Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

• Published in: The Journal of biological chemistry Vol. 292; no. 9; pp. 3800 - 3809
• Main Authors: Zeng, Jia, Deng, Senwen, Wang, Yiping, Li, Ping, Tang, Lian, Pang, Yefeng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2017; American Society for Biochemistry and Molecular Biology
• Subjects: acetyl coenzyme A (acetyl-CoA); Acyl-CoA Oxidase - antagonists & inhibitors; Acyl-CoA Oxidase - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Body Weight; Diet, High-Fat; fatty acid; fatty acid metabolism; fatty acid oxidation; Fatty Acids, Unsaturated - pharmacology; inhibitor; Insulin - metabolism; Lipids - chemistry; Liver - metabolism; Male; Metabolism; Mitochondria - metabolism; Oxygen - chemistry; Peroxisomes - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; Recombinant Proteins - metabolism; Sirtuin 1 - metabolism; fatty acid; metabolism; fatty acid oxidation; inhibitor; fatty acid metabolism; acetyl coenzyme A (acetyl-CoA)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M116.763532

A chronic high fat diet results in hepatic mitochondrial dysfunction and induction of peroxisomal fatty acid oxidation (FAO); whether specific inhibition of peroxisomal FAO benefits mitochondrial FAO and reactive oxygen species (ROS) metabolism remains unclear. In this study a specific inhibitor for the rate-limiting enzyme involved in peroxisomal FAO, acyl-CoA oxidase-1 (ACOX1) was developed and used for the investigation of peroxisomal FAO inhibition upon mitochondrial FAO and ROS metabolism. Specific inhibition of ACOX1 by 10,12-tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5′-monophosphate-activated protein kinase) pathway and proliferator activator receptor α and reduced hydrogen peroxide accumulation in high fat diet-fed rats, which significantly decreased hepatic lipid and ROS contents, reduced body weight gain, and decreased serum triglyceride and insulin levels. Inhibition of ACOX1 is a novel and effective approach for the treatment of high fat diet- or obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism.