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

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.

Autophagy in Hepatic Steatosis: A Structured Review

“…These studies may suggest that, although all NAFLD models culminate in autophagic impairment, specific mechanisms could be favored under each condition. This has also been suggested by other authors based on different responses of autophagy markers comparing HFD with high sucrose and HFHS diets (Simoes et al, 2020). In addition to these evidences, the UPR and autophagy have recently been shown to share common regulatory pathways.…”

Dietary Macronutrient Composition Differentially Modulates the Remodeling of Mitochondrial Oxidative Metabolism during NAFLD

“…Hepatic mitochondria are at the center of this metabolic remodeling during NAFLD, due to their critical roles in integrating oxidative networks (β-oxidation, TCA cycle, ketogenesis, and OXPHOS) with anabolic networks of gluconeogenesis and lipogenesis. Dietary macronutrient composition has a major role in regulating the activity of these metabolic networks and can differentially impact mitochondrial metabolism and oxidative stress responses [ 34 ]. For example, insulin resistance and NAFLD induced by a carbohydrate-rich dietary environment (e.g., high-fructose diet) invariably activates lipogenesis [ 15 , 17 , 21 ], whereas high-fat diet-induced NAFLD could result in the suppression of the lipogenic machinery [ 19 , 20 ].…”

Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane

“…Nevertheless, in view of the active lipid exchange between mitochondria and ER/Golgi apparatus via membrane contact sites and mitochondria-associated membranes [ 51 ], changes in mitochondrial lipid content are likely. Interestingly, mitochondrial SM, PC/PE ratio, and cardiolipin levels have been associated with mitochondrial dysfunction in the context of fatty liver disease [ 52 ]. Similarly, aging and senescence have been associated with changes in the lipid content of mitochondria and mitochondria-associated membranes and membrane contact sites [ 53 ].…”