Determinants of Liver Fat Composition
Condition: Fatty Liver, Nonalcoholic; Insulin Sensitivity
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease; Insulin Resistance
Study type: Observational

Summary: 
      Excessive fat in the liver, in absence of high alcohol consumption, is diagnosed as
      non-alcoholic fatty liver (NAFL). NAFL prevalence is as high as 50-70% in obese people and is
      associated with impairments in metabolic health, e.g. insulin resistance. Not only the
      amount, but also the composition of the fat stored in the liver appears to be linked to
      health outcome measures, such as insulin resistance, but this evidence comes mainly from
      animal studies. Since fat composition has been linked to health outcome measures, it is
      important to understand what determines the fatty acid composition of liver fat. De novo
      lipogenesis (DNL) and adipose tissue fat composition are factors that could determine liver
      fat composition. Since the end product of DNL are saturated fatty acids and as the majority
      of fatty acids in the liver originate from adipose tissue, both may influence hepatic fatty
      acid composition profoundly. Here, our primary hypothesis is that DNL is associated with the
      relative amount of saturated fatty acids in the liver in overweight/obese humans differing in
      liver fat content. Furthermore, we hypothesise that adipose tissue fat composition is
      associated with liver fat composition and that liver fat composition is associated with
      liver, muscle and whole body insulin sensitivity in overweight/obese humans differing in
      liver fat content. To this end, liver fat composition, adipose tissue fat composition, DNL
      and insulin sensitivity will be measured in overweight/obese participants differing in liver
      content.
    

Detailed description: 
      Rationale: Excessive fat in the liver, in absence of high alcohol consumption, is diagnosed
      as nonalcoholic fatty liver (NAFL). NAFL prevalence is as high as 50-70% in obese people and
      is associated with impairments in metabolic health, e.g. insulin resistance. Not only the
      amount, but also the composition of the fat stored in the liver appears to be linked to
      health outcome measures, such as insulin resistance, but this evidence comes mainly from
      animal studies. Since fat composition has been linked to health outcome measures, it is
      important to understand what determines the fatty acid composition of liver fat. De novo
      lipogenesis (DNL) and adipose tissue fat composition are factors that could determine liver
      fat composition. Since the end product of DNL are saturated fatty acids and as the majority
      of fatty acids in the liver originate from adipose tissue, both may influence hepatic fatty
      acid composition profoundly. Up to now, associations between hepatic fatty acid composition,
      DNL and adipose tissue fatty acid composition have never been determined in the same study.

      Objective: The primary objective of this study is to determine the association between DNL
      and hepatic %SFA in overweight/obese subjects differing in liver fat content. The secondary
      objectives are to determine the association between adipose tissue fat composition and liver
      fat composition and to determine the association between liver fat composition and whole
      body, liver and muscle insulin sensitivity.

      Study design: This is a cross-sectional observational study. For this study a design of 3
      groups with different amounts of liver fat are included, in order to create a study
      population with a continuum in liver fat content.

      Study population: Twenty-two healthy overweight/obese males and females, aged between 45-70
      years and BMI between 27-35 kg/m2 will participate in the whole study. To create a continuum
      in liver fat content, eight subjects with liver fat content lower than 5% and 14 subjects
      with liver fat content higher than 5%, of which at least seven subjects have a liver fat
      content of at least 15%, will be included. To be able to include enough people in each group,
      around 31 participants will be included in total. A part of the participants will stop
      participating in the study after determination of liver fat content (in case the liver fat
      content does not match the groups).

      Main study parameters/endpoints: The primary study parameters are %SFA in the liver and DNL.
      %SFA in the liver will be determined using MRS and DNL will be determined by applying stable
      isotope techniques. The secondary study parameters are hepatic fat composition, measured as
      %MUFA and %PUFA in addition to %SFA using MRS, adipose tissue fat composition, determined
      using MRS and biopsies, and insulin sensitivity, measured by a hyperinsulinemic euglycemic 2-
      step clamp.
    

Observational model: Other
Time perspective: Cross-Sectional
Sampling method: Probability Sample
Study population: 
        Twenty-two healthy overweight/obese males and females, aged between 45-70 years and BMI
        between 27-35 kg/m2 will participate in the whole study. To create a continuum in liver fat
        content, eight subjects with liver fat content lower than 5% and 14 subjects with liver fat
        content higher than 5% (NAFL) will be included. At least seven volunteers with NAFL will
        have severely elevated hepatic fat content (liver fat percentage ≥ 15%).