Exploring the Role of Pnpla3 Protein Level Expression in Fatty Liver Disease: Links to Insulin Resistance and Liver Disease Severity

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed non-alcoholic fatty liver disease (NAFLD), is associated with metabolic dysfunction and progressive hepatic injury. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is involved in hepatic lipid metabolism, but the clinical significance of circulating PNPLA3 protein concentrations remains insufficiently characterized.

Objective: To assess the association of serum PNPLA3 protein expression with insulin resistance, liver function parameters, fibrosis indices, and serum lipid profile in patients with fatty liver disease.

Materials and Methods: This cross-sectional analytical study was conducted at ASIAN HOSPITAL, Hyderabad, Pakistan, from March to August 2025. A total of 120 patients with ultrasound-confirmed fatty liver disease were recruited using convenience sampling. Serum PNPLA3 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Participants were categorized into low, moderate, and high PNPLA3 expression groups. Insulin resistance was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR), while fibrosis risk was evaluated using the fibrosis-4 (FIB-4) index. Statistical analysis was performed using IBM SPSS Statistics version 26.0.

Results: Higher PNPLA3 expression was associated with increased HOMA-IR, alanine aminotransferase, aspartate aminotransferase, and FIB-4 values across expression groups. Spearman correlation analysis demonstrated positive associations between PNPLA3 concentrations and HOMA-IR (r=0.45), ALT (r=0.30), and FIB-4 (r=0.28). Associations with serum lipid parameters were not statistically significant.

Conclusion: Serum PNPLA3 protein concentrations were associated with insulin resistance and biochemical indicators of hepatic injury and fibrosis risk. Further multicenter prospective studies using standardized assays and validated fibrosis assessments are needed to establish its clinical utility.