De Novo Lipogenesis, Lipid and Carbohydrate Metabolism in Non-alcoholic Fatty Liver Disease
Condition: Non-alcoholic Fatty Liver Disease; Diabetes
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional

Summary: 
      The worldwide epidemic of obesity is paralleled with increased cases of non-alcoholic liver
      disease (liver fat accumulation) and diabetes. Fat belongs in the adipose tissue, and if
      excess fat accumulates in the liver or muscle, these tissues cannot use sugar efficiently. It
      has been discovered that when large quantities of fructose (a sugar present in soft drinks)
      are consumed, the conversion of carbohydrate (CHO) to fat in the liver increases.

      We hypothesize that: 1) subjects with fatty liver have a higher CHO uptake and conversion to
      fat in their liver when compared to matched control subjects with normal liver fat content;
      and that: 2) when subjects with fatty liver are fed a diet limiting fructose and simple
      sugars will decrease their liver CHO fat content. This reduction in liver fat will normalize
      the way the liver responds to sugar and insulin, reversing the pre-diabetic state.

      The measurement of these parameters will be done using state-of-the-art techniques such as
      safe non-radioactive isotope tracers and non-invasive magnetic resonance spectroscopy.

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Detailed description: 
      Non-alcoholic fatty liver disease (NAFLD) is the most common liver ailment in developed
      countries. Fatty liver - steatosis - affects up to one third of the population. Its
      prevalence is rising and seems to parallel the global increase in obesity and type-2
      diabetes. The etiology of NAFLD in humans is not well understood. We propose that the hepatic
      conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the
      accumulation of excess liver fat and the accompanying dyslipidemia and hepatic insulin
      resistance; and that suppressing DNL by diet will reduce liver fat and improve both lipid and
      carbohydrate metabolism in patients with steatosis. These hypotheses are based on studies in
      which we and others have established that fractional hepatic DNL can vary dramatically
      depending on the diet and/or health status of a subject; and, in particular, that dietary
      fructose is a potent lipogenic stimulus. In this proposal we will perform CRC-based studies
      to compare the rates of DNL and very low density lipoprotein (VLDL) kinetics in steatotic and
      matched non-steatotic controls and evaluate their relationship to lipid profiles and hepatic
      and whole-body insulin resistance and overall carbohydrate metabolism (Aim1). The steatotic
      individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total
      energy intake will then be randomized to consume one of two low-fat diets that differ only in
      CHO type to determine whether diet-induced changes in DNL affect liver fat flux and content
      and hepatic, whole-body insulin sensitivity, and overall carbohydrate metabolism (Aim 2). We
      hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and
      liver fat than one that contains typical amounts of simple CHO, including fructose. This
      dietary intervention study includes a 6-week 25% energy restriction outpatient phase to
      promote moderate weight loss and improve insulin sensitivity, followed by a two weeks weight
      maintenance with the last 4 days as an inpatient stay during which all of the studies
      performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques
      will be used to assess hepatic DNL, apoB100 turnover, VLDL-triglyceride (TG) fluxes, and
      lipolysis under fasting and fed conditions. Hepatic and extra-hepatic insulin sensitivity
      will be measured using hyperinsulinemic-euglycemic clamps and stable isotope studies of
      endogenous glucose production and glycogen flux. Liver and muscle fat will be measured by
      proton magnetic resonance spectroscopy (MRS), visceral fat by magnetic resonance imaging
      (MRI), and whole-body composition by dual-energy X-ray absorptiometry (DEXA). These studies
      will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content
      and flux, and the significance of CHO quality in dietary guidance for steatotic patients.
    

Intervention name(s): Dietary intervention (calorie restricted diet); Dietary intervention (calorie restricted diet)
Intervention type(s): Other; Other
Intervention description(s): Participants in Aim 2 will receive a calorie restricted diet. This group will receive all their food for approximately 8 weeks which is the similar composition of their current diet.; Participants in Aim 2 will receive a calorie restricted diet. This group will receive all their food for approximately 8 weeks which is lower in simple sugars, specifically fructose.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Steatosis; Diabetes