NEW YORK – A team led by investigators in China used multiomic analyses to highlight a handful of molecular subtypes of nonalcoholic fatty liver disease (NAFLD) in the Chinese population, providing insights into the risk of disease progression as well as potential treatment targets.
"The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy," co-corresponding author Jin Chai, a researcher with the Third Military Medical University and director of the institute's Cholestatic Liver Diseases Center, and his colleagues wrote in Science Translational Medicine, adding that the new work "classified NAFLD into three distinct molecular subtypes."
For their study, the researchers used a combination of whole-genome sequencing, liquid chromatography- and tandem mass spectrometry-based proteomic and phosphoproteomic profiling, metabolomics, and lipidomics to assess liver, blood serum, and urine samples collected from Chinese individuals with or without NAFLD, a condition that increases the risk of other serious liver conditions such as cirrhosis or hepatocellular carcinoma (HCC).
"NAFLD/[nonalcoholic steatohepatitis] is becoming one of the leading causes of HCC worldwide," the authors explained, referring to NASH, a severe form of NAFLD. "However, the existing NAFLD clinical, genetic, and metabolic classifications unsatisfactorily identify the risk of HCC development in people with NAFLD."
Based on proteomic and phosphoproteomic data for liver samples from up to 103 NAFLD cases and 17 controls — coupled with whole-genome sequencing on blood samples from 86 NAFLD patients and proteomic, lipidomic, and metabolomic profiling on blood and urine samples from dozens of individuals with or without NAFLD — the team defined subtypes known as NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII that each display distinct molecular features.
"These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC," the authors noted.
While NAFLD-mSI subtype samples were marked by damped-down hepatic steatosis symptoms, altered fatty acid-related signaling, and increased CYP1A2 and CYP3A4 expression, for example, the NAFLD-mSII subtype samples had increased levels of the lipid-related CCL2 and CRP markers, an uptick in M1 and M2 macrophage cell infiltration, and appeared particularly prone to progress to liver cirrhosis.
On the other hand, the investigators highlighted higher-than-usual HCC risk for tumors classified as NAFLD-mSIII, which showed enhanced oncogene expression linked to an uptick in signaling via a pathway containing EGF, EGF receptor, PI3K, and AKT.
The team went on to validate the molecular subtypes using multiplex immunofluorescence testing focused on three biomarkers analyzed by machine learning in a group of 92 additional NAFLD patients treated at three hospitals in China.
Together, the authors said, these and other findings from the study "may shed light on precision diagnosis and potential therapeutic targets for treating and preventing NAFLD and its adverse clinical outcomes."