Hepatic De Novo Lipogenesis (DNL)in the Pathogenesis of Hepatic Steatosis in Obese Youth
Condition: Hepatic Steatosis; Fatty Liver
MeSH terms: Fatty Liver
Study type: Observational

Summary: 
      Nonalcoholic Fatty Liver Disease (NAFLD) is becoming the most common cause of liver disease
      in pediatrics, but little is known about its pathophysiology in children. While studies in
      obese adults with hepatic steatosis have described an increased hepatic de novo lipogenesis
      (DNL) depending on the diet, there are no studies exploring the mechanisms by which excess
      hepatic triglycerides increases in obese youths, thus explaining the accompanying
      dyslipidemia and the metabolic syndrome. The central hypothesis of this study is that hepatic
      conversion of carbohydrates to lipid (DNL) is enhanced and associated with accumulation of
      excess liver fat, dyslipidemia and hepatic insulin resistance in obese youths with hepatic
      steatosis. The overall goal is to examine whether hepatic DNL is increased in obese youths
      with steatosis compared to matched controls without steatosis.

      Hypotheses: Hepatic conversion of carbohydrates to lipid (DNL) is enhanced and is associated
      with accumulation of excess liver fat, dyslipidemia and hepatic insulin resistance in obese
      youths with hepatic steatosis.
    

Detailed description: 
      In this study obese youths, adolescents and young adults (12-30 years) will undergo MRI
      (magnetic resonance imaging) measurement of liver lipid content to determine hepatic fat
      content. They will undergo a sugary drink (75 grams of glucose and 25 grams of fructose)
      challenge and Hepatic de novo lipogenesis will be determined as the incorporation of
      deuterium, from deuterium labeled water (D2O), into plasma triglycerides. Subjects will
      undergo a 6 hours study assessing de novo lipogenesis, an oral glucose tolerance test, dual
      energy x-ray absorptiometry, magnetic resonance imaging, and Euglycemic-Hyperinsulinemic
      Clamp.

      This study record has been re-opened in 2019 and updated to reflect any changes having
      remained open since its inception with the Yale University IRB and also having obtained
      additional funding though NIDDK.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The majority of the research subjects will be recruited from the Yale Pediatric Obesity
        Clinic and the Endocrine Clinic. Following the oral glucose tolerance test (OGTT):normal
        glucose tolerant if plasma glucose at two hours is <140 mg/dl and impaired glucose tolerant
        if plasma glucose is ≥140 mg/dl. All subjects must be in good general health, have a normal
        medical history and physical exam, and have no endocrinopathies or other diseases that
        might affect glucose metabolism. They will not be on any medications that are known to
        alter glucose or insulin metabolism or certain psychiatric medications. Subjects determined
        to be eligible will receive a MRI to determine Hepatic Fat Content. Subjects will agree to
        genetic testing to determine genotype.
      
Biospecimen description: 
      Serum
    
Keywords: De Novo Lipogenesis; Fatty Liver; Hepatic Steatosis; Gene variants