Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real-time quantitative reverse-transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI-TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention. (HEPATOLOGY 2005;42:665-674.) N onalcoholic fatty liver disease (NAFLD) is an important cause of chronic liver disease that has gained increasing recognition over the past decade. 1-5 NAFLD includes a spectrum of clinico-pathological syndromes associated with varying degrees of risk for progression to cirrhosis. For example, nonalcoholic steatohepatitis (NASH) is considered potentially progressive, whereas patients with liver biopsies showing steatosis alone follow a more benign course with little or no pro-gression. Furthermore, burned-out NASH may be an important cause of cryptogenic cirrhosis. The current rise in the prevalence of NAFLD and NASH may be related to parallel increases in the prevalence of obesity and metabolic syndrome. Both endogenous and exogenous factors may influence differential progression of these liver diseases. For example, environmental factors contributing to oxidative stress may compound hepatic injury in some patients, whereas genetic factors may be more important in others. 17-21 Furthermore, an interaction among these factors may influence the disease course and tip the balance in favor of progression.
New genomic and proteomic technologies have the potential to help clarify the complex pathogenic mechanisms of NAFLD and related progressive liver disease. 22-27 For example, simultaneous assessment of gene expression in a large number of genes and protein peaks can help identify molecular pathways that are active in NAFLD. Furthermore, molecular pathways that protect against disease progression can be differentiated from those that may contribute to the progression of NAFLD. This study relates the patterns of gene expression in liver tissue and protein peak