Non-alcoholic steatohepatitis (NASH) is a condition characterized by elevated liver triglyceride (TG), liverdamage, and inflammation in the setting of obesity, insulin resistance, and type 2 diabetes. We havepreviously identified and quantified the sources of excess TG found in the liver in NASH patients as derivingfrom the plasma FFA pool, newly-synthesized fatty acids from dietary carbohydrate (CHO), and dietary fatthat entered the liver postprandially. Further, we have found significant ethnic differences in the prevalenceof hepatic steatosis, with African Americans being protected relative to Caucasians and Hispanics. Clinicalstudies have shown that weight loss can reduce hepatosteatosis, improve liver function tests, and reduceliver fibrosis in NASH. A clinical trial will be conducted to compare the therapeutic efficacy of two different,energy-restricted diets (low-CHO and low-fat). Obese, hyperinsulinemic men and women (12 Hispanics and12 African Americans with NASH) will be randomized to consume one of the two diets to produce a 6%weight loss over a 5-mo period. Before and after weight loss, we will determine the relative effects of thesediets on hepatic-TG content and inflammation using non-invasive imaging technologies, histologicalassessment of liver biopsy specimens, and clinical chemistry. Stable isotopes, along with gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy, will be used to characterize andcompare the metabolic effects of the two diets in the ethnic groups. This study represents the first timethese two methodologies have been used simultaneously to assess in vivo metabolism. The study isdesigned to test the following hypotheses: H1, Weight reduction due to energy restriction, regardless ofdietary macronutrient composition, will reduce liver-TG content; H2, Compared to a low-fat diet, a low-CHOdiet will markedly reduce inflammation coincident with greater improvements in insulin sensitivity; H3,Differences in hepatic insulin resistance, lipogenesis, and/or dietary fatty acid flux between SMI-matchedHispanics and African Americans will explain the impact of dietary CHO restriction to regress liver fat. Bydiscovering the inter-relationships between hepatic glucose and lipid metabolism in NASH, a betterunderstanding of the metabolic mechanisms causing NASH will be gained, with the goal of more effectivetreatment strategies for obesity and diabetes-related liver disease in the future.
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