Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cells. 2024 Oct 12;13(20):1687. doi: 10.3390/cells13201687.
"Bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during mouse brain development, facilitating the activation of long-chain fatty acids (LCFA) and their incorporation into lipid species that are crucial for brain function. ACSBG1 converts LCFA into acyl-CoA derivatives, supporting vital metabolic processes. Fruit fly mutants lacking ACSBG1 exhibited neurodegeneration and had elevated levels of very long-chain fatty acids (VLCFA), characteristics of human X-linked adrenoleukodystrophy (XALD). To explore ACSBG1's function and potential as a therapeutic target in XALD, we created an ACSBG1 knockout (Acsbg1) mouse and examined the effects on brain FA metabolism during development. Phenotypically, Acsbg1 mice resembled wild type (w.t.) mice. ACSBG1 expression was found mainly in tissue affected pathologically in XALD, namely the brain, adrenal gland and testis. ACSBG1 depletion did not significantly reduce the total ACS enzyme activity in these tissue types. In adult mouse brain, ACSBG1 expression was highest in the cerebellum; the low levels detected during the first week of life dramatically increased thereafter. Unexpectedly, lower, rather than higher, saturated VLCFA levels were found in cerebella from Acsbg1 vs. w.t. mice, especially after one week of age. Developmental changes in monounsaturated ω9 FA and polyunsaturated ω3 FA levels also differed between w.t. and Acsbg1 mice. ACSBG1 deficiency impacted the developmental expression of several cerebellar FA metabolism enzymes, including those required for the synthesis of ω3 polyunsaturated FA, precursors of bioactive signaling molecules like eicosanoids and docosanoids. These changes in membrane lipid FA composition likely affect membrane fluidity and may thus influence the body's response to inflammation. We conclude that, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD, decreasing its potential as a therapeutic target. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.
“泡泡糖”酰基辅酶 A 合成酶 (ACSBG1) 是小鼠大脑发育过程中脂质代谢的关键因子，促进长链脂肪酸 (LCFA) 的激活及其掺入对脑功能至关重要的脂质物种。ACSBG1 将 LCFA 转化为酰基辅酶 A 衍生物，支持重要的代谢过程。缺乏 ACSBG1 的果蝇突变体表现出神经退行性变，并且非常长链脂肪酸 (VLCFA) 水平升高，这是人类 X 连锁肾上腺脑白质营养不良 (XALD) 的特征。为了探索 ACSBG1 在 XALD 中的功能和作为治疗靶点的潜力，我们创建了 ACSBG1 敲除 (Acsbg1) 小鼠，并研究了其对发育过程中脑 FA 代谢的影响。表型上，Acsbg1 小鼠与野生型 (w.t.) 小鼠相似。ACSBG1 表达主要在 XALD 病理上受影响的组织中发现，即大脑、肾上腺和睾丸。ACSBG1 耗竭并未显著降低这些组织类型中的总 ACS 酶活性。在成年小鼠大脑中，ACSBG1 表达在小脑最高；生命第一周检测到的低水平此后急剧增加。出乎意料的是，与 w.t. 小鼠相比，Acsbg1 小鼠小脑中的饱和 VLCFA 水平较低，而不是较高，尤其是在一周龄以后。w.t. 和 Acsbg1 小鼠之间，ω9 单不饱和 FA 和 ω3 多不饱和 FA 水平的发育变化也不同。ACSBG1 缺乏会影响几种小脑 FA 代谢酶的发育表达，包括合成生物活性信号分子如类二十烷酸和 docosanoids 的前体所需的酶。膜脂 FA 组成的这些变化可能会影响膜的流动性，并因此影响身体对炎症的反应。我们得出结论，尽管有令人信服的间接证据，但 ACSBG1 不太可能直接导致 XALD 的病理学，降低了其作为治疗靶点的潜力。相反，应该进一步研究 ACSBG1 敲除对类二十烷酸和/或 docosanoids 调节的过程的影响。
