Department of Life Sciences, Chosun University College of Natural Science, Gwangju, Korea.
Department of Pharmacy, Kyungsung University College of Pharmacy, Busan, Korea.
Endocrinol Metab (Seoul). 2024 Feb;39(1):127-139. doi: 10.3803/EnM.2023.1826. Epub 2024 Feb 22.
Hepatic steatosis, which involves the excessive accumulation of lipid droplets in hepatocytes, presents a significant global health concern due to its association with obesity and metabolic disorders. Inflammation plays a crucial role in the progression of hepatic steatosis; however, the precise molecular mechanisms responsible for this process remain unknown.
This study investigated the involvement of the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome and the forkhead box O6 (FoxO6) transcription factor in the pathogenesis of hepatic steatosis. We monitored the NLRP3 inflammasome and lipogenesis in mice overexpressing the constitutively active (CA)-FoxO6 allele and FoxO6-null mice. In an in vitro study, we administered palmitate to liver cells overexpressing CA-FoxO6 and measured changes in lipid metabolism.
We administered palmitate treatment to clarify the mechanisms through which FoxO6 activates cytokine interleukin (IL)-1β through the NLRP3 inflammasome. The initial experiments revealed that dephosphorylation led to palmitate-induced FoxO6 transcriptional activity. Further palmitate experiments showed increased expression of IL-1β and the hepatic NLRP3 inflammasome complex, including adaptor protein apoptotic speck protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Furthermore, thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox conditions upstream of the NLRP3 inflammasome, was induced by FoxO6 in the liver and HepG2 cells.
The findings of this study shed light on the molecular mechanisms underpinning the FoxO6-NLRP3 inflammasome axis in promoting inflammation and lipid accumulation in the liver.
肝脂肪变性涉及肝细胞内脂质滴的过度积累，由于与肥胖和代谢紊乱有关，因此成为一个重大的全球健康问题。炎症在肝脂肪变性的进展中起着关键作用；然而，导致这一过程的确切分子机制尚不清楚。
本研究探讨核苷酸结合寡聚化结构域样受体含吡咯结构域蛋白 3（NLRP3）炎性小体和叉头框 O6（FoxO6）转录因子在肝脂肪变性发病机制中的作用。我们监测了过表达组成型激活（CA）-FoxO6 等位基因的小鼠和 FoxO6 缺失小鼠中的 NLRP3 炎性小体和脂生成。在一项体外研究中，我们用棕榈酸处理过表达 CA-FoxO6 的肝细胞，并测量脂质代谢的变化。
我们用棕榈酸处理来阐明 FoxO6 通过 NLRP3 炎性小体激活细胞因子白细胞介素（IL）-1β的机制。最初的实验表明，去磷酸化导致棕榈酸诱导的 FoxO6 转录活性。进一步的棕榈酸实验显示，IL-1β和肝脏 NLRP3 炎性小体复合物（包括衔接蛋白凋亡斑点样蛋白含有半胱氨酸蛋白酶募集结构域（ASC）和前胱天蛋白酶-1）的表达增加。此外，FoxO6 在肝脏和 HepG2 细胞中诱导了硫氧还蛋白相互作用蛋白（TXNIP），这是 NLRP3 炎性小体上游细胞氧化还原状态的关键调节剂。
本研究结果揭示了 FoxO6-NLRP3 炎性小体轴在促进肝脏炎症和脂质积累中的分子机制。
