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Updated: May 5, 2026
Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
Published on: March 11, 2017
Proteomic insights into metabolic dysfunction-associated steatotic disease: Identifying therapeutic targets and
Luojia Dai1, Zhenqiu Liu2, Chengnan Guo3
1Department of Epidemiology, School of Public Health, Key Laboratory of Public Health Safety (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China.
Aims:
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising sharply, yet treatment options remain inadequate. To uncover new therapeutic targets for MASLD, we conducted a comprehensive proteome-wide Mendelian randomization (MR) and phenome-wide association study (PheWAS).
Materials And Methods:
Discovery MR utilized protein quantitative trait loci (pQTL) data on 4907 plasma protein levels from 35,559 individuals, alongside genome-wide association study (GWAS) on MASLD from the Million Veteran Program (68,725 cases / 95,482 controls). Validation comprised five pairwise combinations of these discovery datasets with three additional datasets: pQTL data for 2923 proteins from the UK Biobank, and liver biopsy-confirmed MASLD GWAS (1483 cases/17,781 controls) and MRI-liver fat GWAS (31,377 subjects) (excluding discovery pair). Candidate proteins underwent druggability assessment and on-target side effect evaluation via PheWAS.
Key Findings:
We identified 26 proteins associated with MASLD after Bonferroni correction (P < 1.16 × 10-5), with 19 of them showing no significant reverse association. Interleukin-6 (IL-6), alpha-1-antitrypsin (α1-antitrypsin), 5-hydroxytryptamine receptor 7 (5-HT7R), ephrin-B1 (EFNB1), and protein MENT (CA056) were replicated. Notably, IL-6 (OR = 2.02; 95 % CI 1.54-2.64), 5-HT7R (OR = 2.73; 95 % CI 1.96-3.80), and EFNB1 (OR = 1.82; 95 % CI 1.59-2.08) were positively associated with MASLD risk, whereas α1-antitrypsin (OR = 0.84; 95 % CI 0.78-0.90) and CA056 (OR = 0.90; 95 % CI 0.86-0.94) appeared protective. Among these, IL-6, 5-HT7R, and α1-antitrypsin were druggable. PheWAS identified potential cardiovascular side effects for 5-HT7R and α1-antitrypsin.
Significance:
The integrative study identified several plasma proteins associated with MASLD. IL-6, α1-antitrypsin, 5-HT7R, EFNB1 and CA056 deserve further investigation as potential drug targets for MASLD.
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