Plasma proteomic signature of fatty liver disease: The Rotterdam Study

Abstract

Background and Aims: Fatty liver disease (FLD) is caused by excess fat in the liver, and its global prevalence exceeds 33%. The role of protein expression on the pathogenesis of FLD and accompanied fibrosis and its potential as a disease biomarker is currently not clear. Hence, we aimed to identify plasma proteomics associated with FLD and fibrosis using population-based data. Approach and Results: Blood samples were collected from 2578 participants from the population-based Rotterdam Study cohort. The proximity extension assay reliably measured plasma levels of 171 cardiometabolic and inflammatory-related proteins (Olink Proteomics). FLD was assessed by ultrasound, and fibrosis by transient elastography. Logistic regression models quantified the association of plasma proteomics with FLD and fibrosis. In addition, we aimed to validate our results in liver organoids. The cross-sectional analysis identified 27 proteins significantly associated with FLD surpassing the Bonferroni-corrected p<2.92×10−4. The strongest association was observed for FGF-21 (β=0.45, p=1.07×10−18) and carboxylesterase 1 (CES1) protein (β=0.66, p=4.91×10−40). Importantly, 15 of the 27 proteins significantly associated with FLD were also associated with liver fibrosis. Finally, consistent with plasma proteomic profiling, we found the expression levels of IL-18 receptor 1 (IL-18R1) and CES1 to be upregulated in an FLD model of 3-dimensional culture human liver organoids. Conclusions: Among the general population, several inflammatory and cardiometabolic plasma proteins were associated with FLD and fibrosis. Particularly, plasma levels of FGF-21, IL-18R1, and CES1 were largely dependent on the presence of FLD and fibrosis and may therefore be important in their pathogenesis.

Serum/Plasma Proteome in Non-Malignant Liver Disease

“…With regard to the latter, an eightprotein biomarker panel was superior to the currently used surrogates and ADAMTSL2 emerged as a novel, attractive biomarker [130]. Finally, a recent manuscript applied the Olink platform to a large population-based cohort and identified several potential biomarkers of fatty liver disease as well as reflecting liver fibrosis [131].…”

Transcriptomics reveal a molecular signature in the progression of nonalcoholic steatohepatitis and identifies PAI‑1 and MMP‑9 as biomarkers in in vivo and in vitro studies

“…Authoritative studies have proposed that serum biomarkers such as fibroblast growth factor 21 and cytokeratin-18 exhibit promise as potential targets for NAFLD treatment ( 40 – 42 ). Moreover, the identification of novel serum biomarkers for NAFLD diagnosis and prognosis has been reported to expedite the identification of novel therapeutic targets ( 43 – 45 ). These findings underscore the substantial potential of serum biomarkers as targets for NAFLD treatment, meriting further research in this realm ( 46 ).…”

Proteome profiling to advance management of metabolic dysfunction-associated fatty liver disease

“…In a recent study, Abozaid et al ( 6 ) analyzed the proteome alterations linked to hepatic steatosis and fibrosis. The objective was to discover new biomarkers that might indicate the severity of FLD and gain novel insights into its pathogenesis.…”

“…In order to examine the translational implications of their findings, the authors ( 6 ) showed that utilizing plasma proteomic data was more effective than using the fibrosis-4 index in predicting significant fibrosis. However, it was not superior to using a sonogram or the fatty liver index in identifying steatosis.…”