School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, China.
School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, China
J Biol Chem. 2020 Jul 24;295(30):10168-10179. doi: 10.1074/jbc.RA120.013583. Epub 2020 Jun 3.
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.
菜籽油（芥花油）中高浓度的芥酸已知会导致动物肝脏脂肪变性。线粒体脂肪酸氧化在肝脏脂质动态平衡中起着核心作用，因此，芥酸的肝脏代谢可能会降低线粒体脂肪酸氧化。然而，芥酸水平与线粒体脂肪酸氧化之间的确切机制关系尚不清楚。本研究使用雄性 Sprague-Dawley 大鼠，结合生化和分子生物学方法，报告了芥酸的过氧化物酶体β-氧化刺激肝脏中丙二酰辅酶 A 的形成，从而抑制线粒体脂肪酸氧化。过量的肝脏摄取和过氧化物酶体β-氧化导致可观的游离乙酸从过氧化物酶体释放，然后用于细胞质乙酰辅酶 A 的合成。芥酸的过氧化物酶体代谢还显著增加了细胞质 NADH/NAD 比，抑制了 SIRT1（沉默调节蛋白 1）活性，从而激活了乙酰辅酶 A 羧化酶，刺激了乙酰辅酶 A 从丙二酰辅酶 A 合成丙二酰辅酶 A。长期喂食包括高芥酸油菜籽油的饮食会降低线粒体脂肪酸氧化，并导致大鼠肝脏脂肪变性和胰岛素抵抗。值得注意的是，特定的过氧化物酶体β-氧化抑制剂可减轻这些影响。我们的发现确立了过氧化物酶体和线粒体脂肪酸氧化之间的串扰。它们表明，长链脂肪酸的过氧化物酶体氧化通过刺激丙二酰辅酶 A 的形成来抑制线粒体脂肪酸氧化，这可能在脂肪酸诱导的肝脏脂肪变性和相关代谢紊乱中发挥作用。
