Mazur Anna, Chen Xue, Denning Krista L, Xu Wei, Lawrence Logan M, Lu Yongke
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV, 25755, USA.
Department of Pathology, Joan C. Edwards School of Medicine, Marshall University, 1700 3rd Avenue, Huntington, WV, 25755, USA.
Free Radic Biol Med. 2025 Jul 30;239:213-218. doi: 10.1016/j.freeradbiomed.2025.07.050.
There is an interaction between peroxisomal fatty acid β-oxidation and catalase-dependent ethanol metabolism. HO is essential for catalase to metabolize ethanol. Peroxisomal fatty acid β-oxidation rate limiting enzyme is acyl-CoA oxidase (ACOX), which generates HO for catalase to metabolize ethanol. Usually, ACOX1 oxidizes very long-chain fatty acids and ACOX2 oxidizes branched-chain fatty acids. Previously we reported that PPARα agonist WY-14,643 induced ACOX1 to ameliorate alcoholic steatosis, and the induced ACOX1 coordinated with the induced catalase to enhance ethanol metabolism. In this study, we examined the effects of phytol on alcoholic steatosis and ethanol metabolism. Phytol is a precursor of pristanic acid, a substrate for ACOX2. Phytol can also induce ACOX1 and catalase. Phytol was added in the Lieber-DeCarli liquid diets up to 0.2 %. After 3 weeks of feeding, phytol induced ACOX1 to ameliorate alcoholic steatosis, which was not observed in the Pparα mice, implicating that the induction of ACOX1 is essential for protection against alcoholic steatosis. Phytol also enhanced ethanol metabolism, and among the ethanol metabolizing enzymes, only catalase was induced by phytol, suggesting that phytol enhances catalase-dependent ethanol metabolism. However, unlike WY-14,643, phytol induced catalase to enhance ethanol metabolism in a PPARα-independent manner because phytol but not WY-14,643 still induced catalase to enhance ethanol metabolism in the Pparα mice, suggesting that ACOX1 is dispensable for catalase-dependent ethanol metabolism. It is possible that when phytol cannot induce ACOX1 in the Pparα mice, phytol-derived pristanic acid is still oxidized by ACOX2 to generate HO for catalase metabolism of ethanol.
过氧化物酶体脂肪酸β氧化与过氧化氢酶依赖性乙醇代谢之间存在相互作用。HO对于过氧化氢酶代谢乙醇至关重要。过氧化物酶体脂肪酸β氧化限速酶是酰基辅酶A氧化酶（ACOX），其产生HO以供过氧化氢酶代谢乙醇。通常，ACOX1氧化极长链脂肪酸，ACOX2氧化支链脂肪酸。此前我们报道过，PPARα激动剂WY-14,643诱导ACOX1改善酒精性脂肪变性，且诱导的ACOX1与诱导的过氧化氢酶协同作用以增强乙醇代谢。在本研究中，我们检测了植醇对酒精性脂肪变性和乙醇代谢的影响。植醇是降植烷酸的前体，而降植烷酸是ACOX2的底物。植醇还可诱导ACOX1和过氧化氢酶。将植醇添加到Lieber-DeCarli液体饮食中，浓度高达0.2%。喂养3周后，植醇诱导ACOX1改善酒精性脂肪变性，而在Pparα基因敲除小鼠中未观察到这种现象，这表明ACOX1的诱导对于预防酒精性脂肪变性至关重要。植醇还增强了乙醇代谢，在乙醇代谢酶中，只有过氧化氢酶被植醇诱导，这表明植醇增强了过氧化氢酶依赖性乙醇代谢。然而，与WY-14,643不同，植醇以不依赖PPARα的方式诱导过氧化氢酶增强乙醇代谢，因为在Pparα基因敲除小鼠中，植醇而非WY-14,643仍能诱导过氧化氢酶增强乙醇代谢，这表明ACOX1对于过氧化氢酶依赖性乙醇代谢并非必需。有可能当植醇在Pparα基因敲除小鼠中无法诱导ACOX1时，植醇衍生的降植烷酸仍可被ACOX2氧化以产生HO用于乙醇的过氧化氢酶代谢。
