Adipose Tissue Involvement in Alcohol-induced Liver Inflammation in Human
Condition: Alcoholic Hepatitis; Alcoholic Cirrhosis
MeSH terms: Hepatitis; Hepatitis, Alcoholic; Liver Cirrhosis, Alcoholic; Inflammation; Fibrosis
Study type: Interventional

Summary: 
      The histological characteristics of alcoholic liver disease (ALD) and non-alcoholic
      steatohepatitis (NASH) related to overweight and obesity suggest the presence of partly
      common physiopathological mechanisms. We reported that the ponderal overload was an
      independent risk factor of alcoholic cirrhosis. The adipose tissue was considered for a long
      time as a simple place of storage of fat. However, it is now recognized that the adipose
      tissue can secrete cytokines called ADIPOKINES.

      The adipose tissue can secrete others cytokines such as TNF-alpha, IL6, IL10 and IL1-Ra.
      Increase in the production of the leptin and TNF-alpha by the adipose tissue after alcohol
      administration in the rat, as well as the role of leptin in inflammation and liver
      fibrogenesis in the murine model of chemical hepatotoxicity strongly suggest that activation
      of adipocytes by alcohol can explain the strong correlation observed between the body mass
      index (BMI) and the severity of ethanol-induced liver injury. Conversely, it was suggested in
      a murine model that the reduction in adiponectin production would sensitize the liver with
      the toxicity of alcohol. The PPAR alpha and gamma are the receptors which play a role both in
      inflammation and glucide and lipid metabolism. Taking into account the inhibiting role of
      PPAR alpha on the proliferation of the hepatic stellate cells, responsible for the fibrosis,
      the PPAR could also be implied in the relation between the overweight and the hepatic
      fibrosis in the alcoholic.
    

Detailed description: 
      The aim of this project is to demonstrate that ADIPOKINES, as well as the PPAR alpha and
      gamma are implied in the intensity of the steatosis and in the regulation of the inflammatory
      process and the hepatic fibrogenesis in alcoholic liver disease. In order to prove this
      hypothesis, we will study among patients having a ALD at various stages of histological
      severity: 1) the hepatic and subcutaneous abdominal adipose tissue expression of the PPAR
      alpha and PPAR gamma, 2) the hepatic and subcutaneous abdominal adipose tissue expression of
      the TNF alpha, the IL1Ra, the IL6 and the IL10, 3) the hepatic and subcutaneous abdominal
      adipose tissue expression of the ADIPOKINES (leptin, adiponectin, resistin), 4) the serum
      ADIPOKINES values, the cyanotic of the mRNA expression and of the serum ADIPOKINES values
      after 7 days of alcohol withdrawal 50 patients will be studied (25 having ALD without
      cirrhosis, with or without acute alcoholic hepatitis (AAH) and 25 having alcoholic cirrhosis
      with or without AAH). A part of liver biopsy will be frozen in a dry tube. The percutaneous
      adipose tissue will be obtained with a punction on the abdominal level at the time of
      inclusion of the patients having AAH and, for the second time, after 7 days of alcohol
      withdrawal, than will be frozen. The TNF alpha, the IL1Ra, the IL6, the IL10, the leptin, the
      adiponectin and the resistin expression as well as the hepatic and adipose tissue PPAR alpha
      and gamma will be evaluated by PCR in real time. The serum concentration of the ADIPOKINES
      (leptin, adiponectin, resistin) will be measured by ELISA or RIA.

      If our hypothesis is true, severity of liver lesions (steatosis, AAH, fibrosis) could be
      positively correlated with the expression in the liver and the adipose tissue and / or the
      serum values of the anti-inflammatory cytokines and ADIPOKINES (TNF alpha, IL6, leptin,
      resistin) and negatively with the cytokines and ADIPOKINES which are potentially
      anti-inflammatory (IL1Ra, IL10, adiponectin). We also expect to find a negative correlation
      between the amount of hepatic and adipose tissue PPAR-alpha and PPAR-gamma mRNA and the
      severity of the liver disease.
    

Intervention name(s): blood and biopsies
Intervention type(s): Other
Intervention description(s): blood and biopsies
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Alcohol; Hepatitis; Cirrhosis; Inflammation; Cytokines; ADIPOKINES; Adipose tissue