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首页> 外文期刊>Journal of Clinical Medicine >Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD
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Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD

机译：HNF4α-PPARγ网络的紧急性质可能会在NAFLD中推动随后的表型可塑性

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Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decoded the emergent dynamics of underlying gene regulatory networks that were identified to drive the initiation and the progression of NAFLD. We developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a “hybrid” adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD.
机译：非酒精性脂肪肝病（NAFLD）是成人和儿童中最常见的慢性肝病形式。它的特征在于没有任何过量的酒精摄入量的患者肝细胞中脂质的过度积累。全球存在24％和有限的治疗选择，NAFLD的疾病负担正在增加。因此，必须在系统级别了解疾病进展的动态成为必要的。在这里，我们解释了所识别的基因监管网络的紧急动态，该网络被识别出来推动爆发和NAFLD的进展。我们开发了一种数学模型来阐明HNF4α-PPARγ基因监管网络的动态。我们的模拟表明，该网络可以在某些生物条件下实现多种共存表型：脂肪细胞，肝细胞和肝细胞的“杂交”脂肪细胞样状态。这些表型也可以彼此之间切换，从而能够实现表型可塑性，从而使得同时放松能够保持肝脏身份和/或促进脂肪细胞性状的部分或完全获取的分子水平。这些预测趋势得到了临床数据的分析，进一步证实了表型可塑性在驾驶NAFLD方面的推定作用。我们的结果解开了潜在的监管网络的紧急动态如何促进表型可塑性，从而推动临床观察到的基因表达的变化通常与NAFLD相关。

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