Serum Phospholipid Profiles Can Predict the Degree of Liver Fibrosis in Metabolic Dysfunction–associated Steatotic Liver Disease

Background & aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) leads to liver cirrhosis and is therefore a major public health concern worldwide. Although plasma/serum phospholipids are proposed non-invasive biomarkers of MASLD progression, they have not been put into clinical practice, in part because the mechanism underlying their efficacy remains unknown. We therefore evaluated serum phospholipid profiles to develop a novel biomarker for assessing the extent of liver fibrosis in MASLD patients and elucidate the underlying mechanism in this cross-sectional study. Approach & results: Liquid chromatography–tandem mass spectrometry was used to comprehensively analyze serum phospholipid profiles in 100 patients with clinically diagnosed MASLD. Phospholipid profiles were associated with laboratory data and fibrosis grade in liver biopsy. MASLD patients with liver fibrosis exhibited distinct changes in serum phospholipids, characterized by reduced sphingomyelin and phosphatidylcholine levels and elevated phosphatidylethanolamine levels. Based on these phospholipid changes, we developed a fibrosis prediction model that outperformed other serum biomarkers. We also elucidated the underlying mechanism of these phospholipid changes in relation to serum lipoproteins and liver transcriptomics. Specifically, a significant correlation between serum sphingomyelin and LDL-cholesterol levels was identified. Reduced serum LDL-cholesterol levels could be attributed to fibrotic liver and down-regulated expression of LIPC, which encodes the hepatic lipase that catalyzes LDL-cholesterol synthesis. Conclusions: Serum phospholipid profiles represent an effective biomarker of liver fibrosis and help enhance understanding of the pathology of MASLD.