Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by the development of steatosis, which can ultimately compromise liver function. Mitochondria are key players in obesity-induced metabolic disorders; however, the distinct role of hypercaloric diet constituents in hepatic cellular oxidative stress and metabolism is unknown. Male mice were fed either a high-fat (HF) diet, a high-sucrose (HS) diet or a combined HF plus HS (HFHS) diet for 16 weeks. This study shows that hypercaloric diets caused steatosis; however, the HFHS diet induced severe fibrotic phenotype. At the mitochondrial level, lipidomic analysis showed an increased cardiolipin content for all tested diets. Despite this, no alterations were found in the coupling efficiency of oxidative phosphorylation and neither in mitochondrial fatty acid oxidation (FAO). Consistent with unchanged mitochondrial function, no alterations in mitochondrial-induced reactive oxygen species (ROS) and antioxidant capacity were found. In contrast, the HF and HS diets caused lipid peroxidation and provoked altered antioxidant enzyme levels/activities in liver tissue. Our work provides evidence that hepatic oxidative damage may be caused by augmented levels of peroxisomes and consequently higher peroxisomal FAO-induced ROS in the early NAFLD stage. Hepatic damage is also associated with autophagic flux impairment, which was demonstrated to be diet-type dependent. The HS diet induced a reduction in autophagosomal formation, while the HF diet reduced levels of cathepsins. The accumulation of damaged organelles could instigate hepatocyte injuries and NAFLD progression.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, affecting 25% of the population [1]
Mechanisms such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, inflammasome stimulation or apoptotic pathway activation have been suggested to be involved in the pathognomonic progression from "simple" steatosis to nonalcoholic steatohepatitis (NASH) [2]
Our results demonstrate that mitochondria-independent pathways contribute to hepatic damage in nonalcoholic fatty liver (NAFL), mainly involving both peroxisomal fatty acid oxidation (FAO)-induced oxidative damage and autophagy impairment
Summary
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, affecting 25% of the population [1]. In vivo studies have shown that a high-fat, high-sucrose (HFHS) diet, resembling unhealthy Western eating habits, causes most of the features of human NASH, but the pathognomonic mechanisms underlying disease development are still unclear [11]. 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 alter cellular signaling cascades leading to hepatocellular inflammation and fibrosis [15,16,17]. To determine the role of HF, HS and HFHS diets in the development of NAFL in mice, we examined hepatic redox- and mitochondrial-related alterations. Our work provides the first line of evidence that diets rich in sucrose and fat induce oxidative damage in a peroxisomal FAO-dependent manner and not via mitochondria. Elevated fat intake, rather than elevated sucrose intake, contributes to the impairment of hepatic autophagic flux in the step of autolysosome acidification
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