Purpose of the Review: Mitochondrial dysfunction has long been proposed to play a crucial role in the pathogenesis of a considerable number of disorders, such as neurodegeneration, cancer, cardiovascular, and metabolic disorders, including obesity-related insulin resistance and non-alcoholic fatty liver disease (NAFLD). Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify their formation through biogenesis and the opposite processes of fission and fusion, the fragmentation, and connection of mitochondrial network areas respectively. Herein, we review and discuss the current literature on the significance of mitochondrial adaptations in obesity and metabolic dysregulation, emphasizing on the role of hepatocyte mitochondrial flexibility in obesity and NAFLD. Recent Findings: Accumulating evidence suggests the involvement of mitochondrial morphology and bioenergetics dysregulations to the emergence of NAFLD and its progress to non-alcoholic steatohepatitis (NASH). Summary: Most relevant data suggests that changes in liver mitochondrial dynamics and bioenergetics hold a key role in the pathogenesis of NAFLD. During obesity and NAFLD, oxidative stress occurs due to the excessive production of ROS, leading to mitochondrial dysfunction. As a result, mitochondria become incompetent and uncoupled from respiratory chain activities, further promoting hepatic fat accumulation, while leading to liver inflammation, insulin resistance, and disease’s deterioration. Elucidation of the mechanisms leading to dysfunctional mitochondrial activity of the hepatocytes during NAFLD is of predominant importance for the development of novel therapeutic approaches towards the treatment of this metabolic disorder.

Detailed investigation of the lipidome remodeling upon normal weight conditions, obesity, or weight loss, as well as the influence of physical activity, can help to understand the mechanisms underlying dyslipidemia in metabolic conditions correlated to the emergence and progression of non-alcoholic fatty liver disease (NAFLD). C57BL/6 male mice were fed a normal diet (ND) or a high-fat diet (HFD) for 20 weeks. Subgroups within the high-fat diet (HFD) group underwent different interventions: some engaged in exercise (HFDex), others were subjected to weight loss (WL) by changing from the HFD to ND, and some underwent a combination of weight loss and exercise (WLex) during the final 8 weeks of the 20-week feeding period. To support our understanding, not only tissue-specific lipid remodeling mechanisms but also the cross-talk between different tissues and their impact on the systemic regulation of lipid metabolism are essential. Exercise and weight loss-induced specific adaptations in the liver and visceral adipose tissue lipidomes of mice were explored by the UPLC–TOF–MS/MS untargeted lipidomics methodology. Lipidomic signatures of ND and HFD-fed mice undergoing weight loss were compared with animals with and without physical exercise. Several lipid classes were identified as contributing factors in the discrimination of the groups by multivariate analysis models, such as glycerolipids, glycerophospholipids, sphingolipids, and fatty acids, with respect to liver samples, whereas triglycerides were the only lipid class identified in visceral adipose tissue. Lipids found to be dysregulated in HFD animals are related to well-established pathways involved in the biosynthesis of PC, PE, and TG metabolism. These show a reversing trend back to basic levels of ND when animals change to a normal diet after 12 weeks, whereas the impact of exercise, though in some cases it slightly enhances the reversing trend, is not clear.

Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role of the pro-inflammatory adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in HSCs in NASH. VCAM-1 expression was upregulated in the liver upon NASH induction, and VCAM-1 was found to be present on activated HSCs. We therefore utilized HSC-specific VCAM-1-deficient and appropriate control mice to explore the role of VCAM-1 on HSCs in NASH. However, HSC-specific VCAM-1-deficient mice, as compared to control mice, did not show a difference with regards to steatosis, inflammation and fibrosis in two different models of NASH. Hence, VCAM-1 on HSCs is dispensable for NASH development and progression in mice.

Background: The present study aims at deciphering the potential benefits of aerobic exercise and dietary restriction on liver senescence, which is an established hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition with limited therapeutic options. Methods: C57BL6 mice were subjected to normal diet (ND, 10% of kilocalories from fat) or a high-fat diet (HFD, 60% of kilocalories deriving from fat and water supplemented with 5% High-fructose Corn Syrup, HFCS) for 12 weeks. Then, for additional 8 weeks, the ND group continued with the same diet, while the HFD group was divided into four subgroups: a) mice that continued with the same HFD-5% HFCS in water scheme (HFD), b) mice that continued with the same HFD-5% HFCS in water scheme and underwent supervised aerobic exercise 3-times/week (HFDEX), c) mice that were switched to ND (dietary restriction, DR) and d) mice that were switched to ND while undergoing supervised aerobic exercise 3-times/week (DREX). Phenotypic and histological characterization of obesity and MASLD were performed in all groups. Biomarkers of senescence were analyzed in terms of their mRNA expression levels to assess the impact of all interventions on MASLD-related senescence in the liver. GL13 and p21 immunohistochemical stainings were conducted to examine the protein levels of senescence-associated lipofuscin and p21 ^WAF1/CIP1 respectively, so as to finally investigate their relationship with the grade of steatosis observed in each individual animal. Results: DR and DREX groups exhibited significantly reduced features of obesity and MASLD-related hepatic steatosis, to a greater extent than the respective amelioration driven by aerobic exercise-only in HFDEX animals. A statistically significant increase of the mRNA expression of cyclin-dependent kinase p21 ^WAF1/CIP1 was detected in HFD livers as compared to ND, which was also reversed upon DR-inclusive interventions. In contrast, the gene expression levels of cyclin-dependent kinase p16 ^INK4a remained similar in all groups even after a combined intervention. Increased hepatic expression of the p27 and p53 components of the p53-p21 ^CIP/WAF -driven axis of cellular senescence as well as their restoration to ND-like levels upon DR and DREX, suggest an active participation of the p21 ^WAF1/CIP1 mechanism of senescence in the emergence of MASLD, but also in its reversal through DR or/and EX interventions. Immunohistochemical stainings _for GL13 and p21 confirmed the aforementioned alterations of p21 ^WAF1/CIP1 at the tissular level. Conclusion: Liver senescence is responsive both to exercise and dietary restriction, but its amelioration in the context of MASLD is more robust upon DR-inclusive interventions.