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

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.

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

“…The abovementioned results were recently supported by Chen et al [108], reporting that feeding animals a diet high in rapeseed oil (rich in erucic acid, a very-long-chain fatty acid) leads to PPARα activation with an adaptive elevation in peroxisomal β-oxidation capacity, which suggested that erucic acid might act as a potential ligand for PPARα. In line with prior communicated data, Maheshwari et al [109] reported that treating rat Fao cells with a fungal lipid extract rich in monomethyl BCFAs (Conidiobolus heterosporous) increases mRNA levels of the PPARα target genes Acox1, Cyp4a1, Cpt1A, and Slc22A5, strongly suggesting that BCFAs are similarly potent PPARα activators [109].…”

“…Several peroxisomal β-oxidation substrates display a substantial role as PPARα modulators. It is believed that the activities of (inducible and non-inducible) peroxisomal fatty acid β-oxidation systems are modulated by PPARα [108]. Moreover, several findings provide significant evidence that VLCFA and BCFA, which are considered potentially toxic fatty acids, are potent inducers of PPARα that enhance the transcription of peroxisomal enzymes mediating fatty acid β-oxidation [57,188].…”

“…Likewise, the transcriptome, lipidome, and metabolome results communicated by Régnier et al and Batatinha et al [217,218] demonstrate the significant contribution of extrahepatic PPARα activity to the metabolic homeostasis response to HFD consumption. By using double-knockout mice, Ppara -/-/Cyp2a5 -/-, Chen et al [108,206] together indicate that PPARα interacts with CYP2a5 (cytochrome P450 2A5) an antioxidant enzyme to protect against steatosis. Fibroblast growth factor 21 (FGF21) acts as a downstream molecule of the PPARα signaling pathway to regulate the liver lipid metabolism and contribute to the CYP2a5 protective effects on alcoholic fatty liver disease [206].…”

Genome‐scale metabolic modelling of SARS‐CoV‐2 in cancer cells reveals an increased shift to glycolytic energy production

“…The third and final reaction chosen occurs in peroxisomes, where lactate and NAD+ are converted to pyruvate and NADH by NAD+ oxidoreductase. The pyruvate/lactate ratio is linked with the NAD+/NADH ratio [ 62 ], potentially suggesting that the pyruvate is then shuttled back into the cytosol to be recycled into the citric acid cycle. Following the evidence described above, we set the lower bound of phosphogluconate dehydrogenase, acyl‐CoA oxidase and NAD+ oxidoreductase to 80% of their maximum value.…”

Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation

“…Peroxisomes play particularly important roles in FAO, ether-phospholipid biosynthesis, and ROS metabolism ( Figure 1 ). Previous studies have shown that β-oxidation of FAs predominantly occurs in mitochondria;, although peroxisomes also participate in FA oxidation ( Chen X. et al, 2020 ; Luppi et al, 2020 ). Although the integral compounds and full-scale function of peroxisomes remain unclear, it has been demonstrated that peroxin (PEX) families are essential components that maintain their structure and function, and peroxisome proliferator-activated receptors (PPARs), a set of three receptor subtypes (PPARα, γ, and δ) regulate a broad range of genes in many metabolically active tissues.…”