DS0411 - Recherche translationnelle en santé

NASH and type 2 Diabetes: role of the Receptor Activator of Nuclear factor-kB (RANK) and its ligand (RANKL) – NADRANK

Submission summary

Non-alcoholic fatty liver diseases (NAFLD) include several entities ranging from simple steatosis to hepatic fibrosis or cirrhosis. Steatosis, considered benign and the first stage of the disease, is characterized by the accumulation of triglycerides in the liver. It may in some cases progress to nonalcoholic steatohepatitis (NASH), which is characterized by the presence of a marked inflammation with or without fibrosis. NAFLD is the most common liver disease in the world and is particularly associated with type 2 diabetes (T2D) (80% in the diabetic population). While NASH is characterized by a higher prevalence of mortality from a cardiac and hepatic (cirrhosis and cancer) origin, therapeutic resources are almost non-existent.
RANK (receptor activator of NF-kB) and its ligand RANKL (a member of the TNFalpha family) have emerged in recent years as new players in bone pathophysiology. By binding to its receptor, RANKL induces a number of signaling pathway and in particular the NF-kB pathway (Nuclear factor-kB), a major player in inflammation. Recent literature shows that the role of RANK / RANKL is not confined to the bone but may be involved in the genesis of inflammation in other tissues. It has been shown recently that a high circulating level of RANKL was a risk factor predictor of T2DM. Furthermore, the invalidation of RANK specifically in hepatocytes protects from insulin resistance and hepatic steatosis induced by a high fat diet in mice.
The aim of our project is to provide a proof of concept that the RANKL / RANK system plays an important role in the pathogenesis of NAFLD and in the progression of this disease to NASH.
We propose to study the RANKL / RANK system in animals and humans (3 observational studies and one intervention study). In animals, we will study the role of this system (i) in the development of hepatic steatosis, inflammation and fibrosis. These studies will be carried out: in vitro in primary cultures of hepatocytes, Kupffer cells (responsible for inflammation), stellate liver cells (responsible for fibrosis) and adipocytes, which will be treated by the ligand RANKL, and in vivo in mice invalidated specifically for RANK in these different cell types (floxed-RANK mice crossed with the appropriate Cre mice).
In humans we will study in 3 cohorts of patients (already established) developing an NAFLD, the expression of various actors of the RANK / RANKL system in the liver, the adipose tissue and serum. In the first study, we will use the liver tissues and sera from 60 patients at various stages of NAFLD (already constituted bank of tissues and serum of patients with a biopsy (Hepatology Unit)). In the second study, we will use the database DIACART conducted in type 2 diabetic patients (PHRC 2012 - Diabetology Unit, last inclusions planned in December 2015) that contains data on biomarkers of steatosis, NASH and fibrosis and determination of serum RANKL for 200 patients. In the third study, we will use sera and adipose tissue of healthy and obese patients (Geoffroy St Hilaire clinic). Finally we will perform an interventional study to inhibit RANKL action by denosumab, a monoclonal antibody (IgG2) that is used in clinical practice for the treatment of osteoporosis. This study will be conducted in patients with NAFLD and osteoporosis in order to show that inhibiting RANK / RANKL limits the development and progression of NAFLD. This translational project could therefore have a significant and rapid therapeutic benefit in the field of NAFLD.

Project coordinator

Madame Fabienne FOUFELLE (UMRS1138)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

AP/HP Service de Rhumatologie CHU Pitié Salpétrière
AP/HP Service de radiologie centrale CHU Pitié Salpétrière
AP/HP Centre d'Investigation Clinique Paris-Est CHU Pitié-Salpêtrière
AP/HP Service de Diabétologie CHU Pitié-Salpêtrière
AP/HP Service d'hépato-gastro-entérologie CHU Pitié Salpétrière
INSERM UMRS1138

Help of the ANR 329,680 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

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