School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, PR China.
School of Life Science, Hunan University of Science and Technology, Xiangtan, Hunan, PR China.
J Biol Chem. 2023 Feb;299(2):102845. doi: 10.1016/j.jbc.2022.102845. Epub 2022 Dec 28.
Obesity and diabetes normally cause mitochondrial dysfunction and hepatic lipid accumulation, while fatty acid synthesis is suppressed and malonyl-CoA is depleted in the liver of severe obese or diabetic animals. Therefore, a negative regulatory mechanism might work for the control of mitochondrial fatty acid metabolism that is independent of malonyl-CoA in the diabetic animals. As mitochondrial β-oxidation is controlled by the acetyl-CoA/CoA ratio, and the acetyl-CoA generated in peroxisomal β-oxidation could be transported into mitochondria via carnitine shuttles, we hypothesize that peroxisomal β-oxidation might play a role in regulating mitochondrial fatty acid oxidation and inducing hepatic steatosis under the condition of obesity or diabetes. This study reveals a novel mechanism by which peroxisomal β-oxidation controls mitochondrial fatty acid oxidation in diabetic animals. We determined that excessive oxidation of fatty acids by peroxisomes generates considerable acetyl-carnitine in the liver of diabetic mice, which significantly elevates the mitochondrial acetyl-CoA/CoA ratio and causes feedback suppression of mitochondrial β-oxidation. Additionally, we found that specific suppression of peroxisomal β-oxidation enhances mitochondrial fatty acid oxidation by reducing acetyl-carnitine formation in the liver of obese mice. In conclusion, we suggest that induction of peroxisomal fatty acid oxidation serves as a mechanism for diabetes-induced hepatic lipid accumulation. Targeting peroxisomal β-oxidation might be a promising pathway in improving hepatic steatosis and insulin resistance as induced by obesity or diabetes.
肥胖和糖尿病通常会导致线粒体功能障碍和肝脂质积累，而在严重肥胖或糖尿病动物的肝脏中，脂肪酸合成受到抑制，丙二酰辅酶 A 耗尽。因此，在糖尿病动物中，可能存在一种独立于丙二酰辅酶 A 的负反馈调节机制来控制线粒体脂肪酸代谢。由于线粒体β-氧化受乙酰辅酶 A/辅酶 A 比值的控制，并且过氧化物酶体β-氧化产生的乙酰辅酶 A 可以通过肉碱穿梭进入线粒体，我们假设过氧化物酶体β-氧化可能在肥胖或糖尿病条件下通过调节线粒体脂肪酸氧化来发挥作用，并诱导肝脂肪变性。本研究揭示了一种新的机制，即过氧化物酶体β-氧化在糖尿病动物中控制线粒体脂肪酸氧化。我们确定，过氧化物酶体对脂肪酸的过度氧化会在糖尿病小鼠的肝脏中产生大量的乙酰肉碱，这显著增加了线粒体乙酰辅酶 A/辅酶 A 比值，并导致线粒体β-氧化的反馈抑制。此外，我们发现，特异性抑制过氧化物酶体β-氧化通过减少肥胖小鼠肝脏中乙酰肉碱的形成，增强了线粒体脂肪酸氧化。总之，我们认为诱导过氧化物酶体脂肪酸氧化是糖尿病引起肝脂质积累的一种机制。靶向过氧化物酶体β-氧化可能是改善肥胖或糖尿病引起的肝脂肪变性和胰岛素抵抗的有前途的途径。
