Targeting adipose tissue-liver cross talk 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, dyslipidemia and insulin resistance and it has become clear that that the adipose tissue produces many signals that control hepatic metabolism, inflammation and fibrosis.

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

By analyzing the secretome of adipose tissue from lean insulin-sensitive and obese insulin-resistant individuals, we will identify novel endocrine signals of human fat that promote or prevent NASH.

Moreover, we will use the established platform to screen libraries of lead-like molecules 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.