Effect of Dietary Macronutrient Composition and Weight Loss on Liver Substrate Me

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Non-alcoholic steatohepatitis (NASH) is a condition characterized by elevated liver triglyceride (TG), liver damage, and inflammation in the setting of obesity, insulin resistance, and type 2 diabetes. We have previously identified and quantified the sources of excess TG found in the liver in NASH patients as deriving from the plasma FFA pool, newly-synthesized fatty acids from dietary carbohydrate (CHO), and dietary fat that entered the liver postprandially. Further, we have found significant ethnic differences in the prevalence of hepatic steatosis, with African Americans being protected relative to Caucasians and Hispanics. Clinical studies have shown that weight loss can reduce hepatosteatosis, improve liver function tests, and reduce liver 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 and 12 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 these diets on hepatic-TG content and inflammation using non-invasive imaging technologies, histological assessment 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 and compare the metabolic effects of the two diets in the ethnic groups. This study represents the first time these two methodologies have been used simultaneously to assess in vivo metabolism. The study is designed to test the following hypotheses: H1, Weight reduction due to energy restriction, regardless of dietary macronutrient composition, will reduce liver-TG content; H2, Compared to a low-fat diet, a low-CHO diet 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-matched Hispanics and African Americans will explain the impact of dietary CHO restriction to regress liver fat. By discovering the inter-relationships between hepatic glucose and lipid metabolism in NASH, a better understanding of the metabolic mechanisms causing NASH will be gained, with the goal of more effective treatment strategies for obesity and diabetes-related liver disease in the future.