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Nonalcoholic Fatty Liver Disease Progression Can Be Traced by Gene Expression Signature

NEW YORK — An expression signature of more than two dozen genes can trace the progression of nonalcoholic fatty liver to nonalcoholic steatohepatitis, a new analysis has found. 

 Nonalcoholic fatty liver disease (NAFLD) is a common condition marked by the accumulation of triglycerides and other lipids in the liver and is associated with metabolic syndrome, type 2 diabetes, hypertension, and dyslipidemia. NAFLD can be divided into two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL can develop into NASH and advanced fibrosis.

By examining the transcriptomes of more than 200 patients with NAFL or NASH, researchers led by Newcastle University's Quentin Anstee found a number of genes that were differentially expressed along the disease continuum. These genes implicated inflammatory and metabolic pathways in the progression of NAFL to NASH and suggested that the circulating levels of proteins like AKR1B10 and GDF15 might be able to distinguish individuals with differing disease severity.

"This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression," Anstee and his colleagues wrote in their paper, which appeared in Science Translational Medicine on Wednesday.

The researchers performed RNA-sequencing on liver biopsies from a discovery cohort of 206 patients, 53 with NAFL and 153 with NASH. Unsupervised clustering separated the cohort into two groups, one of which was marked by more advanced fibrosis and included more patients diagnosed with NASH. Nearly 1,300 genes were differentially expressed between the two clusters.

The researchers additionally identified more than 2,600 differentially expressed genes between their discovery cohort and a set of healthy obese controls. They also uncovered genes that were differentially expressed between the various stages of NASH progression.

They then homed in on a set of 25 genes that were associated with progression from NAFL to NASH and to more severe forms of NASH. Using NanoString Technology's gene expression platform, they replicated 21 of the 25 genes in the signature as significantly differentially expressed when comparing different stages of the liver disease in a cohort of 175 patients. This set of genes included several involved in inflammation, retinol metabolism, and Wnt signaling, and the researchers found that many could be induced by endoplasmic reticulum stress. 

By combining publicly available single-cell RNA-seq data from healthy and cirrhotic livers with their NAFLD and NASH cohort data, the researchers examined how their 25-gene panel is expressed by various cell types. In particular, they noted that some epithelial cells had high expression of 10 of the 25 genes in advanced NASH, while genes expressed by macrophages changed with disease state.

Using immunohistochemistry, they confirmed that certain markers like AKR1B10, GDF15, and STMN2 were expressed by particular liver cells. AKR1B10, for instance, was more likely to be found in ballooned hepatocytes, and the number of AKR1B10-positive hepatocytes increased with disease stage. 

This suggested that the gene set could reflect potential protein biomarkers that might be able to gauge disease severity. To study this further, the researchers conducted a proteomic analysis of 305 serum samples to find that they could detect 13 proteins, reflecting 14 of the 25 genes in their signature. Serum levels of AKR1B10 and GDF15 increased significantly with fibrosis stage, they reported. 

"These transcriptomic data, from a large histologically characterized NAFLD cohort, provide insights into disease pathophysiology, identifying both stable and dynamic differences in gene expression that occur during NAFLD progression," they added.