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The Association between SOCS1−1656G>A Polymorphism, Insulin Resistance and Obesity in Nonalcoholic Fatty Liver Disease (NAFLD) Patients
Open AccessArticle

Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD

1
Undergraduate Programme, Indian Institute of Science, Bangalore 560012, India
2
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
J. Clin. Med. 2020, 9(3), 870; https://doi.org/10.3390/jcm9030870
Received: 18 February 2020 / Revised: 15 March 2020 / Accepted: 18 March 2020 / Published: 22 March 2020
(This article belongs to the Special Issue Non-Alcoholic Steatohepatitis (NASH))
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. View Full-Text
Keywords: NAFLD; NASH; phenotypic plasticity; mathematical modeling; systems biology; HNF4a; PPARg NAFLD; NASH; phenotypic plasticity; mathematical modeling; systems biology; HNF4a; PPARg
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MDPI and ACS Style

Sahoo, S.; Singh, D.; Chakraborty, P.; Jolly, M.K. Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD. J. Clin. Med. 2020, 9, 870.

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