Background

An important but often clinically undiagnosed liver disorder of obesity is non-alcoholic steatohepatitis (NASH), which begins as fatty liver (steatosis) that induces an inflammatory reaction (steatohepatitis) that leads to scarring (fibrosis) and cirrhosis, one of the top 10 causes of death in the United States. NASH has become a leading cause of cryptogenic cirrhosis, and may eventually surpass alcohol as the leading cause of cirrhosis. Weight loss is an effective treatment for NASH and bariatric surgery appears to reverse NASH. The common blood test, liver function tests (LFTs) are used to screen for NASH but are non-specific and very insensitive. Liver biopsy is the only definitive and clinically accepted method to make the diagnosis of NASH, which is based upon findings that include steatosis (fat accumulation), inflammation, and fibrosis. Our long-term objectives are to identify non-invasive blood markers for NASH. We used a molecular approach to identify lead candidate biomarkers for the inflammatory stage of NASH, i.e., steatohepatitis. Gene expression profiling was performed on pooled liver RNA samples from ~50 morbidly patients with steatohepatitis without fibrosis and ~50 morbidly obese patients with normal histology. Patients were matched for age, gender, and major clinical features, such as co-morbid conditions, to the extent possible as proposed in the application. Surprisingly, no genes were found to be more than 100% up-regulated (two-fold increase in expression level). However, a large family of small nucleolar RNAs were found to be down-regulated by more than 50% (two-fold decrease in expression). Small nucleolar RNAs are key components of small nucleolar ribonucleoprotein particles that are involved in methylation and regulation of gene expression. Very little information is known about the expression and role of small nucleolar RNAs in NASH, but may serve as potential molecular markers of disease.