A new angle on NAFLD

Transcriptome sequencing of patients with liver disease reveals gene expression changes that could help to track disease severity and progression

December 4, 2020
Kelsey Kaustinen

NEWCASTLE UPON TYNE, U.K.—Research conducted under the EPoS and LITMUS consortia by Newcastle University researchers has uncovered genes that could help diagnose and track disease progression for individuals with nonalcoholic fatty liver disease (NAFLD). The results of this work were published in Science Translational Medicine under the title “Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis.”

Funding for this project came from the European Union’s Horizon 2020 research funding program and the Innovative Medicines Initiative 2 (EU-IMI2) Joint Undertaking, the latter of which receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA.

NAFLD affects roughly 25 percent of adults worldwide, with numbers on the rise alongside increased global obesity. The disease is characterized by a buildup of fat in the liver, which causes inflammation and scarring that can lead to cirrhosis or even liver cancer. Current diagnosis requires a liver biopsy, highlighting the need for a simple, non-invasive option.

“NAFLD is subdivided into “simple” steatosis [nonalcoholic fatty liver (NAFL)] and nonalcoholic steatohepatitis (NASH), defined by the presence of necroinflammation and hepatocyte ballooning. If NASH persists, fibrosis occurs and may progress to cirrhosis and, ultimately, end-stage liver disease,” the authors explained in their paper. “NAFL was traditionally considered a stable and relatively benign disease state that lacked the capacity to progress. However, recent data from serial biopsy studies have demonstrated that NAFL may transit into NASH and onward to advanced fibrosis. NAFLD is therefore best considered a dynamic disease with steatohepatitic activity waxing and waning, and fibrosis stage also progressing and regressing subject to the actions of a variety of genetic, epigenetic, and environmental modifiers.”

The research team studied the messenger RNA (mRNA) profiles of patients with varying degrees of disease severity, using RNA sequencing to determine which genes are actively expressed and which aren't. The study used more than 400 liver biopsies—381 samples from patients with NAFLD and 22 control samples—making it one of the largest such NAFLD studies to date.

High-throughput RNA sequencing was conducted on samples from 206 patients, 153 of whom had NASH and 53 of whom had NAFLD. Alterations were noted in genes that control liver metabolism, inflammation and tissue scarring, and the team identified a “gene expression signature” of 25 genes that changed as the disease progressed. Many of the expression changes in those 25 genes also result in protein alterations that can be detected in the blood.

“Each of the 25 genes correlated strongly with increasing severity of inflammation, ballooning, and fibrosis, with 12 genes showing additional overlap with steatosis (AKR1B10, CCL20, COL1A1, COL1A2, DTNA, DUSP8, GDF15, PDGFA, PPAPDC1A, STMN2, THY1, and TNFRSF12A),” the authors reported.

“We also demonstrated that 21 of these 25 genes discriminated mild from advanced disease (NAFL-NASH F0/F1 versus NASH F ≥ 2) in an independent replication cohort and so have transcriptionally defined a key group of high-risk patients who are most likely to progress to advanced disease or experience clinical events and so should be investigated as potential therapeutic targets,” they added.

Promisingly, the researchers pinpointed two proteins in particular that could have diagnostic potential for NAFLD: AKR1B10 and GDF15, both of which are described in the paper as being “strongly associated with disease activity and fibrosis stage.”

Twenty-nine collaborating authors contributed to this publication, with first author Dr. Olivier Govaere and senior authors Prof. Ann Daly and Prof. Quentin Anstee hailing from Newcastle University Translational and Clinical Research Institute. The biomarkers identified in this work will undergo further assessment under the EU-IMI2 LITMUS project coordinated by Anstee.

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