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Emergent properties of the HNF4Α-pparγ network may drive consequent phenotypic plasticity in NAFLD

Sahoo, S and Singh, D and Chakraborty, P and Jolly, MK (2020) Emergent properties of the HNF4Α-pparγ network may drive consequent phenotypic plasticity in NAFLD. In: Journal of Clinical Medicine, 9 (3).

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Official URL: https://doi.org/10.3390/jcm9030870


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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Item Type: Journal Article
Publication: Journal of Clinical Medicine
Publisher: MDPI
Additional Information: The copyright for this article belongs to the Authors.
Keywords: hepatocyte nuclear factor 4alpha; peroxisome proliferator activated receptor gamma, alcoholic fatty liver; Article; disease exacerbation; fatty acid metabolism; gene expression; gene interaction; gene regulatory network; human; lipogenesis; mathematical model; nonalcoholic fatty liver; phenotypic plasticity; protein expression; signal transduction; upregulation
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 24 Jan 2023 09:27
Last Modified: 24 Jan 2023 09:27
URI: https://eprints.iisc.ac.in/id/eprint/79401

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