UC Merced

Non-alcoholic fatty liver disease (NAFLD) afflicts 25% of the world’s population and is projected to increase due to the increasing prevalence of diabetes and obesity. The metabolic syndrome (MetS) is a cluster of conditions that raise the risk of cardiovascular disease. A strong association exists between MetS and NAFLD, and these two conditions share many characteristics (e.g., increased waist circumference, triacylglycerol, glucose, and blood pressure), along with insulin resistance, that promote their pathogenesis. The classical signaling pathway of the renin-angiotensin system (RAS) has been related to the development and progression of metabolic disease. The objectives of these projects were to elucidate the mechanisms associated with RAS that promote hepatic steatosis in a metabolic syndrome model and to investigate the effects of a nutrient overload via a glucose challenge. The first chapter describes the potential mechanisms by which chronic blockade of the classical RAS pathway decreased hepatic lipid accumulation and increased insulin sensitivity. The second chapter describes that blockade of the classical RAS pathway increased angiotensin 1-7 (Ang 1-7), which acts on the non-classical pathway of RAS. Ang 1-7 signaling is suggested to counteract RAS pathogenic signaling. The increased Ang 1-7 was associated with decreased hepatic lipid levels, triacylglycerol synthesis, fatty acid oxidation, gluconeogenesis, and improved glucose tolerance. Finally, the third chapter examined part of the redox status, which is a component of the “hit” hypotheses describing the pathogenesis of NAFLD, through the expression of hepatic glutathione enzymes. Chronic blockade of the classical RAS pathway decreased the expression of enzymes regulating glutathione metabolism (synthesis, usage, and reduction). Collectively, these data demonstrated that the classical RAS pathway contributes to the dysregulation of metabolism in the liver, which promotes the pathogenesis of NAFLD and MetS. Additionally, overactivation of RAS via AT1-mediated signaling may worsen the hepatic redox status, affecting liver glutathione regulation, which has systemic impact in controlling increased oxidant production. Because the mechanisms behind the development of NAFLD are not fully elucidated, understanding the molecules that dysregulate the metabolic and oxidative homeostasis may provide specific targets for the treatment and prevention of metabolic diseases.