Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

Abstract

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.

The Role of NRF2 in Obesity-Associated Cardiovascular Risk Factors

“…Of note, obesity is an important risk factor for cardiac fibrosis, including structural and functional cardiac alterations, and heart failure, which increase the risk of sudden death. As recently reviewed by Gutierrez-Cuevas et al, the increased cardiac work as a consequence of obesity elevates the blood volume, stroke volume, and cardiac output, which may result in LV dilatation and LVH, causing the development of coronary heart disease (CHD) and atrial fibrillation, heart failure, and ischemic stroke [ 2 ]. Furthermore, oxidative stress from epicardial fat may play a role in the genesis of atrial fibrillation (reviewed in [ 46 ]).…”

“…Obesity also induces LV remodeling, leading to both systolic and, particularly, diastolic dysfunctions. Additionally, obesity increases the risk of heart failure due to the enlargement of the left atrium, caused by both increased blood volume and diastolic ventricular dysfunction (reviewed in [ 2 ]). Other alterations induced by obesity in the myocardial structure include LV remodeling with increased wall thickness and mass, including increased thickness and volume of the right ventricle (reviewed in [ 2 ]).…”

“…Obesity is an independent risk factor for cardiovascular disease (CVD), and increases the risk of dyslipidemia, insulin resistance, hypertension, and atherosclerosis. Other risk factors induced by obesity include inflammation, oxidative stress, endothelial dysfunction, heart attack, stroke, and diabetes (reviewed in [ 1 , 2 ]). In obesity with insulin resistance or diabetes, the heart tissue is exposed to high levels of fatty acids and carbohydrates, which are deposited in the form of lipid vesicles in the myocardium.…”

“…In obesity with insulin resistance or diabetes, the heart tissue is exposed to high levels of fatty acids and carbohydrates, which are deposited in the form of lipid vesicles in the myocardium. In addition, insulin-resistance-induced hyperglycemia triggers oxidative stress and causes inflammation, thus inducing cell damage (as recently summarized by [ 2 ]). As recently reviewed by Gutierrez-Cuevas et al, obesity has been related to the development of several alterations in the myocardial structure and cardiac arrhythmias, including cardiac fibrosis, left ventricular hypertrophy (LVH), and diastolic dysfunction (reviewed in [ 1 , 2 ]).…”

Progressive Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

“…Non-alcoholic steatohepatitis (NASH) has been demonstrated to have a close association with obesity and obesity-related complications, such as type 2 diabetes (T2D) [ 2 , 3 ]. With the urbanization of the global population in addition to changes in dietary habits, the incidence and prevalence of obesity have been constantly rising.…”