Fatty Acids, Genes and Microbiota in Fatty Liver
Condition: Nonalcoholic Fatty Liver Disease; Steatosis; Nonalcoholic Steatohepatitis
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Observational

Summary: 
      The first aim of this study is to assess oxidative stress and nutritional status in patients
      with elevated liver enzymes who were found to have either simple steatosis (SS) or
      nonalcoholic steatohepatitis (NASH) or normal histological findings on liver biopsy by
      measuring liver lipid peroxides and tumor necrosis factor (TNF)-α, liver pathology and
      immunohistochemistry, liver function tests, liver and red blood cell membrane fatty
      composition, insulin resistance (IR) parameters, plasma lipid peroxides, plasma antioxidant
      vitamins and antioxidant power, lipid profile, subject demographics, medical history and
      medication use. The second aim is to detect differences in hepatic gene expression (messenger
      RNA, mRNA) and epigenetic regulation (micro RNA, miRNA) between patients with SS or NASH and
      healthy controls, in addition to determine in patients with non-alcoholic fatty liver disease
      (NAFLD = SS+NASH combined) whether there is an association between hepatic n-3 PUFA content
      and gene expression. The third aim is to determine the intestinal microbiome (microbial
      composition and metagenome) in patients with SS or NASH and healthy controls.
    

Detailed description: 
      NASH is associated with obesity, diabetes and hyperlipidemia. Fat accumulation in the liver
      is likely due to variable degrees of disordered fatty-acid metabolism and insulin resistance
      (IR). Liver steatosis, especially polyunsaturated fatty acids (PUFA) in the liver, increases
      lipid peroxidation and is associated with a reduction in the antioxidant defense system. This
      oxidative stress can lead to increased production of pro-inflammatory cytokines (TNF-α,
      transforming growth factor-beta) contributing to the development of steatohepatitis and
      fibrosis.TNF-α - may further contribute to IR. In addition, changes in fatty acid composition
      within the liver may influence lipid metabolism and inflammation. In particular, n-3 PUFA
      have an effect on the insulin sensitivity, transcription of antioxidant genes, inflammatory
      response and production of reactive oxygen species. Differences might be seen on the gene
      expression level (mRNA) and also in epigenetic regulation (miRNA).

      Microbiota composition might influence energy metabolism, and inflammatory tone and IR
      through increased endotoxemia and therefore could also play a role in the development of
      NAFLD.
    

Observational model: Cohort
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Healthy living liver donors from the Multiorgan transplant program at the University Health
        Network Patients with nonalcoholic fatty liver disease (SS or NASH on liver biopsy) or
        patients with elevated liver enzymes but no significant findings on liver biopsy.
      
Biospecimen description: 
      DNA - samples retained, with potential for extraction of DNA from at least one of the types
      of samples retained (e.g., frozen tissue, whole blood
    
Keywords: Nonalcoholic fatty liver disease; Steatosis; Nonalcoholic steatohepatitis