Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver

Xiaocui Chen,Lin Shang,Senwen Deng,Ping Li,Kai Chen,Ting Gao,Xiao Zhang,Zhilan Chen,Jia Zeng

doi:10.1074/jbc.ra120.013583

Abstract

Feeding of rapeseed (canola) oil with a high erucic acid concentration is known to cause hepatic steatosis in animals. Mitochondrial fatty acid oxidation plays a central role in liver lipid homeostasis, so it is possible that hepatic metabolism of erucic acid might decrease mitochondrial fatty acid oxidation. However, the precise mechanistic relationship between erucic acid levels and mitochondrial fatty acid oxidation is unclear. Using male Sprague-Dawley rats, along with biochemical and molecular biology approaches, we report here that peroxisomal β-oxidation of erucic acid stimulates malonyl-CoA formation in the liver and thereby suppresses mitochondrial fatty acid oxidation. Excessive hepatic uptake and peroxisomal β-oxidation of erucic acid resulted in appreciable peroxisomal release of free acetate, which was then used in the synthesis of cytosolic acetyl-CoA. Peroxisomal metabolism of erucic acid also remarkably increased the cytosolic NADH/NAD+ ratio, suppressed sirtuin 1 (SIRT1) activity, and thereby activated acetyl-CoA carboxylase, which stimulated malonyl-CoA biosynthesis from acetyl-CoA. Chronic feeding of a diet including high-erucic-acid rapeseed oil diminished mitochondrial fatty acid oxidation and caused hepatic steatosis and insulin resistance in the rats. Of note, administration of a specific peroxisomal β-oxidation inhibitor attenuated these effects. Our findings establish a cross-talk between peroxisomal and mitochondrial fatty acid oxidation. They suggest that peroxisomal oxidation of long-chain fatty acids suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation, which might play a role in fatty acid-induced hepatic steatosis and related metabolic disorders.

Highlights

It is well-known that high-erucic-acid rapeseed oil feeding develops transient cardiac lipidosis in animals as well as in humans, and the imbalance between the input and oxidation of erucic acid was proposed to be a critical cause for the acute lipid deposition in heart [1,2,3]
This study investigated the effect of peroxisomal oxidation of erucic acid on mitochondrial fatty acid oxidation as well as the potential mechanism by which metabolism of erucic acid leads to hepatic steatosis in animals
For carnitine palmitoyltransferase-1 (CPT1), the enzyme responsible for the transport of long-chain fatty acids into mitochondria, the Vmax value for C22:1-CoA is nearly 1 order of magnitude lower than that for C16-CoA, whereas its Km value was 1 order of magnitude higher, which was in accordance with previous reports that CPT1 or CPT2 showed no obvious activity toward very long-chain fatty acid (.C22) [13, 14]

Summary

Introduction

It is well-known that high-erucic-acid rapeseed oil feeding develops transient cardiac lipidosis in animals as well as in humans, and the imbalance between the input and oxidation of erucic acid was proposed to be a critical cause for the acute lipid deposition in heart [1,2,3]. Liver long-chain acyl-CoAs increased significantly in HROfed rats (by 133 and 90% versus the HOO and LRO groups, respectively), and CFB treatment further elevated longchain acyl-CoAs in HRO-fed rats, as reduced by the treatment with TDYA (Fig. 3A).

Results

Conclusion