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Anti‐Retroviral Therapy Increases Hepatic Gluconeogenic and Lipogenic Enzyme Expression but does not Alter Expression of Insulin Signaling Cascade Proteins in Chronic Binge Alcohol‐Administered SIV‐Infected Rhesus Macaques
Author(s) -
Ford Stephen Michael,
Nelson Steve,
Bagby Gregory J.,
Simon Liz,
Molina Patricia E.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1089.11
Subject(s) - simian immunodeficiency virus , insulin , endocrinology , medicine , phosphoenolpyruvate carboxykinase , biology , glucose 6 phosphatase , insulin receptor , pten , carbohydrate metabolism , viral load , immunology , insulin resistance , virus , enzyme , pi3k/akt/mtor pathway , signal transduction , biochemistry
Chronic alcohol consumption, HIV infection, and anti‐retroviral therapy (ART) have independently been shown to increase risk for metabolic dysregulation. Previously we demonstrated that chronic binge alcohol (CBA) administration to simian immunodeficiency virus (SIV) infected male rhesus macaques impaired glucose‐insulin dynamics at 11 months post‐SIV infection. This was reflected in reduced acute insulin response to a glucose load, and decreased whole body glucose effectiveness, a measure of the rate of systemic glucose disappearance. The aim of this study was to determine whether CBA and/or ART altered hepatic gene expression of gluconeogenic and lipogenic enzymes and insulin signaling proteins in association with our previous findings of CBA‐mediated impairments in whole body glucose‐insulin dynamics. CBA or sucrose (SUC) was administered intragastrically through a surgically implanted indwelling catheter beginning at 3 mos prior to infection with SIV mac251 (and continued for the duration of the study) in male rhesus macaques. At 2.5 mos. post‐SIV infection, daily administration of ART was initiated in half of the SUC/SIV and CBA/SIV macaques. At necropsy (11 mos post‐SIV infection), livers were collected for analyses of mRNA and protein expression. Liver from ART‐treated SIV‐infected macaques showed increased mRNA expression of phosphoenolpyruvate carboxykinase‐1 (PEPCK‐1), glucose‐6‐phosphatase (G6Pase), and acetyl CoA carboxylase (ACC), compared to that of ART‐negative macaques, irrespective of CBA or SUC administration. Neither CBA nor ART administration altered hepatic protein expression of phosphatase and tensin homolog (PTEN) or protein tyrosine phosphatase 1B (PTP1B), phosphatase enzymes that attenuate insulin signaling. In addition, neither CBA nor ART reduced insulin signaling as determined by the ratio of phosphorylated/total protein expression for mTOR (S2448) and Akt (S473). ART‐treated animals showed higher P‐AMPK (T172)/total AMPK ratio irrespective of SUC or CBA administration, compared to ART‐negative animals. These findings suggest that ART contributes to impaired anabolic metabolism in an organ‐specific manner. Ongoing studies will demonstrate whether CBA and/or ART adversely affect(s) catabolic pathways of metabolism, including the glycolytic pathway. Taken together, our data suggest that chronic alcohol and ART may act synergistically to potentiate the progression of metabolic dysregulation in people living with HIV/AIDS. Support or Funding Information The work was supported by National Institutes of Health (NIH) grants: P60AA09803, T32AA07577, and F30AA024030‐01A1.