VLDL lipidomics reveals hepatocellular lipidome changes in metabolic dysfunction-associated steatotic liver disease.

BACKGROUND

The production of VLDL is one of the primary mechanisms through which liver cells regulate intracellular lipid homeostasis. We hypothesize that the disease characteristics of metabolic dysfunction-associated steatotic liver disease (MASLD) differentially impact VLDL lipid composition. This study comprehensively examines the relationship between VLDL-lipidome and MASLD histology and disease-associated genetics, aiming to define MASLD-related VLDL changes.

METHODS

We performed untargeted lipidomics on serum VLDL particles in a cohort of biopsy-proven MASLD patients to examine the relationship between VLDL-lipidome and MASLD disease features as well as MASLD-related genetic variants.

RESULTS

Among 1514 detected lipid species in VLDL, triglyceride (TG), phosphatidylcholine (PC), and ceramide (Cer) were the top classes. Moderate to severe hepatic steatosis was associated an increase in VLDL-TG, especially those with palmitic acid (C16:0). A unified acyl chain distribution analysis revealed that steatosis was associated with increases in TGs with saturated and monounsaturated fatty acyl chains, but decreases in polyunsaturated fatty acyl chains, a pattern that was not mirrored in acyl chains from VLDL-PC or VLDL-Cer. Lobular inflammation was associated with reductions in lipids with polyunsaturated acyl chains, particularly docosahexaenoic acid (C22:6). Meanwhile, patients with advanced liver fibrosis (stages 3-4) had reductions in VLDL-TGs with both saturated and polyunsaturated acyl chains and overall enrichment in Cer species. Furthermore, MASLD-associated genetic variants in PNPLA3, TM6SF2, GPAM, HSD17B13, and MTARC1 demonstrated distinct VLDL-lipidomic signatures in keeping with their biology in lipoprotein metabolism.

CONCLUSIONS

Hepatic steatosis and liver fibrosis in MASLD are associated with distinct VLDL-lipidomic signatures, respectively. This relationship is further modified by MASLD-genetics, suggesting a differential impact of pathogenic features on hepatocellular lipid homeostasis.