Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China.
Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China.
Lipids Health Dis. 2024 May 17;23(1):144. doi: 10.1186/s12944-024-02126-9.
Cancer-associated cachexia (CAC) arises from malignant tumors and leads to a debilitating wasting syndrome. In the pathophysiology of CAC, the depletion of fat plays an important role. The mechanisms of CAC-induced fat loss include the enhancement of lipolysis, inhibition of lipogenesis, and browning of white adipose tissue (WAT). However, few lipid-metabolic enzymes have been reported to be involved in CAC. This study hypothesized that ELOVL6, a critical enzyme for the elongation of fatty acids, may be involved in fat loss in CAC.
Transcriptome sequencing technology was used to identify CAC-related genes in the WAT of a CAC rodent model. Then, the expression level of ELOVL6 and the fatty acid composition were analyzed in a large clinical sample. Elovl6 was knocked down by siRNA in 3T3-L1 mouse preadipocytes to compare with wild-type 3T3-L1 cells treated with tumor cell conditioned medium.
In the WAT of patients with CAC, a significant decrease in the expression of ELOVL6 was found, which was linearly correlated with the extent of body mass reduction. Gas chromatographic analysis revealed an increase in palmitic acid (C16:0) and a decrease in linoleic acid (C18:2n-6) in these tissue samples. After treatment with tumor cell-conditioned medium, 3T3-L1 mouse preadipocytes showed a decrease in Elovl6 expression, and Elovl6-knockdown cells exhibited a reduction in preadipocyte differentiation and lipogenesis. Similarly, the knockdown of Elovl6 in 3T3-L1 cells resulted in a significant increase in palmitic acid (C16:0) and a marked decrease in oleic acid (C18:1n-9) content.
Overall, the expression of ELOVL6 was decreased in the WAT of CAC patients. Decreased expression of ELOVL6 might induce fat loss in CAC patients by potentially altering the fatty acid composition of adipocytes. These findings suggest that ELOVL6 may be used as a valuable biomarker for the early diagnosis of CAC and may hold promise as a target for future therapies.
癌症相关性恶病质（CAC）由恶性肿瘤引起，导致衰弱性消耗综合征。在 CAC 的病理生理学中，脂肪的消耗起着重要作用。CAC 引起的脂肪损失的机制包括脂解增强、脂肪生成抑制和白色脂肪组织（WAT）的褐色化。然而，很少有脂质代谢酶被报道参与 CAC。本研究假设，脂肪酸延长的关键酶 ELOVL6 可能参与 CAC 中的脂肪损失。
使用转录组测序技术鉴定 CAC 啮齿动物模型 WAT 中的 CAC 相关基因。然后，在大的临床样本中分析 ELOVL6 的表达水平和脂肪酸组成。用 siRNA 敲低 3T3-L1 小鼠前脂肪细胞中的 Elovl6，与用肿瘤细胞条件培养基处理的野生型 3T3-L1 细胞进行比较。
在 CAC 患者的 WAT 中，发现 ELOVL6 的表达显著降低，与体重减轻程度呈线性相关。气相色谱分析显示这些组织样本中的棕榈酸（C16:0）增加，亚油酸（C18:2n-6）减少。用肿瘤细胞条件培养基处理后，3T3-L1 小鼠前脂肪细胞的 Elovl6 表达下降，Elovl6 敲低细胞的前脂肪细胞分化和脂肪生成减少。同样，3T3-L1 细胞中 Elovl6 的敲低导致棕榈酸（C16:0）显著增加，油酸（C18:1n-9）含量明显减少。
总体而言，CAC 患者的 WAT 中 ELOVL6 的表达降低。ELOVL6 表达降低可能通过潜在改变脂肪细胞的脂肪酸组成导致 CAC 患者的脂肪损失。这些发现表明，ELOVL6 可用作 CAC 早期诊断的有价值的生物标志物，并可能成为未来治疗的靶点。
