Lam Sum, Lui David T W, Fong Carol H Y, Wong Ying, Shiu Sammy W M, Lam Karen S L, Mak Lung-Yi, Yuen Man-Fung, Lee Chi-Ho, Tan Kathryn Choon-Beng
Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Sci Rep. 2025 Jul 1;15(1):21883. doi: 10.1038/s41598-025-06431-w.
Background Tsukushi (TSK), a recently identified hepatokine, has been shown to affect systemic cholesterol homeostasis and reduce HDL cholesterol (HDL-C) in murine studies. We have investigated whether TSK is associated with HDL-C and HDL function in subjects with and without MASLD. Methods Vibration-controlled transient elastography was performed in 896 subjects (63.1% with type 2 diabetes (T2D)). The presence of MASLD was defined as controlled attenuation parameter ≥ 248 dB/m with at least one cardiometabolic criteria. Serum TSK levels were measured by ELISA. Cholesterol efflux capacity (CEC), an indicator of HDL function, was determined by measuring the efflux of tritiated cholesterol from RAW264.7 macrophages to apolipoprotein B-depleted serum. Results Serum TSK levels were higher in subjects with MASLD than those without (p < 0.001) whereas plasma HDL-C and CEC (18.4 ± 5.2% versus 20.6 ± 6.2% respectively, p < 0.001) was significantly lower in MASLD subjects irrespective of the status of diabetes. Subgroup analysis stratified by the T2D and MASLD status showed that non-diabetic MASLD subjects had reduced CEC (p < 0.001). Interestingly, CEC was also reduced in diabetic subjects without MASLD (p < 0.001) suggesting that the status of T2D alone could affect the CEC of HDL, and the greatest degree of reduction in CEC was seen in subjects with both T2D and MASLD (p < 0.001). On multivariable linear regression analyses, TSK and HDL-C were significant independent determinants of CEC in both subjects with and without T2D after adjusting for hepatic steatosis and other potential confounders. Conclusion Elevated TSK level was negatively associated with HDL-C and CEC in subjects with MASLD, and the presence of T2D further exacerbated the reduction in CEC.
筑丝蛋白（TSK）是一种最近发现的肝脏因子，在小鼠研究中已显示其会影响全身胆固醇稳态并降低高密度脂蛋白胆固醇（HDL-C）。我们研究了TSK是否与有无代谢功能障碍相关脂肪性肝病（MASLD）的受试者的HDL-C及HDL功能有关。方法：对896名受试者进行了振动控制瞬时弹性成像检查（其中63.1%患有2型糖尿病（T2D））。MASLD的存在定义为控制衰减参数≥248 dB/m且至少符合一项心血管代谢标准。采用酶联免疫吸附测定法（ELISA）检测血清TSK水平。通过测量氚标记胆固醇从RAW264.7巨噬细胞向载脂蛋白B缺乏血清的流出量来确定胆固醇流出能力（CEC），这是HDL功能的一个指标。结果：患有MASLD的受试者血清TSK水平高于未患MASLD的受试者（p < 0.001），而无论糖尿病状态如何，MASLD受试者的血浆HDL-C和CEC（分别为18.4±5.2%和20.6±6.2%，p < 0.001）均显著降低。按T2D和MASLD状态分层的亚组分析显示，非糖尿病MASLD受试者的CEC降低（p < 0.001）。有趣的是，无MASLD的糖尿病受试者的CEC也降低（p < 0.001），这表明仅T2D状态就可能影响HDL的CEC，而CEC降低程度最大的是同时患有T2D和MASLD的受试者（p < 0.001）。在多变量线性回归分析中，在调整肝脂肪变性和其他潜在混杂因素后，TSK和HDL-C是患有和未患T2D的受试者CEC的显著独立决定因素。结论：在患有MASLD的受试者中，TSK水平升高与HDL-C和CEC呈负相关，且T2D的存在进一步加剧了CEC的降低。
