Oxidative Stress in Liver Disease

Liver, being the second largest organ, maintains homeostasis by undergoing a number of risk factors that include alcohol, drugs, environmental pollutants, and radiation. All these factors are capable of inducing oxidative stress by generating free radicals that eventually result in various forms of severe liver diseases. In this chapter, the consequences of oxidative stress are studied, along with its pathophysiology, its effects on organelles, physiological alterations, and the common diseases that occur due to oxidative stress. The progression of various liver diseases primarily involves lipid peroxidation, deoxyribonucleic acid (DNA) damage, signaling of inflammatory mediators, and ultimately generation of free radicals. The inarguable role of prooxidants in hepatic pathogenesis can be evidenced by an increase in the levels of biomarkers of oxidative stress, namely, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), to name a few. These markers are paralleled by utilizing endogenous antioxidant mechanisms, thus decreasing the levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and glutathione (GSH). This challenge was overcome by a diverse and rapid development in the field of biomarkers and antioxidants. Newer advances in the field of biomarkers outlined strategies to identify diseases at an early stage so that the treatment procedure could be both clinically useful and cost-effective. Advanced research on antioxidants, to treat liver disease, resulted in the emergence of natural substances that contain common natural herbal extracts, vitamins, and other compounds. Antioxidant use, either as a single compound or in combination, has become key molecules today for counteracting our stressed system and to achieve healthy homeostasis. However, new research should be carried out at cellular and molecular pharmacology levels in combination with drug targeting systems so as to get innovative ideas for the therapeutics of hepatic disease, which are not known enough

Liver ubiquitome uncovers nutrient-stress-mediated trafficking and secretion of complement C3

Adaptation to changes in nutrient availability is crucial for cells and organisms. Posttranslational modifications of signaling proteins are very dynamic and are therefore key to promptly respond to nutrient deprivation or overload. Herein we screened for ubiquitylation of proteins in the livers of fasted and refed mice using a comprehensive systemic proteomic approach. Among 1641 identified proteins, 117 were differentially ubiquitylated upon fasting or refeeding. Endoplasmic reticulum (ER) and secretory proteins were enriched in the livers of refed mice in part owing to an ER-stress-mediated response engaging retro-translocation and ubiquitylation of proteins from the ER. Complement C3, an innate immune factor, emerged as the most prominent ER-related hit of our screen. Accordingly, we found that secretion of C3 from the liver and primary hepatocytes as well as its dynamic trafficking are nutrient dependent. Finally, obese mice with a chronic nutrient overload show constitutive trafficking of C3 in the livers despite acute changes in nutrition, which goes in line with increased C3 levels and low-grade inflammation reported for obese patients. Our study thus suggests that nutrient sensing in the liver is coupled to release of C3 and potentially its metabolic and inflammatory functions