Gene regulatory networks in the progression and regression of human NASH

Non-Alcoholic Steatohepatitis (NASH) is affecting 3-5% of the global population and is a main cause of cirrhosis and hepatocellular carcinoma. NASH is often associated with overweight and Type-2 diabetes among adults, but increasingly, both, leaner and younger patients are seen in the clinic with inflammation and scar formation in their livers. At the cellular level, profound transcriptional changes in liver-resident cell types concur with the infiltration of innate immune cells. Complex crosstalk between cells and cell interactions with the extracellular matrix trigger both compensatory and self-reinforcing pathogenic mechanisms, which obscure causality.

In this project we combine RNA-sequencing, single-cell RNA-sequencing, mass spectrometry, and multiplexed single-molecule FISH to analyze hepatic changes in bariatric patients enrolled in a prospective study. Our aim is to clarify cellular interactions and understand NASH development and resolution at the molecular level.

Project description by postdoc Frederik Tibert Larsen

Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), is the hepatic manifestation of obesity-induced metabolic syndrome. NASH can progress to liver cirrhosis and eventually hepatocellular carcinoma. NASH may regress if the aetiological agent is removed by approaches such as lifestyle or surgical intervention. In the Ravnskjaer group aim to understand the transcriptional program related to human NASH regression by investigating the dynamic transcriptional and hepatocellular changes over time. Through a collaboration with hepatologists, we have collected liver biopsies from severely obese individuals enrolled in a surgical weight-loss program. Using advanced microscopy-based methods and RNA sequencing approaches such as spatial- and single-cell RNA sequencing we illuminate the transcriptional and hepatocellular changes during NASH regression.