{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T23:27:00Z","timestamp":1778628420921,"version":"3.51.4"},"reference-count":90,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,22]],"date-time":"2020-03-22T00:00:00Z","timestamp":1584835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","award":["SB\/S2\/RJN-049\/2018"],"award-info":[{"award-number":["SB\/S2\/RJN-049\/2018"]}],"id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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 HNF4\u03b1-PPAR\u03b3 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 \u201chybrid\u201d 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.<\/jats:p>","DOI":"10.3390\/jcm9030870","type":"journal-article","created":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T13:04:04Z","timestamp":1585055044000},"page":"870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Emergent Properties of the HNF4\u03b1-PPAR\u03b3 Network May Drive Consequent Phenotypic Plasticity in NAFLD"],"prefix":"10.3390","volume":"9","author":[{"given":"Sarthak","family":"Sahoo","sequence":"first","affiliation":[{"name":"Undergraduate Programme, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1552-2701","authenticated-orcid":false,"given":"Divyoj","family":"Singh","sequence":"additional","affiliation":[{"name":"Undergraduate Programme, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyanka","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-2109","authenticated-orcid":false,"given":"Mohit Kumar","family":"Jolly","sequence":"additional","affiliation":[{"name":"Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. 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