Nonalcoholic fatty liver disease (NAFLD) results from excessive accumulation of fat in the liver. By itself, hepatic fat accumulation is not life-threatening, but a significant proportion of NAFLD patients progress to more severe forms of the disease characterized by inflammation, fibrosis, and cirrhosis, a condition known as nonalcoholic steatohepatitis (NASH). Although some factors, such as diet, obesity, insulin resistance, and ethnicity, have been associated with hepatic fat storage, clinical characteristics predicting NAFLD progression to more severe forms of fatty liver disease have not yet been identified. Further, little is known of the underlying physiology governing disease progression, and this gap in knowledge is a barrier to predicting which NAFLD patients will develop fibrosis and cirrhosis. The overall plan for this project, therefore, is to identify factors that predict progression of NAFLD to more severe forms of the disease. The specific goals of this study are to first evaluate the relationship between individual and composite predictors of NAFLD progression to steatohepatitis, fibrosis, and cirrhosis. Next, we will utilize a genome-wide approach to genotype 1M markers in 2075 obese individuals and assess association between these markers and NASH severity, as defined by histological grade of hepatic biopsy. All trait-associated markers and haplotypes will be validated in two independent study samples. Finally, we will perform RNA sequencing to measure hepatic gene expression and identify gene networks that are correlated with progressive NASH severity. We will also combine genotype and RNA sequencing data in an innovative approach to identify genetic variants associated with mRNA expression levels in liver samples comprising the entire spectrum of NAFLD stages. Completion of these aims will advance our understanding of NASH development and progression to more severe forms of the disease and may lead to better treatment and prevention strategies for at-risk individuals.
Individuals suffering from obesity, insulin resistance and/or type 2 diabetes often store excessive fat in the liver. By itself, hepatic fat accumulation is not life-threatening, but some affected patients will develop more severe forms of fatty liver disease including steatohepatitis, fibrosis, and cirrhosis;however, no clinical measures are yet available to identify which individuals are most likely to progress. This study will identify genetic variants that modulate severity and progression of nonalcoholic fatty liver disease, which will lead to better treatment and prevention strategies in at-risk individuals.
|DiStefano, Johanna K; Gerhard, Glenn S (2016) Circulating microRNAs in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 10:161-3|
|Wood, G Craig; Gerhard, Glenn S; Benotti, Peter et al. (2015) Preoperative use of incretins is associated with increased diabetes remission after RYGB surgery among patients taking insulin: a retrospective cohort analysis. Ann Surg 261:125-8|
|Hayes, Sharon; Napolitano, Melissa A; Lent, Michelle R et al. (2015) The effect of insurance status on pre- and post-operative bariatric surgery outcomes. Obes Surg 25:191-4|
|Leti, Fatjon; Malenica, Ivana; Doshi, Meera et al. (2015) High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease-related fibrosis. Transl Res 166:304-14|
|Gerhard, Glenn S; DiStefano, Johanna K (2015) Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol 7:226-34|
|DiStefano, Johanna K; Kingsley, Christopher; Craig Wood, G et al. (2015) Genome-wide analysis of hepatic lipid content in extreme obesity. Acta Diabetol 52:373-82|
|Petrick, Anthony; Benotti, Peter; Wood, G Craig et al. (2015) Utility of Ultrasound, Transaminases, and Visual Inspection to Assess Nonalcoholic Fatty Liver Disease in Bariatric Surgery Patients. Obes Surg 25:2368-75|
|Roesch, Stephen L; Styer, Amanda M; Wood, G Craig et al. (2015) Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes. PLoS One 10:e0116928|
|Gerhard, G S; Styer, A M; Strodel, W E et al. (2014) Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity. Int J Obes (Lond) 38:371-8|
|Still, Christopher D; Wood, G Craig; Chu, Xin et al. (2014) Clinical factors associated with weight loss outcomes after Roux-en-Y gastric bypass surgery. Obesity (Silver Spring) 22:888-94|
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