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

Lian Tang,Senwen Deng,Jia Zeng,Ping Li,Yefeng Pang,Yiping Wang

doi:10.1074/jbc.m116.763532

Abstract

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.

Highlights

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
Peroxisomes are sensitive to external signals and are easy to proliferate under conditions of high fat diet (HFD) [6, 7], diabetes [8], or hypolipidemic drug treatment [9]; peroxisomal FAO is induced, oxidation capacity is increased by 2–10fold, and peroxisomal FAO is regulated by the peroxisome proliferator activator receptor ␣ isoform (PPAR␣) [5]
A number of reports indicated that the hydrogen peroxidegenerating enzyme acyl-CoA oxidase-1 (ACOX1) was inducible, whereas the hydrogen peroxide-scavenging enzyme catalase was not induced under conditions of HFD or exposure to PPAR␣ ligands, which resulted in a net increase of hydrogen peroxide in peroxisomes and accumulation of cellular ROS (9 –12) and further led to induction of the NF-␬B signal pathway and caused cellular oxidative injury [12]

Summary

Introduction

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. Specific inhibition of ACOX1 by 10,12tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5؅-monophosphateactivated protein kinase) pathway and proliferator activator receptor ␣ 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. A number of reports indicated that the hydrogen peroxidegenerating enzyme ACOX1 was inducible, whereas the hydrogen peroxide-scavenging enzyme catalase was not induced under conditions of HFD or exposure to PPAR␣ ligands, which resulted in a net increase of hydrogen peroxide in peroxisomes and accumulation of cellular ROS (9 –12) and further led to induction of the NF-␬B signal pathway and caused cellular oxidative injury [12]

Objectives

Results

Conclusion