Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression

Abstract

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the major cause of chronic liver disease, especially in western countries. NAFLD encompasses a wide spectrum of hepatic histological alterations, from simple steatosis to steatohepatitis and cirrhosis with a potential development of hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and fibrosis. Several studies reported that insulin resistance, redox unbalance, inflammation, and lipid metabolism dysregulation are involved in NAFLD progression. However, the mechanisms beyond the evolution of simple steatosis to NASH are not clearly understood yet. Recent findings suggest that different oxidized products, such as lipids, cholesterol, aldehydes and other macromolecules could drive the inflammation onset. On the other hand, new evidence indicates innate and adaptive immunity activation as the driving force in establishing liver inflammation and fibrosis. In this review, we discuss how immunity, triggered by oxidative products and promoting in turn oxidative stress in a vicious cycle, fuels NAFLD progression. Furthermore, we explored the emerging importance of immune cell metabolism in determining inflammation, describing the potential application of trained immune discoveries in the NASH pathological context.

Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD

“…The most important source of oxidative stress in NAFLD is located in the mitochondria and is the result of increasing lipid accumulation. To counteract this, there is evidence of an increased enzyme activity of SOD and Gpx in patients with NAFLD (7). In our study, we identified two significant gene-by-Mastiha interaction associations; in the MLLT3 and LSS loci.…”

“…Oxidative stress is a hallmark of NAFLD, inducing cytokine production and inflammatory response from both the innate and adaptive immune system (7). Genetic variation, microRNAs, gut microbiota dysbiosis, dietary and lifestyle factors have also been implicated in the pathology of NAFLD (7,15).…”

“…Oxidative stress is a hallmark of NAFLD, inducing cytokine production and inflammatory response from both the innate and adaptive immune system (7). Genetic variation, microRNAs, gut microbiota dysbiosis, dietary and lifestyle factors have also been implicated in the pathology of NAFLD (7,15). Among the potential non-pharmaceutical treatments for NAFLD, there is evidence that Mastiha could be beneficial, due to its antioxidant and anti-inflammatory effects (13).…”

“…NAFLD is associated with insulin resistance, type 2 diabetes, obesity and the metabolic syndrome (4). There is also growing evidence that inflammatory markers and oxidative stress play a pivotal role in the pathophysiology of the disease, highlighting their role as potential therapeutic targets (3,(5)(6)(7).…”

Exploring the Protective Effects and Mechanism of Crocetin From Saffron Against NAFLD by Network Pharmacology and Experimental Validation

“…Further elucidation of the molecular mechanism of NAFLD has revealed that oxidative stress, endoplasmic reticulum stress, perturbation of autophagy, mitochondrial dysfunction, hepatocellular apoptosis, and inflammatory responses cause liver damage in NAFLD (8). Among them, the role of oxidative stress in the pathogenesis of NAFLD has attracted significant attention (9). Previous studies have suggested multiple molecular pathways related to oxidative stress that is involved in NAFLD, including IRs-1/Akt, CYP2E1/JNK, SIRT1/SIRT3-FOXO3a, A(10)MPK/Nrf2, Nrf2/HO-1, and AMPK signaling pathways (10)(11)(12)(13).…”