Differential contribution of chronic binge alcohol and antiretroviral therapy to metabolic dysregulation in SIV-infected male macaques

Abstract

TThe incidence of alcohol use disorder (AUD) is higher among people living with HIV (PLWH). The advent and continued development of antiretroviral therapy (ART) has significantly reduced mortality, shifting the course of HIV-infection to a chronic illness. However, this is associated with an increased incidence of comorbid conditions including type 2 diabetes mellitus, insulin resistance and cardiovascular complications. Using a non-human primate model of Simian Immunodeficiency Virus (SIV) infection, previous studies have demonstrated that chronic binge alcohol (CBA) administration decreases whole body insulin responsiveness, irrespective of ART administration. The objective of the current study was to determine the effects of CBA and ART on insulin-sensitive peripheral tissues prior to the development of overt clinical symptoms of SIV disease. Our results show that CBA reduced omental adipocyte cell size, increased collagen expression and decreased the in vitro differentiation potential of adipose derived stem cells. In contrast, it did not alter skeletal muscle, omental or hepatic expression of insulin signaling proteins. However, ART significantly decreased skeletal muscle expression of phosphatase and tensin homolog (PTEN), total mammalian Target of Rapamycin (mTOR) and ribosomal protein S6 (rpS6). In addition, ART increased hepatic phosphorylation of AMP-activated protein kinase α (AMPKα) and increased gene expression of key enzymes required for gluconeogenesis and fatty acid synthesis. These findings suggest that CBA and ART differentially promote adverse metabolic effects in an organ-specific manner that may underlie insulin resistance associated with alcohol, SIV and ART. Whether this is translated in PLWH with AUD remain to be determined.

Ethanol‐Impaired Myogenic Differentiation is Associated With Decreased Myoblast Glycolytic Function

“…Muscle samples used for isolation of myoblasts used in the present study were obtained from animals included in 2 parent longitudinal studies. The detailed experimental design and data collected from the parent study for the male cohort have been previously published (Ford et al, 2016, 2018; Molina et al, 2014; Simon et al, 2017, 2018). The parent study for the female cohort is ongoing.…”

A review of alcohol–pathogen interactions: New insights into combined disease pathomechanisms

“…Chronic immune activation‐mediated alteration in energy homeostasis one of the principal mechanisms leading to end‐stage organ injury. This metabolic instability was associated with alcohol induced alterations in endocrine pancreas function, decreased functional SKM mass, adipose tissue inflammation and fibrosis, and an antiretroviral (ART)‐associated increase in gluconeogenic and lipogenic capacity (Dodd et al, 2014; Ford et al, 2018; LeCapitaine et al, 2011; Simon et al, 2015). A salient mechanism underlying whole body metabolic instability in end‐stage HIV infection appears to involve alterations in genes regulating mitochondrial function in the skeletal muscle.…”

Pathophysiological Consequences of At-Risk Alcohol Use; Implications for Comorbidity Risk in Persons Living With Human Immunodeficiency Virus

“…In addition, alcohol-mediated oxidative stress induces transforming growth factor beta-1 (TGFβ1) ( Sueblinvong et al, 2014 ), which in turn activates Smad signaling impacting target genes involved in maintaining ECM homeostasis such as PAI-1, urokinase plasminogen activator (uPA), and collagen ( Seth et al, 2010 ). Alcohol dysregulates ECM remodeling producing a profibrotic milieu in SKM ( Dodd et al, 2014 ; Simon et al, 2015 ) and adipose tissue ( Ford et al, 2018 ) and these alterations in the matrisome are associated with decreased SKM metabolic function and regenerative capacity ( LeCapitaine et al, 2011 ; Simon et al, 2014 ; Duplanty et al, 2018 ; Ford et al, 2018 ) in SIV-infection. Thus, alcohol-induced dysregulation of the ECM contributes to tissue injury and risk of CMS.…”