease induced by fructose or fat is related to degree of mitochondrial dysfunction, we compared the effects of diets containing high fat (HF), fructose (Fr) or high fat plus fructose (HF + Fr) on NAFLD development, mitochondrial function, ROS production and lipid peroxidation. Methods Wistar rats were assigned to four groups: Control, fed with standard rodent chow; High fat (HF), supplemented with lard and hydrogenated vegetable oil; Fructose (Fr), supplemented with 25% fructose in the drinking water; High fat plus fructose group (HF + Fr), fed with both HF and Fr diets. Rats were sacrificed after 6 weeks of diets consumption and the liver was excised for histopathological analysis by hematoxylin and eosin staining and for mitochondria isolation. Mitochondrial function was evaluated by measuring both mitochondrial respiration and complex I activity. Lipid peroxidation and ROS production were evaluated in mitochondria by the thiobarbituric acid method and with the fluorescent ROS probe 2,4-H 2 DCFDA, respectively. Results Fr group underwent the lower degree of both liver damage and mitochondrial dysfunction that manifested like less than 20% of hepatocytes with microvesicular steatosis and partial decrease in state 3 respiration, respectively. HF group displayed an intermediate degree of damage as it showed 40% of hepatocytes with microvesicular steatosis and diminution of both state 3 respiration and complex I activity. HF + Fr group displayed more severe damage as showed microvesicular steatosis in 60% of hepatocytes and inflammation, while mitochondria exhibited fully inhibited state 3 respiration, impaired complex I activity and increased ROS generation. Exacerbation of mitochondrial lipid peroxidation was observed in both the Fr and HF + Fr groups. Conclusion Severity of liver injury induced by fructose or fat was related to the degree of dysfunction and oxidative damage in mitochondria. Attention should be paid on the serious effects observed in the HF + Fr group as the typical Western diet is rich in both fat and carbohydrates.

Mitochondrial Dysfunction in the Transition from NASH to HCC

“…In addition to its ability to promote de novo lipogenesis and block β-oxidation of fatty acids, fructose consumption seems to cause a drop in ATP and an elevation of uric acid, which can further induce mitochondrial oxidative stress [129]. Moreover, a diet rich in fructose is associated with increased oxidative mtDNA lesions in rat liver coupled with reduced mitochondrial repair capacity [130] and rats consuming a diet high in fat and rich in fructose have increased hepatocyte damage, inflammation, and lipid peroxidation coupled with impaired mitochondrial respiration and activity [131]. Studies show that dietary fructose induces fatty liver [132,133,134] and inflammation in mice after 8–24 weeks of exposure [52,135,136], as well as hepatic fibrosis in rhesus monkeys after seven years [137].…”

Western Diet Causes Obesity-Induced Nonalcoholic Fatty Liver Disease Development by Differentially Compromising the Autophagic Response

“…However, the abolished mt-FAO response in NAFLD can be associated with different mitochondrial alterations, such as reduced oxidative phosphorylation (OXPHOS), diminished ATP production and enhanced sensitivity for mitochondrial permeability transition pore (mPTP) opening [ 12 , 13 , 14 ]. The progression of NAFL towards NASH in a nonreversible manner was reported to involve a prooxidative state and mitochondrial-induced reactive oxygen species (ROS) production, which ultimately alter cellular signaling cascades leading to hepatocellular inflammation and fibrosis [ 15 , 16 , 17 ]. Conversely, recent evidence has questioned the role of oxidative stress as a trigger of NAFL progression.…”

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…The evaluation of the oxidative stress response through the progression of the disease represents a challenge to merge features of NAFLD patients and mouse models and provide mechanistic insights and therapeutic opportunities (see Table 4). High-fructose diet [269] Mitochondrial ROS production Lipid peroxidation High-fat and high-fructose diet [270] Superoxide generation Mitochondrial NADPH oxidase 4 (NOX4) High-fat and high-sucrose diet [167] Lipid peroxidation Copper deficient diet [271] Obesity has been widely studied in recent decades, and a close connection between excessive body weight and ROS overproduction has been established [272]. A high-fat low-carbohydrate diet leads to impaired mitochondrial function and increased cellular oxidative damage [273].…”

“…A low-fat, fructose-rich diet results in marked oxidative stress levels in hepatocytes [269]. Moreover, García-Berumen et al demonstrated that the supplementation of a HF diet with fructose induces more severe hepatic damage as shown by the inhibition of state 3 and the impairment of Complex I activity, which subsequently promotes further mitochondrial ROS production [270]. Recent work has pointed to the crucial role of fructose and its close relationship with sucrose in the development of NAFLD.…”