Targeting tissue crosstalk to combat non-alcoholic fatty liver disease

Non-alcoholic steatohepatitis (NASH) is a prevalent liver disease that affects up to 2-6% of the general population and 15-40% of obese persons.

NASH is characterized by steatosis, chronic inflammation and hepatocyte injury and is prone to progress into liver cirrhosis and liver cancer. However, despite tremendous efforts, there are currently no approved treatments for NASH.

NASH is closely linked to obesity, sarcopenia, dyslipidemia and insulin resistance and it has become clear that multiple extrahepatic tissues, including pancreas, skeletal muscle and adipose tissue produce signals that orchestrate hepatic metabolism, inflammation and fibrosis.

However, the underlying mechanisms in humans remain poorly understood.Here, we will integrate patient-derived ex vivo tissue models of liver, pancreas, skeletal muscle and fat to comprehensively map human metabolic crosstalk.

By analyzing the secretome from healthy and diseased individuals, we will identify novel endocrine signals that contribute to NASH etiology and progression.

Moreover, we will use the established platform to screen chemogenomic libraries to identify compounds that activate “healthy” signals or inhibit “disease” cues.

This project thus provides a conceptually novel perspective that considers NASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.