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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Linked Research project Grant (RL1)
Project #
3RL1DK081187-05S1
Application #
8321773
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Laughlin, Maren R
Project Start
2007-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$75,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lee, Joseph J; Lambert, Jennifer E; Hovhannisyan, Yelena et al. (2015) Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis. Am J Clin Nutr 101:34-43
Satapati, Santhosh; Kucejova, Blanka; Duarte, Joao A G et al. (2015) Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 125:4447-62
Lambert, Jennifer E; Ramos-Roman, Maria A; Browning, Jeffrey D et al. (2014) Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146:726-35
Shetty, Shoba; Ramos-Roman, Maria A; Cho, You-Ree et al. (2012) Enhanced fatty acid flux triggered by adiponectin overexpression. Endocrinology 153:113-22
Browning, Jeffrey D; Burgess, Shawn C (2012) Use of (2)H(2)O for estimating rates of gluconeogenesis: determination and correction of error due to transaldolase exchange. Am J Physiol Endocrinol Metab 303:E1304-12
Ramos-Roman, Maria A; Lapidot, Smadar A; Phair, Robert D et al. (2012) Insulin activation of plasma nonesterified fatty acid uptake in metabolic syndrome. Arterioscler Thromb Vasc Biol 32:1799-808
Browning, Jeffrey D; Baxter, Jeannie; Satapati, Santhosh et al. (2012) The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. J Lipid Res 53:577-86
Ramos-Roman, Maria A; Sweetman, Lawrence; Valdez, Maressa J et al. (2012) Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity. Metabolism 61:202-12
Lambert, Jennifer E; Parks, Elizabeth J (2012) Postprandial metabolism of meal triglyceride in humans. Biochim Biophys Acta 1821:721-6
Browning, Jeffrey D; Baker, Jonathan A; Rogers, Thomas et al. (2011) Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr 93:1048-52

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