| First Author | Franklin MP | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 8 | Pages | 2112-2123 |
| PubMed ID | 28607105 | Mgi Jnum | J:252833 |
| Mgi Id | MGI:5924588 | Doi | 10.2337/db16-1519 |
| Citation | Franklin MP, et al. (2017) Acyl-CoA Thioesterase 1 (ACOT1) Regulates PPARalpha to Couple Fatty Acid Flux With Oxidative Capacity During Fasting. Diabetes 66(8):2112-2123 |
| abstractText | Hepatic acyl-CoA thioesterase 1 (ACOT1) catalyzes the conversion of acyl-CoAs to fatty acids (FAs) and CoA. We sought to determine the role of ACOT1 in hepatic lipid metabolism in C57Bl/6J male mice 1 week after adenovirus-mediated Acot1 knockdown. Acot1 knockdown reduced liver triglyceride (TG) as a result of enhanced TG hydrolysis and subsequent FA oxidation. In vitro experiments demonstrated that Acot1 knockdown led to greater TG turnover and FA oxidation, suggesting that ACOT1 is important for controlling the rate of FA oxidation. Despite increased FA oxidation, Acot1 knockdown reduced the expression of peroxisome proliferator-activated receptor alpha (PPARalpha) target genes, whereas overexpression increased PPARalpha reporter activity, suggesting ACOT1 regulates PPARalpha by producing FA ligands. Moreover, ACOT1 exhibited partial nuclear localization during fasting and cAMP/cAMP-dependent protein kinase signaling, suggesting local regulation of PPARalpha. As a consequence of increased FA oxidation and reduced PPARalpha activity, Acot1 knockdown enhanced hepatic oxidative stress and inflammation. The effects of Acot1 knockdown on PPARalpha activity, oxidative stress, and inflammation were rescued by supplementation with Wy-14643, a synthetic PPARalpha ligand. We demonstrate through these results that ACOT1 regulates fasting hepatic FA metabolism by balancing oxidative flux and capacity. |
