NAFLD Clinical Trial
Official title:
NASH and Type 2 Diabetes: Role of the Receptor Activator of Nuclear Factor-κB (RANK) and Its Ligand (RANKL)
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.
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.
The investigator propose to study the RANKL / RANK expression in serum and liver biopsies of
type 2 diabetic patients at different stages of NAFLD.
Objectives:
To show that (i) expression of mRNA and proteins of the RANKL pathway (RANK, RANKL, OPG) in
liver and (ii) serum concentration of RANKL/OPG proteins are correlated with the gravity of
the NAFLD.
Study protocol:
Identify patients with different stages of NAFLD (mere steatosis, NASH, and moderate or
advanced fibrosis) from the database of patients who have undergone liver biopsy in the
hepatology department of the Pitié-Salpêtrière Hospital . From the hepatic tissue, the
paraffin-embedded liver biopsies and the serum of these patients, study of the expression of
mRNA (quantitative RtPCR) and proteins (immunohistochemistry, western blots) of the RANKL
pathway (RANK, RANKL, OPG) in liver. In the serum of these patients, measure of concentration
of RANKL and OPG proteins as described above.
Study Type: monocentric, observational, case-control, analytical study Study duration: 18
months (time for data collection, for cellular biological experimentations and for data
analysis)
Patient Population:
5 groups of patients very well phenotyped and with liver biopsy (with at our disposal frozen
liver tissue, paraffin-embedded liver tissue and serum for all the patients):
- 1) steatosis group (n=10)
- 2) NASH group without fibrosis (n=10)
- 3) moderate fibrosis (n=10)
- 4) advanced fibrosis (n=10)
- 5) healthy control group without liver disease (n=10) Comprehensive clinical and
laboratory data were observed at the time of the liver biopsy and are available for all
the patients.
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