Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly, and unmet treatment can result in the development of hepatitis, fibrosis, and liver failure. There are difficulties involved in diagnosing NAFLD early and for this reason there are challenges involved in its treatment. Furthermore, no drugs are currently approved to alleviate complications, a fact which highlights the need for further insight into disease mechanisms. NAFLD pathogenesis is associated with complex cellular changes, including hepatocyte steatosis, immune cell infiltration, endothelial dysfunction, hepatic stellate cell activation, and epithelial ductular reaction. Many of these cellular changes are controlled by dramatic changes in gene expression orchestrated by the cis-regulatory genome and associated transcription factors. Thus, to understand disease mechanisms, we need extensive insights into the gene regulatory mechanisms associated with tissue remodeling. Mapping cis-regulatory regions genome-wide is a step towards this objective and several current and emerging technologies allow detection of accessible chromatin and specific histone modifications in enriched cell populations of the liver, as well as in single cells. Here, we discuss recent insights into the cis-regulatory genome in NAFLD both at the organ-level and in specific cell populations of the liver. Moreover, we highlight emerging technologies that enable single-cell resolved analysis of the cis-regulatory genome of the liver.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is driven by a western lifestyle-associated increased flux of lipids and carbohydrates into the liver and remodeling of the gutmicrobiome [1–3]
Failure of the parenchymal hepatocytes to cope with the chronically high lipid load is a critical event in NAFLD pathology, and the consequential lipotoxicity triggers a cascade of pathogenic events in the non-parenchymal cell populations such as the activation of Kupffer cells (KCs), immune cell infiltration, liver sinusoidal endothelial cell (LSEC) capillarization, hepatic stellate cell (HSC) activation, and epithelial ductular reaction comprising activation, proliferation, and potential transdifferentiation amongst cholangiocytes, bipotent biliary progenitor cells or hepatocytes, or a combination of these [2,4–8]
Genomics studies of intact liver tissue have provided some general insights into the cis-regulatory landscape involved in the development of NAFLD
Summary
Non-alcoholic fatty liver disease (NAFLD) is driven by a western lifestyle-associated increased flux of lipids and carbohydrates into the liver and remodeling of the gutmicrobiome [1–3]. Failure of the parenchymal hepatocytes to cope with the chronically high lipid load is a critical event in NAFLD pathology, and the consequential lipotoxicity triggers a cascade of pathogenic events in the non-parenchymal cell populations such as the activation of Kupffer cells (KCs), immune cell infiltration, liver sinusoidal endothelial cell (LSEC) capillarization, hepatic stellate cell (HSC) activation, and epithelial ductular reaction comprising activation, proliferation, and potential transdifferentiation amongst cholangiocytes, bipotent biliary progenitor cells or hepatocytes, or a combination of these [2,4–8] This causes dramatic alterations of tissue architecture and function that may lead to NASH and can result in cirrhosis and liver failure [2,9]. We feature emerging single-cell epigenetic technologies used to study cell-type-resolved gene regulatory networks in NAFLD, which we foresee will open up important new avenues of diagnosis and therapy possibilities in the coming years
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
