title: HIV-protease inhibitors suppress skeletal muscle fatty acid oxidation by reducing CD36 and CPT1 fatty acid transporters.
abstract: Infection with human immunodeficiency virus (HIV) and treatment with HIV-protease inhibitor (PI)-based highly active antiretroviral therapies (HAART) is associated with dysregulated fatty acid and lipid metabolism. Enhanced lipolysis, increased circulating fatty acid levels, and hepatic and intramuscular lipid accumulation appear to contribute to insulin resistance in HIV-infected people treated with PI-based HAART. However, it is unclear whether currently prescribed HIV-PIs directly alter skeletal muscle fatty acid transport, oxidation, and storage. We find that ritonavir (r, 5micromol/l) plus 20micromol/l of atazanavir (ATV), lopinavir (LPV), or darunavir (DRV) reduce palmitate oxidation(16-21%) in differentiated C2C12 myotubes. Palmitate oxidation was increased following exposure to high fatty acid media but this effect was blunted when myotubes were pre-exposed to the HIV-PIs. However, LPV/r and DRV/r, but not ATV/r suppressed palmitate uptake into myotubes. We found no effect of the HIV-PIs on FATP1, FATP4, or FABPpm but both CD36/FAT and carnitine palmitoyltransferase 1 (CPT1) were reduced by all three regimens though ATV/r caused only a small decrease in CPT1, relative to LPV/r or DRV/r. In contrast, sterol regulatory element binding protein-1 was increased by all 3 HIV-PIs. These findings suggest that HIV-PIs suppress fatty acid oxidation in murine skeletal muscle cells and that this may be related to decreases in cytosolic- and mitochondrial-associated fatty acid transporters. HIV-PIs may also directly impair fatty acid handling and partitioning in skeletal muscle, and this may contribute to the cluster of metabolic complications that occur in people living with HIV.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Richmond
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Carper
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Lei
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Yarasheski
authors.forename: Sasanka
authors.initials: S
authors.lastname: Ramanadham
mesh_terms: D000818:Animals; D000069446:Atazanavir Sulfate; D018955:CD36 Antigens / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002460:Cell Line; D000069454:Darunavir; D004305:Dose-Response Relationship, Drug; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D061466:Lopinavir; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010084:Oxidation-Reduction; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D018955:CD36 Antigens; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D013449:Sulfonamides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D002334:Carnitine O-Palmitoyltransferase; D019438:Ritonavir; D000069454:Darunavir