An Essential Role of the N-Terminal Region of ACSL1 in Linking Free Fatty Acids to Mitochondrial β-Oxidation in C2C12 Myotubes
Jinyan Nan 1, Ji Seon Lee 1, Seung-Ah Lee 2, Dong-Sup Lee 1, Kyong Soo Park 3,4, and Sung Soo Chung 5,*
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea, 2Genomic Medicine Institute, Seoul National University Medical Research Center, Seoul 03080, Korea, 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea, 4Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, Seoul 03080, Korea, 5Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea
Received April 8, 2021; Revised July 15, 2021; Accepted August 3, 2021.; Published online September 13, 2021.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

Free fatty acids are converted to acyl-CoA by long-chain acyl-CoA synthetases (ACSLs) before entering into metabolic pathways for lipid biosynthesis or degradation. ACSL family members have highly conserved amino acid sequences except for their N-terminal regions. Several reports have shown that ACSL1, among the ACSLs, is located in mitochondria and mainly leads fatty acids to the β-oxidation pathway in various cell types. In this study, we investigated how ACSL1 was localized in mitochondria and whether ACSL1 overexpression affected fatty acid oxidation (FAO) rates in C2C12 myotubes. We generated an ACSL1 mutant in which the N-terminal 100 amino acids were deleted and compared its localization and function with those of the ACSL1 wild type. We found that ACSL1 adjoined the outer membrane of mitochondria through interaction of its N-terminal region with carnitine palmitoyltransferase-1b (CPT1b) in C2C12 myotubes. In addition, overexpressed ACSL1, but not the ACSL1 mutant, increased FAO, and ameliorated palmitate-induced insulin resistance in C2C12 myotubes. These results suggested that targeting of ACSL1 to mitochondria is essential in increasing FAO in myotubes, which can reduce insulin resistance in obesity and related metabolic disorders.
Keywords: ACSL1, fatty acid oxidation, insulin resistance, mitochondria, myotubes

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31 August 2021 Volume 44,
Number 8, pp. 541~625
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