Integrated Transcriptomic and Proteomic Analysis Identifies Plasma Biomarkers of Hepatocellular Failure in Alcohol-Associated Hepatitis
Josepmaria Argemi 1 , Komal Kedia 2 , Marina A Gritsenko 3 , Ana Clemente-Sanchez 4 , Aliya Asghar 5 , Jose Mari Herranz 6 , Zhang-Xu Liu 7 , Stephen R Atkinson 8 , Richard D Smith 3 , Trina M Norden-Krichmar 9 , Le Z Day 3 , Andrew Stolz 7 , John A Tayek 10 , Ramon Bataller 8 , Timothy R Morgan 11 , Jon M Jacobs 12 , Southern California Alcoholic Hepatitis Consortium and the InTeam Consortium 8
Alcohol-associated hepatitis (AH) is a form of liver failure with high short-term mortality. Recent results have shown that HNF4a defective function and systemic inflammation are major disease drivers of AH.
Plasma biomarkers of hepatocyte function could be useful for diagnostic and prognostic purposes. Herein an integrative analysis of hepatic RNAseq and liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to identify plasma protein signatures for mild and severe AH patients.
Alcohol-related liver disease cirrhosis (ALD), non-alcoholic fatty liver disease (NALFD), and healthy subjects (HC) were used as comparator groups. Identified proteins primarily involved in hepatocellular function were decreased in AH patients which included hepatokines, clotting factors, complement cascade components, and hepatocyte growth activators.
A protein signature of AH disease severity was identified including thrombin (THRB), hepatocyte growth factor alpha (HGFA), clusterin (CLUS), human serum factor H-related protein (FHR1) and kallistatin (KAIN), which exhibited large abundance shifts between severe and non-severe AH.
The combination of THRB and HGFA discriminated between severe and non-severe AH with high sensitivity and specificity. These findings were correlated with the liver expression of genes encoding secreted proteins in a similar cohort, finding a highly consistent plasma protein signature reflecting HNF4A and HNF1A functions.
This unbiased proteomic-transcriptome analysis identified plasma protein signatures and pathways associated with disease severity, reflecting HNF4A/1A activity useful for diagnostic assessment in AH.