Zhang Wei, Zhang Lina, Yao Haoya, Wang Yaoqing, Zhang Xiao, Shang Lin, Chen Xiaocui, Zeng Jia
School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, P. R. China.
School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, P. R. China.
J Biol Chem. 2023 Sep;299(9):105174. doi: 10.1016/j.jbc.2023.105174. Epub 2023 Aug 19.
Recent studies provide evidence that peroxisomal β-oxidation negatively regulates mitochondrial fatty acid oxidation, and induction of peroxisomal β-oxidation causes hepatic lipid accumulation. However, whether there exists a triggering mechanism inducing peroxisomal β-oxidation is not clear. Long-chain dicarboxylic acids (LCDAs) are the product of mono fatty acids subjected to ω-oxidation, and both fatty acid ω-oxidation and peroxisomal β-oxidation are induced under ketogenic conditions, indicating there might be a crosstalk between. Here, we revealed that administration of LCDAs strongly induces peroxisomal fatty acid β-oxidation and causes hepatic steatosis in mice through the metabolites acetyl-CoA and hydrogen peroxide. Under ketogenic conditions, upregulation of fatty acid ω-oxidation resulted in increased generation of LCDAs and induction of peroxisomal β-oxidation, which causes hepatic accumulation of lipid droplets in animals. Inhibition of fatty acid ω-oxidation reduced LCDA formation and significantly lowered peroxisomal β-oxidation and improved hepatic steatosis. Our results suggest that endogenous LCDAs act as triggering molecules inducing peroxisomal β-oxidation and hepatic triacylglycerol deposition. Targeting fatty acid ω-oxidation might be an effective pathway in treating fatty liver and related metabolic diseases through regulating peroxisomal β-oxidation.
最近的研究表明，过氧化物酶体β-氧化对线粒体脂肪酸氧化起负调控作用，过氧化物酶体β-氧化的诱导会导致肝脏脂质蓄积。然而，是否存在诱导过氧化物酶体β-氧化的触发机制尚不清楚。长链二羧酸（LCDAs）是单脂肪酸经ω-氧化的产物，在生酮条件下脂肪酸ω-氧化和过氧化物酶体β-氧化均被诱导，这表明两者之间可能存在相互作用。在此，我们发现给予LCDAs可强烈诱导小鼠过氧化物酶体脂肪酸β-氧化，并通过代谢产物乙酰辅酶A和过氧化氢导致肝脏脂肪变性。在生酮条件下，脂肪酸ω-氧化的上调导致LCDAs生成增加和过氧化物酶体β-氧化的诱导，进而导致动物肝脏脂质滴蓄积。抑制脂肪酸ω-氧化可减少LCDA的形成，并显著降低过氧化物酶体β-氧化，改善肝脏脂肪变性。我们的结果表明，内源性LCDAs作为触发分子诱导过氧化物酶体β-氧化和肝脏三酰甘油沉积。靶向脂肪酸ω-氧化可能是通过调节过氧化物酶体β-氧化来治疗脂肪肝及相关代谢性疾病的有效途径。
