Department of Molecular Biology, Semmelweis University, H-1085 Budapest, Hungary.
Nutrients. 2024 Sep 26;16(19):3259. doi: 10.3390/nu16193259.
A considerable proportion of the symptoms associated with excessive dietary intake can be attributed to systemic imbalances in lipid metabolism. The prominent toxicity of saturated fatty acids has been repeatedly demonstrated and sheds light on the protective role of stearoyl-CoA desaturase-1 (SCD1), the key enzyme for fatty acid desaturation. SCD1 protein expression is regulated at the levels of transcription, translation, and degradation. However, the modulating effect of the variability of the human genome must also be taken into account. Therefore, we aimed to ascertain whether natural missense or frameshift mutations in SCD1 (p.H125P, p.M224L, p.A333T, p.R253AfsTer7) could influence the expression, degradation, or function of the enzyme.
In silico and in vitro experiments were conducted to comprehensively evaluate the consequences associated with each genetic variation, with the objective of using the results to propose a risk or severity ranking of SCD1 variants.
As anticipated, the p.R253AfsTer7 variant was identified as the most deleterious in structural, functional, and quantitative terms. The p.H125P variant also reduced the desaturation capacity of the enzyme in accordance with the predicted structural alterations and augmented degradation resulting from folding complications. This was aggravated by increased mRNA instability and accompanied by mild endoplasmic reticulum stress induction. The p.A333T protein exhibited an intermediate phenotype, whereas p.M224L showed no deleterious effects and even increased the amount of SCD1.
In conclusion, the large-scale identification of genetic variations needs to be supplemented with comprehensive functional characterization of these variations to facilitate adequate personalized prevention and treatment of lipid metabolism-related conditions.
与过度饮食相关的许多症状都可以归因于脂质代谢的全身性失衡。饱和脂肪酸的显著毒性已被反复证明，这揭示了硬脂酰辅酶 A 去饱和酶-1（SCD1）的保护作用，SCD1 是脂肪酸去饱和的关键酶。SCD1 蛋白表达受转录、翻译和降解水平的调节。然而，还必须考虑人类基因组变异的调节作用。因此，我们旨在确定 SCD1 中的自然错义或移码突变（p.H125P、p.M224L、p.A333T、p.R253AfsTer7）是否会影响酶的表达、降解或功能。
进行了计算机模拟和体外实验，以全面评估与每种遗传变异相关的后果，旨在利用这些结果对 SCD1 变异体进行风险或严重程度的排序。
正如预期的那样，p.R253AfsTer7 变体被确定为在结构、功能和定量方面最具危害性的。p.H125P 变体也降低了酶的去饱和能力，这与预测的结构改变一致，并由于折叠复杂化导致降解增加。这加剧了 mRNA 不稳定性的增加，并伴有轻度内质网应激诱导。p.A333T 蛋白表现出中间表型，而 p.M224L 则没有有害影响，甚至增加了 SCD1 的数量。
总之，需要对遗传变异进行大规模的鉴定，并辅以对这些变异的全面功能特征分析，以促进对脂质代谢相关疾病的充分个性化预防和治疗。
