Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Cells. 2023 Jun 8;12(12):1582. doi: 10.3390/cells12121582.
Circadian rhythm governs many aspects of liver physiology and its disruption exacerbates chronic disease. CLOCKΔ19 mice disrupted circadian rhythm and spontaneously developed obesity and metabolic syndrome, a phenotype that parallels the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD represents an increasing health burden with an estimated incidence of around 25% and is associated with an increased risk of progression towards inflammation, fibrosis and carcinomas. Excessive extracellular matrix deposition (fibrosis) is the key driver of chronic disease progression. However, little attention was paid to the impact of disrupted circadian rhythm in hepatic stellate cells (HSCs) which are the primary mediator of fibrotic ECM deposition. Here, we showed in vitro and in vivo that liver fibrosis is significantly increased when circadian rhythm is disrupted by CLOCK mutation. Quiescent HSCs from CLOCKΔ19 mice showed higher expression of RhoGDI pathway components and accelerated activation. Genes altered in this primed CLOCKΔ19 qHSC state may provide biomarkers for early liver disease detection, and include AOC3, which correlated with disease severity in patient serum samples. Integration of CLOCKΔ19 microarray data with ATAC-seq data from WT qHSCs suggested a potential CLOCK regulome promoting a quiescent state and downregulating genes involved in cell projection assembly. CLOCKΔ19 mice showed higher baseline COL1 deposition and significantly worse fibrotic injury after CCl treatment. Our data demonstrate that disruption to circadian rhythm primes HSCs towards an accelerated fibrotic response which worsens liver disease.
昼夜节律调控着肝脏生理的诸多方面，其紊乱会加剧慢性疾病。ClockΔ19 小鼠的昼夜节律被打乱，会自发肥胖和代谢综合征，这一表型与非酒精性脂肪性肝病 (NAFLD) 的进展相似。NAFLD 给健康带来的负担日益加重，发病率约为 25%，与炎症、纤维化和癌前病变的进展风险增加有关。细胞外基质（纤维化）的过度沉积是慢性疾病进展的关键驱动因素。然而，人们对肝星状细胞（HSCs）中昼夜节律紊乱的影响关注甚少，HSCs 是纤维性 ECM 沉积的主要介导者。在这里，我们通过 Clock 突变在体外和体内显示，昼夜节律紊乱会显著增加肝脏纤维化。ClockΔ19 小鼠的静止 HSCs 表现出 RhoGDI 途径成分的高表达和加速激活。在这种被激活的 ClockΔ19 qHSC 状态下改变的基因可能为早期肝病检测提供生物标志物，包括与患者血清样本中疾病严重程度相关的 AOC3。ClockΔ19 微阵列数据与 WT qHSCs 的 ATAC-seq 数据的整合表明，一个潜在的 Clock 调控组可能会促进静止状态，并下调参与细胞突起组装的基因。ClockΔ19 小鼠在 CCl 处理后显示出更高的基线 COL1 沉积和更严重的纤维化损伤。我们的数据表明，昼夜节律紊乱使 HSCs 向加速纤维化反应发展，从而使肝病恶化。
