Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the United States. The high prevalence of NAFLD is largely on the basis of relentless increases in the prevalences of obesity and insulin resistance. The basis of progressive histological injury in a proportion of patients with NAFLD is poorly understood. The overall goals of this project are to 1) develop a model to identify patients with more histologically severe grades of NAFLD and 2) better define the pathophysiological basis of histological progression of NAFLD. Two hypotheses and specific aims have been developed to achieve these goals. Our first hypothesis is that indices of insulin sensitivity, hyperinsulinemia and/or subclinical inflammation can be used to generate a model capable of identifying patients at increased risk for more histologically severe grades of NAFLD. The first specific aim is to prospectively screen a panel of biological parameters for their ability to identify patients at risk for histologically severe NAFLD, as measured by NAFLD grade. In a pilot study of patients with varying degrees of severity of NAFLD, we found that more histologically severe NAFLD is independently associated with greater percent body fat, higher C-reactive protein and fasting insulin levels. Strong trends for an association with severity of NAFLD grade were also seen for higher IGFBP-1 levels, % truncal fat, HGH levels, and continuous glucose monitoring profiles. We now propose to carry out detailed assessments of these and other markers of subclinical inflammation, insulin sensitivity, insulin-like growth factor axis and assessments of anthropometry in patients with grades 1-3 of NAFLD and in controls. Our second hypothesis is that the inflammation and progressive fibrosis that can occur in NAFLD are substantially due to increased oxidative stress. The second specific aim is to determine the mechanism and effects of increased oxidative stress in NAFLD. Oxidative stress is thought to be central to hepatocellular injury in NAFLD. Our preliminary data demonstrate a possible pre-transcriptional basis of increased oxidative stress in patients with more histologically progressive NASH. In a logical extension of these experiments, we now propose to use high-throughput mass spectrometry analysis, using an ICAT tagging technique, to measure differential hepatic protein abundance, including of peroxisomal proteins, in patients with NAFLD grades 1-3, and also in controls. We believe that these experiments will generate mechanistic insight into the cause and effects of increased oxidative stress in patients with histologically progressive NAFLD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069757-05
Application #
7591261
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$293,657
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Guichelaar, M M J; Gawrieh, S; Olivier, M et al. (2013) Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity. Obesity (Silver Spring) 21:1935-41
Duarte-Rojo, Andres; Deneke, Matthew G; Charlton, Michael R (2013) Interleukin-28B polymorphism in hepatitis C and liver transplantation. Liver Transpl 19:49-58
Duarte-Rojo, Andres; Veldt, Bart J; Goldstein, David D et al. (2012) The course of posttransplant hepatitis C infection: comparative impact of donor and recipient source of the favorable IL28B genotype and other variables. Transplantation 94:197-203
Veldt, B J; Duarte-Rojo, A; Thompson, A J et al. (2012) Recipient IL28B polymorphism is an important independent predictor of posttransplant diabetes mellitus in liver transplant patients with chronic hepatitis C. Am J Transplant 12:737-44
Krishnan, Anuradha; Li, Xia; Kao, Winstonwhei-Yang et al. (2012) Lumican, an extracellular matrix proteoglycan, is a novel requisite for hepatic fibrosis. Lab Invest 92:1712-25
Koehler, Edith; Swain, James; Sanderson, Schuyler et al. (2012) Growth hormone, dehydroepiandrosterone and adiponectin levels in non-alcoholic steatohepatitis: an endocrine signature for advanced fibrosis in obese patients. Liver Int 32:279-86
Charlton, Michael R; Burns, Justin M; Pedersen, Rachel A et al. (2011) Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 141:1249-53
Ribeireiro, Tarsila; Swain, James; Sarr, Michael et al. (2011) NAFLD and insulin resistance do not increase the risk of postoperative complications among patients undergoing bariatric surgery--a prospective analysis. Obes Surg 21:310-5
Massoud, Omar; Heimbach, Julie; Viker, Kimberly et al. (2011) Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: a proteomic signature validated by enzyme-linked immunosorbent assay. Liver Transpl 17:723-32
Cazanave, Sophie C; Mott, Justin L; Bronk, Steven F et al. (2011) Death receptor 5 signaling promotes hepatocyte lipoapoptosis. J Biol Chem 286:39336-48

Showing the most recent 10 out of 19 publications