The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease.

Cardiometabolic disease (CMD), which encompasses metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD) and cardiovascular disease (CVD), has been increasing considerably in the past 50 years. CMD is a complex disease that can be influenced by genetics and environmental factors such as diet. With the increased reliance on processed foods containing saturated fats, fructose and cholesterol, a mechanistic understanding of how these molecules cause metabolic disease is required. A major pathway by which excessive nutrients contribute to CMD is through oxidative stress. In this review, we discuss how oxidative stress can drive CMD and the role of aberrant nutrient metabolism and genetic risk factors and how they potentially interact to promote progression of MAFLD, CVD and CKD. This review will focus on genetic mutations that are known to alter nutrient metabolism. We discuss the major genetic risk factors for MAFLD, which include Patatin-like phospholipase domain-containing protein 3 (PNPLA3), Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) and Transmembrane 6 Superfamily Member 2 (TM6SF2). In addition, mutations that prevent nutrient uptake cause hypercholesterolemia that contributes to CVD. We also discuss the mechanisms by which MAFLD, CKD and CVD are mutually associated with one another. In addition, some of the genetic risk factors which are associated with MAFLD and CVD are also associated with CKD, while some genetic risk factors seem to dissociate one disease from the other. Through a better understanding of the causative effect of genetic mutations in CMD and how aberrant nutrient metabolism intersects with our genetics, novel therapies and precision approaches can be developed for treating CMD.

Thermogenic Adipose Redox Mechanisms: Potential Targets for Metabolic Disease Therapies.

Metabolic diseases, such as diabetes and non-alcoholic fatty liver disease (NAFLD), have several negative health outcomes on affected humans. Dysregulated energy metabolism is a key component underlying the pathophysiology of these conditions. Adipose tissue is a fundamental regulator of energy homeostasis that utilizes several redox reactions to carry out the metabolism. Brown and beige adipose tissues, in particular, perform highly oxidative reactions during non-shivering thermogenesis to dissipate energy as heat. The appropriate regulation of energy metabolism then requires coordinated antioxidant mechanisms to counterbalance the oxidation reactions. Indeed, non-shivering thermogenesis activation can cause striking changes in concentrations of both oxidants and antioxidants in order to adapt to various oxidative environments. Current therapeutic options for metabolic diseases either translate poorly from rodent models to humans (in part due to the challenges of creating a physiologically relevant rodent model) or tend to have numerous side effects, necessitating novel therapies. As increased brown adipose tissue activity results in enhanced energy expenditure and is associated with beneficial effects on metabolic health, such as decreased obesity, it has gathered great interest as a modulator of metabolic disease. One potential reason for the beneficial health effects may be that although non-shivering thermogenesis is enormously oxidative, it is also associated with decreased oxidant formation after its activation. However, targeting its redox mechanisms specifically to alter metabolic disease remains an underexplored area. Therefore, this review will discuss the role of adipose tissue in energy homeostasis, non-shivering thermogenesis in adults, and redox mechanisms that may serve as novel therapeutic targets of metabolic disease.

The Link Between 15-F2t-Isoprostane Activity and Acute Bovine Endothelial Inflammation Remains Elusive.

Modern dairy cattle suffer from increased incidence and severity of mastitis during major physiological transitions of the lactation cycle. Oxidative stress, a condition resulting from inadequate antioxidant defense against reactive oxygen and nitrogen species, is a major underlying component of mastitis pathophysiology. Isoprostanes (IsoP) are molecules derived from cellular lipid membranes upon non-enzymatic interaction with reactive species during inflammation, and are regarded as highly sensitive and specific biomarkers of oxidative stress. Changes in IsoP concentrations have been noted during major physiological transitions and diseases such as coliform mastitis in dairy cattle. However, the biological role of IsoP during oxidative stress in dairy cows has not been well-elucidated. Therefore, this study aimed to characterize the impacts of IsoP on oxidative stress outcomes in a bovine model of acute endothelial inflammation. Bovine aortic endothelial cells (BAEC; n = 4) were stimulated with 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) or lipopolysaccharide (LPS) with or without 15-F2t-IsoP to determine how IsoP influence oxidative stress outcomes. Our endothelial inflammation model showed relatively decreased reactive metabolites and increased barrier integrity in cells treated with both the agonist and IsoP compared to agonist treatment alone. However, IsoP do not appear to affect oxidative stress outcomes during acute inflammation. Understanding the effect of IsoP on BAEC is an early step in elucidating how IsoP impact dairy cows during times of oxidative stress in the context of acute clinical mastitis. Future studies should define the optimal dosing and treatment timing of IsoP to maximize their cytoprotective potential during acute inflammation.

