title: TBC1D1 reduces palmitate oxidation by inhibiting β-HAD activity in skeletal muscle.
abstract: In skeletal muscle the Rab-GTPase-activating protein TBC1D1 has been implicated in the regulation of fatty acid oxidation by an unknown mechanism. We determined whether TBC1D1 altered fatty acid utilization via changes in protein-mediated fatty acid transport and/or selected enzymes regulating mitochondrial fatty acid oxidation. We also determined the effects of TBC1D1 on glucose transport and oxidation. Electrotransfection of mouse soleus muscles with TBC1D1 cDNA increased TBC1D1 protein after 2 wk (P<0.05), without altering its paralog AS160. TBC1D1 overexpression decreased basal palmitate oxidation (-22%) while blunting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated palmitate oxidation (-18%). There was a tendency to increase fatty acid esterification (+10 nmol·g(-1)·60 min(-1), P=0.07), which reflected the reduction in fatty acid oxidation (-12 nmol·g(-1)·60 min(-1)). Concomitantly, basal (+21%) and AICAR-stimulated glucose oxidation (+8%) were increased in TBC1D1-transfected muscles relative to their respective controls (P<0.05), independent of changes in GLUT4 and glucose transport. The reductions in TBC1D1-mediated fatty acid oxidation could not be attributed to changes in the transporter FAT/CD36, muscle mitochondrial content, CPT1 expression or the expression and phosphorylation of AS160, acetyl-CoA carboxylase, or AMPK. However, TBC1D1 overexpression reduced β-HAD enzyme activity (-18%, P<0.05). In conclusion, TBC1D1-mediated reduction of muscle fatty acid oxidation appears to occur via inhibition of β-HAD activity.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: A C
authors.initials: AC
authors.lastname: Maher
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: McFarlan
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Lally
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: L A
authors.initials: LA
authors.lastname: Snook
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Bonen
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism*; D012265:Ribonucleotides
chemical_list: D005227:Fatty Acids; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; D010168:Palmitates; D012265:Ribonucleotides; C095906:Tbc1d1 protein, mouse; D000620:Aminoimidazole Carboxamide; D015094:3-Hydroxyacyl CoA Dehydrogenases; C031143:AICA ribonucleotide; D005947:Glucose
keywords: TBC1D1; lipid oxidation; skeletal muscle; β-HAD activity