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

Sarthak Sahoo,Divyoj Singh,Mohit Kumar Jolly,Priyanka Chakraborty

doi:10.3390/jcm9030870

Sarthak Sahoo, Divyoj Singh + Show 2 more

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https://doi.org/10.3390/jcm9030870

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Abstract

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.

Highlights

The dawn of the 21st century has seen a major global outbreak of obesity and metabolic syndrome
Our results show that, during non-alcoholic fatty liver disease (NAFLD), cells can switch their phenotype from being a hepatocyte to a hybrid adipocyte-like state and vice versa, controlling phenotypic plasticity in the context of NAFLD
We found that, in the biologically relevant range of parameters under which NAFLD seems to be operating, hepatocytes may undergo a phenotypic switch to a hybrid adipocyte-like state of hepatocyte by partially activating the adipogenic program. 3.4

Summary

Introduction

The dawn of the 21st century has seen a major global outbreak of obesity and metabolic syndrome. In 2016, the World Health Organization (WHO) estimated that nearly two billion people are either overweight or obese. Primary factors driving this non-communicable epidemic are caloric excess and a sedentary lifestyle, leading to chronic diseases [1]. In the liver, these chronic diseases manifest as non-alcoholic fatty liver disease (NAFLD). These chronic diseases manifest as non-alcoholic fatty liver disease (NAFLD) It is the most common form of chronic liver disease among adults and children, with a global prevalence of 24% [1,2]. In a small fraction of cases, it can progress to form hepatocellular carcinoma (HCC) [2]

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