| First Author | Jokl E | Year | 2023 |
| Journal | Cells | Volume | 12 |
| Issue | 12 | PubMed ID | 37371052 |
| Mgi Jnum | J:337452 | Mgi Id | MGI:7494603 |
| Doi | 10.3390/cells12121582 | Citation | Jokl E, et al. (2023) Circadian Disruption Primes Myofibroblasts for Accelerated Activation as a Mechanism Underpinning Fibrotic Progression in Non-Alcoholic Fatty Liver Disease. Cells 12(12) |
| abstractText | Circadian rhythm governs many aspects of liver physiology and its disruption exacerbates chronic disease. CLOCKDelta19 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 CLOCKDelta19 mice showed higher expression of RhoGDI pathway components and accelerated activation. Genes altered in this primed CLOCKDelta19 qHSC state may provide biomarkers for early liver disease detection, and include AOC3, which correlated with disease severity in patient serum samples. Integration of CLOCKDelta19 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. CLOCKDelta19 mice showed higher baseline COL1 deposition and significantly worse fibrotic injury after CCl(4) treatment. Our data demonstrate that disruption to circadian rhythm primes HSCs towards an accelerated fibrotic response which worsens liver disease. |
