Circadian Disruption Primes Myofibroblasts for Accelerated Activation as a Mechanism Underpinning Fibrotic Progression in Non-Alcoholic Fatty Liver Disease.
Circadian Disruption Primes Myofibroblasts for Accelerated Activation as a Mechanism Underpinning Fibrotic Progression in Non-Alcoholic Fatty Liver Disease.
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DOI：
10.3390/cells12121582
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发表时间：
2023-06-08
期刊：
影响因子：
6
通讯作者：
Piper Hanley, Karen
中科院分区：
文献类型：
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作者：
Jokl, Elliot;Llewellyn, Jessica;Simpson, Kara;Adegboye, Oluwatobi;Pritchett, James;Zeef, Leo;Donaldson, Ian;Athwal, Varinder S.;Purssell, Huw;Street, Oliver;Bennett, Lucy;Guha, Indra Neil;Hanley, Neil A.;Meng, Qing-Jun;Piper Hanley, Karen
昼夜节律支配肝脏生理的许多方面，其破坏会加剧慢性疾病。CLOCKΔ19小鼠打乱了昼夜节律，自发发展为肥胖和代谢综合征，这是一种与非酒精性脂肪性肝病（NAFLD）进展平行的表型。NAFLD代表着日益增加的健康负担，估计发病率约为25%，并与炎症，纤维化和癌症进展的风险增加有关。过度的细胞外基质沉积（纤维化）是慢性疾病进展的关键驱动因素。然而，很少有人注意到破坏昼夜节律的影响，肝星状细胞（HSC），这是纤维化ECM沉积的主要介质。在这里，我们在体外和体内表明，当昼夜节律被CLOCK突变破坏时，肝纤维化显著增加。来自CLOCKΔ19小鼠的静止HSC显示RhoGDI通路组分的更高表达和加速活化。在这种启动的CLOCKΔ19 qHSC状态中改变的基因可能为早期肝病检测提供生物标志物，包括AOC 3，其与患者血清样品中的疾病严重程度相关。CLOCKΔ19微阵列数据与来自WT qHSC的ATAC-seq数据的整合表明潜在的CLOCK调节组促进静止状态并下调参与细胞投射组装的基因。CLOCKΔ19小鼠在CCl 4处理后显示出较高的基线COL 1沉积和显著更差的纤维化损伤。我们的数据表明，对昼夜节律的破坏使HSC向加速的纤维化反应启动，这会导致肝脏疾病。
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 CCl4 treatment. Our data demonstrate that disruption to circadian rhythm primes HSCs towards an accelerated fibrotic response which worsens liver disease.
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