METHODS: We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy-proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H2O2 on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined.
RESULTS: Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H2O2 induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people.
CONCLUSIONS: Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy.
方法:我们在活检证实为MAFLD的队列中研究了端粒长度在瘦MAFLD发病机制中的作用(n=303)。我们测量了血清丙二醛(MDA)水平和肝8-羟基脱氧鸟苷(8-OHdG)和4-羟基-2-壬烯醛(4-HNE)表达(活性氧(ROS)标记),生长/分化因子-15(GDF-15),并测试了H2O2对肝细胞细胞系端粒长度和活性的影响。检查了白细胞端粒长度与死亡率之间的关联。
结果:精瘦MAFLD患者端粒长度显著降低(p<0.001)。他们还证明了ROS水平的增加和GDF-15的减少。H2O2诱导肝细胞端粒缩短和端粒活性降低。我们随后证实,基线端粒长度缩短与全因死亡率的危险增加有关;这种有害影响在瘦人中更为深远。
结论:端粒长度的差异部分解释了与非瘦的MAFLD患者相比,瘦的死亡率增加。该效应部分是通过ROS激活介导的,并提供治疗机会。