Non-alcoholic steatohepatitis (NASH) is a serious inflammatory disease that affects and gradually destroys the liver. It is a more advanced form of another condition known as non-alcoholic fatty liver disease (NAFLD), which is characterized by a build-up of fats in the same organ. By deciphering the mechanisms associated with the transition from NAFLD to NASH, Joel Haas hopes to discover prognostic biomarkers and therapeutic targets to counter this harmful progression. Europe has put its trust in him to the tune of €1.5 million in funding.
Affecting nearly 20% of French people and 25% to 30% of the world’s population, non-alcoholic fatty liver disease (NAFLD) is considered the scourge of the century from the metabolic point of view. It corresponds to a build-up of fats in the liver that, although not serious to begin with, marks the first stage of a continuum towards the development of serious liver diseases, namely non-alcoholic steatohepatitis (NASH) characterized by chronic inflammation, followed by fibrosis, and cirrhosis which itself can lead to liver cancer. Joel Haas, Research Fellow at Inserm, decided to explore the molecular mechanisms associated with this progression.
Originally from Iowa in the USA, Haas came to France in 2013 in order to follow his wife, a lecturer in Lille. Doctorate in hand, he knocked on the door of the Inserm laboratory led by Bart Staels at Institut Pasteur in Lille. Staels’s team was studying inter-organ dialogues in cardiometabolic diseases, a theme that was a perfect match for his tastes and expertise: « I had always enjoyed molecular exploration and was already interested in metabolic disorders because they affect a large part of the general population.I had studied the molecular mechanisms induced by insulin resistance in the liver, and those associated with regulating lipid metabolism in this organ, » he explains. So he joined the Lille team with the mission of studying the progression between a simple build-up of fat in the liver and the development of harmful chronic inflammation, in other words: progression from NAFL to NASH.
The immune cells at play
Quickly, he discovered that in humans this development is accompanied by an activation of the hepatic immune system, which particularly involves the dendritic cells. « One of the great strengths of French research is the strong interaction between scientists and clinicians. Something that was already in place when I arrived in Lille. We work with François Pattou, an obesity surgeon in Lille, and Sven Francque, head of the Department of Gastroenterology and Hepatology in Antwerp. They each have a cohort of patients with NAFLD or NASH and provide us with high levels of clinical expertise and patient biological samples, such as liver biopsies and blood samples. This allows us to work directly in humans. » Haas’s team has also been able to study biopsies from patients having undergone bariatric surgery – a procedure known to cause NASH to regress by causing massive weight loss. « In these samples, we found less dendritic cell activation, indicating a very strong correlation between the activity of these cells and patient liver health. »
A stronger team
In a wish to take things further, Haas applied for a European Research Council (ERC) Starting Grant and obtained €1.5 million to explore the molecular transformations associated with the progression from steatosis to NASH. With the purchase of a mass spectrometer to assay the various metabolites in different samples, the development of mouse models, the recruitment of researchers, etc., Haas is now able to pull out all the stops to identify biomarkers of risk of progression of NAFLD and associated complications, as well as discover new therapeutic targets to prevent them. « This European funding is a real accelerator of research. I am very optimistic for the future! » he concludes.
Joel Hass is developing his research as part of the Nuclear Receptors in Metabolic Syndrome team, in the Nuclear Receptors, Metabolic and Cardiovascular Diseases Unit (Inserm Unit 1011/Institut Pasteur/University of Lille/University Hospital Lille), at Institut Pasteur in Lille.