Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei 230027, China.
Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei 230027, China.
Sci Bull (Beijing). 2023 Jul 15;68(13):1413-1429. doi: 10.1016/j.scib.2023.06.003. Epub 2023 Jun 7.
Hepatic insulin resistance (IR), as a downstream sequela of nonalcoholic fatty liver disease (NAFLD), is strongly associated with liver steatosis. Despite numerous mechanism advancements, the molecular underpinnings and pathogenesis of hepatic IR, especially regarding the pattern recognition receptors in hepatocytes, remain elusive. Here, we identified hepatocyte NLRP3 as a direct and previously-unresolved driver of hepatic IR to promote steatosis response. Under the model of NAFLD, we identified hepatocyte NLRP3 as a crucial inducer of hepatic IR by undertaking multilayer transcriptomic searches and further confirmed that its expression was increased in the liver tissues from NAFLD patients and mouse models (high-fat diet (HFD), leptin-receptor-deficient (db/db) mice), and in palmitic acid (PA)-induced hepatocytes. Loss- or gain-of-function of hepatocyte-specific NLRP3 in HFD-induced mice ameliorated or exacerbated hepatic IR and steatosis, respectively. Mechanistically, NLRP3 directly bound to and promoted protein kinase C epsilon (PKCε) activation to impair insulin signaling and increase liver steatosis, while inhibition of PKCε activation dampened the beneficial effects seen in HFD-induced NLRP3-deficient mice. Moreover, we performed screening and discovered that the transcription factor Yin Yang 1 (YY1) positively controlled NLRP3 expression. In translational potential, adeno-associated virus serotype 8 (AAV8)-mediated NLRP3 knockdown in the liver alleviated hepatic IR and steatosis in db/db mice, and pharmacological inhibition of NLRP3 markedly alleviated diet-induced metabolic disorders. This finding reveals a previously-unexpected regulatory axis from YY1 to PKCε via NLRP3 induction for metabolic diseases and establishes the YY1-NLRP3-PKCε axis as a potential therapeutic target for NAFLD.
肝脏胰岛素抵抗（IR）作为非酒精性脂肪性肝病（NAFLD）的下游后果，与肝脂肪变性密切相关。尽管有许多机制进展，但肝脏 IR 的分子基础和发病机制，尤其是关于肝细胞中模式识别受体的机制，仍然难以捉摸。在这里，我们发现肝细胞 NLRP3 是肝脏 IR 的直接且以前未解决的驱动因素，可促进脂肪变性反应。在 NAFLD 模型中，我们通过进行多层转录组搜索，确定了肝细胞 NLRP3 是肝脏 IR 的关键诱导剂，并进一步证实其在 NAFLD 患者和小鼠模型（高脂肪饮食（HFD）、瘦素受体缺陷（db/db）小鼠）的肝组织中表达增加，以及在棕榈酸（PA）诱导的肝细胞中表达增加。在 HFD 诱导的小鼠中敲除或过表达肝细胞特异性 NLRP3 分别改善或加剧肝脏 IR 和脂肪变性。从机制上讲，NLRP3 直接结合并促进蛋白激酶 C ɛ（PKCε）激活，从而损害胰岛素信号转导并增加肝脏脂肪变性，而抑制 PKCε 激活则减弱了 HFD 诱导的 NLRP3 缺陷型小鼠中观察到的有益作用。此外，我们进行了筛选并发现转录因子 Yin Yang 1（YY1）正向控制 NLRP3 的表达。在翻译潜力方面，肝脏中腺相关病毒血清型 8（AAV8）介导的 NLRP3 敲低可减轻 db/db 小鼠的肝脏 IR 和脂肪变性，NLRP3 的药理学抑制可显著减轻饮食引起的代谢紊乱。这一发现揭示了一条以前未被发现的从 YY1 到 PKCε 的调节轴，通过 NLRP3 诱导用于代谢疾病，并确立了 YY1-NLRP3-PKCε 轴作为 NAFLD 的潜在治疗靶点。