15-F2t-Isoprostane Favors an Anti-Inflammatory Phenotype in RAW 264.7 Macrophages during Endotoxin Challenge.

Dysregulated inflammation and oxidative stress are major underlying components of several diseases. Macrophages are critical effector cells in immune responses, functioning to progress and resolve inflammation during such diseases. These mononuclear cells regulate inflammatory responses by exhibiting a range of phenotypes that evolve with the process, first promoting inflammation but then switching to a proresolving subtype to restore tissue homeostasis. Furthermore, macrophages are a primary source of isoprostanes (IsoPs), a nonenzymatic byproduct of lipid peroxidation during inflammation. As highly sensitive and specific indicators of lipid damage, IsoPs are the gold standard biomarker of oxidative stress. However, the physiological role of IsoPs during inflammation is currently not well-established. This study determined how IsoPs affect macrophage phenotype during lipopolysaccharide (LPS) challenge. RAW 264.7 macrophages (n = 7) were challenged with 5 ng/mL LPS for 8 h, followed with or without 500 nM 15-F2t-IsoP for 1 h. Macrophage phenotype was determined using metabolic, transcriptomic, and proteomic markers. Phenotypic markers assessed included ATP production; transcription of proinflammatory Nos2, Il1ß, and anti-inflammatory Il10; and translation markers IL1α and IL6 (proinflammatory) with G-CSF and IL17 (anti-inflammatory). Statistical analyses included one-way ANOVA followed by Tukey's posthoc test. Significance was set at p < 0.05. In combination with LPS, 15-F2t-IsoP increased ATP production relative to LPS-only treated cells. Additionally, gene expression of Nos2 and Il1ß were decreased while Il10 was increased. Cytokine production of IL6 was decreased while IL10, G-CSF, and IL17 were increased. Collectively, these results provide evidence that 15-F2t-IsoP promotes an anti-inflammatory macrophage phenotype during LPS challenge. These data support a novel physiological role of IsoPs, where these lipid mediators may participate in healing pathways during late-stage inflammation when they are elevated. Additionally, the promotion of an anti-inflammatory macrophage phenotype may contribute to preventing or mitigating inflammation during disease. Future studies should be directed towards defining the mechanisms in which IsoPs influence macrophage phenotype, such as receptor interactions and downstream signaling pathways.

Isoprostanes in Veterinary Medicine: Beyond a Biomarker.

Oxidative stress has been associated with many pathologies, in both human and animal medicine. Damage to tissue components such as lipids is a defining feature of oxidative stress and can lead to the generation of many oxidized products, including isoprostanes (IsoP). First recognized in the early 1990s, IsoP are formed in numerous biological fluids and tissues, chemically stable, and easily measured by noninvasive means. Additionally, IsoP are highly specific indicators of lipid peroxidation and thereby are regarded as excellent biomarkers of oxidative stress. Although there have been many advancements in the detection and use of IsoP as a biomarker, there is still a paucity of knowledge regarding the biological activity of these molecules and their potential roles in pathology of oxidative stress. Furthermore, the use of IsoP has been limited in veterinary species thus far and represents an avenue of opportunity for clinical applications in veterinary practice. Examples of clinical applications of IsoP in veterinary medicine include use as a novel biomarker to guide treatment recommendations or as a target to mitigate inflammatory processes. This review will discuss the history, biosynthesis, measurement, use as a biomarker, and biological action of IsoP, particularly in the context of veterinary medicine.