HIV and its Treatment Lead to Metabolic Disturbances as a Result of Disrupted Cellular Respiration and Lipotoxicity

Abstract

Deaths from acquired immunodeficiency syndrome (AIDS) related diseases have declined with the success in the development of antiretroviral therapies. Diseases related to aging, particularly metabolic disorders, are rising in this population due to the longer life expectancies of those living with human immunodeficiency virus (HIV). Metabolic disruptions including abnormal fat distribution, elevated circulating lipid levels, and mitochondrial dysfunction are defining characteristics of individuals with HIV- infection. Current research has yet to define precisely the cellular pathways affected by HIV-associated altered lipid processing. Furthermore, it is unclear if conventional therapeutics, such as exercise, for age, lifestyle, and obesity-associated metabolic disorder may provide the same improvement in the overall metabolic health of those with HIV-related metabolic disorders. Additionally, the role of fibroblast growth factor 21 (FGF-21), a newly-identified protein associated with genetic mitochondrial disease and fat composition alterations, has yet to be defined in the context of HIV-infection. In this dissertation, the effect of exogenous lipid treatment upon multiple cellular pathways, as a model for dysregulated lipid metabolism, was explored. For this purpose, an in vitro model using a rodent myoblast cell line was utilized to analyze the effects of lipid, specifically palmitic acid, upon multiple cellular pathways including cell survival, endoplasmic reticulum (ER) stress response, mitochondrial function, oxidative stress, and antioxidant pathway activation. A 3-month aerobic exercise regimen was employed to evaluate the metabolic benefits of exercise in people living with HIV. Whole-body metabolic measures and mitochondrial function were assessed pre- and post-exercise intervention in HIV-infected individuals. The association of FGF-21 with HIV-related mitochondrial dysfunction and clinical metabolic parameters was also analyzed. The findings from this research suggest that palmitic acid disrupts antioxidant synthesis, induces ER stress, and decreases cell viability. These studies illustrate that a 3-month aerobic exercise regimen is sufficient to increase maximal oxygen consumption as well as increase mitochondrial respiratory capacity and spare respiratory capacity in an HIV- infected group. These studies also demonstrate the association of serum FGF-21 protein concentration to obesity, insulin sensitivity, mitochondrial-specific oxidative DNA damage, and mitochondrial function in HIV-infected individuals. Taken together, the findings of this dissertation indicate that alterations in lipid metabolism and storage, as observed in HIV-infected individuals, can induce alterations in major cellular pathways associated with metabolic disorders such as insulin resistance. Aerobic exercise can improve whole body aerobic metabolism as well as increase mitochondrial metabolism in HIV-infected individuals. The results of this study indicate an association between serum FGF-21 protein concentration and multiple risk factors for metabolic and mitochondrial impairment in HIV-infected individuals. Identification of cellular pathways and an early indicator of metabolic disturbances could lead to an intervention, for example increased aerobic activity, to halt the progression of metabolic disorder. Refined knowledge in this field would lead to more effective therapeutics and improvement in the quality of life of those living with HIV and its comorbidities.