Serum proteomic signature of alcohol detoxification and the role of PNPLA3 genotype

Introduction Alcoholic liver disease (ALD) is the leading cause of liver related death, but its mechanisms remain incompletely understood. To change that, we studied proteomic changes in subjects undergoing inpatient alcohol detoxification with a focus on the role of PNPLA3 variant as the major genetic ALD modifier.

Methods Sera of 95 ALD subjects (44 PNPLA3WT/WT, 20 PNPLA3I148M/I148M) were collected prior to and after undergoing inpatient detoxification (median duration: 6 days) and were compared to sera of 32 liver-healthy controls. All samples were subjected to untargeted mass spectrometry-based proteomic analysis. Based on liver stiffness measurements via transient elastography (cut-off 7.5 kPa), the ALD subjects were subdivided into a lower (n=57) and advanced (n=45) fibrosis group.

Results The proteomic pattern of ALD subjects strongly differed from healthy controls and changes were more pronounced in subjects with advanced vs. low fibrosis. Complement factor 7 (C7), galectin 3-binding protein (LGALS3BP) and polymeric immunoglobulin receptor (PIGR) were among the most prominent species elevated in advanced disease stages while inter-alpha-Trypsin Inhibitor Heavy Chain 1 (ITIH1) and complement factor 6 (C6) were diminished. Detoxification resulted in a partial recovery of these features (e.g. C6, C7, PIGR), while some proteins displayed an even stronger abnormality (von Willebrand factor). Compared to PNPLA3WT/WT, PNPLA3I148M/I148M subjects harbored more pronounced changes in apolipoproteins suggestive of stronger lipidomic alterations.

Conclusion Our data provide novel insights into ALD-related alterations and the role of the PNPLA3 variant in this process.

Keywords Alcohol-Related Liver Disease (ALD), Proteomic Profiling, PNPLA3 Genotype, Apolipoproteins, APRI, fibrosis

Publication History

Article published online:
23 January 2024