Kinetics of Metabolic Cofactors in NAFLD
Condition: Healthy
Study type: Interventional
Phase: Early Phase 1

Summary: 
      There is a strong correlation between major adverse health consequences of obesity and
      development of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by abnormal
      hepatic accumulation of triglycerides and other lipids. It has become a worldwide health
      problem that accelerates cirrhosis, type 2 diabetes mellitus (T2DM), and especially premature
      cardiovascular morbidity and mortality.

      The plasma level of glutathione (GSH) is typically depleted in individuals with metabolism
      related disorders. However, cellular GSH levels cannot be increased by supplementing GSH and
      it must be synthesized within the liver either de novo or by salvation pathway. The level of
      GSH is not enough to maintain and regulate the thiol redox status of the liver in subjects
      with high hepatic steatosis at fasting stage due to the depletion of glycine. Glycine can be
      synthesized via the interconversion of serine. It has been shown that the serine synthesis is
      downregulated in patients with NAFLD and supplementation of serine has attenuated alcoholic
      fatty liver by enhancing homocysteine metabolism in mice and rats. Depleted liver glutathione
      is also restored by the administration of N-acetylcystein as in acetaminophen poising.
      L-carnitine and nicotinamide that both stimulate the transfer of fatty acids from cytosol to
      mitochondria have been identified as two additional cofactors that are depleted in patients
      with NAFLD.

      In this study, the kinetics in blood of pivotal metabolic cofactors, serine, L-carnitine,
      N-acetylcystein and nicotinamide after single and simultaneous dietary supplementation, are
      measured.
    

Detailed description: 
      In 10 healthy subjects with BMI <30 kg/m2 the plasma concentrations of 4 natural compounds
      (nicotinamide riboside, L-carnitine, L-serine and N-acetylcystein) are measured by
      ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMSMS) after individual
      and combined administration, on five consecutive days and at every hour during 9 hours after
      administration. The study will start at 8:00 every morning and at each time point, blood
      samples will be collected.

      The taste and any potential sensing of the co-factors such as vertigo, nausea, bowel movement
      will be recorded.

      Each participant will receive one oral dose of Day 1: 1 g nicotinamide riboside; Day 2: 3 g
      L-carnitine; Day 3: 5 g N-acetylcystein; Day 4: 20 g L-serine; Day 5: combined 1 g
      nicotinamide riboside, 3 g L-carnitine, 5 g N-acetylcystein, and 20 g L-serine

      In addition, untargeted metabolomics analysis as well as O-link proteomics analysis we be
      performed to study effect of the administered cofactors.
    

Intervention name(s): Cofactors
Intervention type(s): Dietary Supplement
Intervention description(s): Oral administration of 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: nicotinamid riboside; L-carnitine; L-serine; N-acetylcystein