A Potential Early Biomarker for MASLD: Oxidized Apolipoproteins

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) were found to exhibit previously unreported—and elevated—sequences of oxidized serum proteins (apolipoproteins), according to a recent study.

These new findings, published in Liver International, still warrant further investigation; however, this biomarker has the potential to transform diagnostic panels and clinical understandings of the metabolic features at work in MASH.¹

MASLD, which was renamed from nonalcoholic fatty liver disease (NAFLD) in 2023, impacts approximately 30% of the global population, and encompasses a variety of histological characteristics, including steatohepatitis (MASH), the inflammatory progression of the disease.²

The authors outlined how lipidomics and proteomics in patients’ blood or liver tissues have been the primary means of studying the pathological mechanisms of MASLD. Alas, “serum mass spectrometry proteomics is analytically challenging as circulating proteins are present over a wide concentration range and are dominated by high abundance proteins such as albumin.” To combat these difficulties, the researchers evaluated the efficacy of peptidomics to broaden clinical knowledge of MASLD using organic, solvent-based precipitation. They add how this method has proved successful in prior studies for removing high concentrations of certain proteins.¹

The NAFLD Service from Cambridge University Hospitals NHS Foundation Trust was used to recruit eligible patients with MASLD, while the NIHR Cambridge BioResource alongside the NHS Blood and Transplant Unit was used to recruit an age- and sex-matched control group.

In total, 149 serum samples were gathered. Some were used for targeted peptidomics (n = 87 patients with MASLD; n = 20 controls). Researchers conducted untargeted serum proteomic and peptidomic analyses on the other 42 male participants, including 9 healthy controls and 33 patients with varying degrees of MASLD, to distinguish between the 2 groups before validating their most important findings with targeted samples.

Researchers found 28 varied protein expressions in the MASLD group that were tied to lipoprotein and lipid metabolism (APOA4, APOD, APOE, APOL1), immune response (C3, VTN, IGKV2D-29, IGKC, HPR, IGKV3-11, IGHA1, IGLV3-19, IGKV1D-12), cellular oxidant detoxification (ALB, HBB, HBD, APOE, HBA1), and antioxidant activity (ALB, APOA4, HPR, APOE). After conducting a Pearson correlation analysis, they saw that the aforementioned proteins greatly correlated with body mass index (BMI), insulin resistance—both of which were markedly higher in patients with MASLD—and transaminase levels.

“Across the MASLD spectrum, after multiple comparison correction, we did not observe significant proteomics differences suggesting that disease progression has limited impact on these hits that are already modulated in the early stages of the disease,” the authors write. Additionally, they observed lower levels of non-oxidized ApoC-III₀, ApoC-III_i and ApoC-III_ii, as well as increased levels of their oxidized proteoforms in those with MASLD vs controls, when they centered on oxidative status for participants’ ApoC-III peptides.

“Oxidised ApoE and ApoC-III peptide fragments were also significantly correlated with obesity, insulin resistance, dyslipidaemia and transaminases, suggesting a potential link between circulating apolipoprotein oxidation and systemic/hepatic metabolic dysfunction,” the researchers add.

Researchers concluded saying that their findings indicate increased oxidation in ApoC-III to be a specific process occurring for those affected by MASLD. Furthermore, these results suggest that oxidation of ApoC-III and ApoE could be an early manifestation of MASLD. The authors urged for further research on non-invasive biomarkers in this patient population to broaden clinical understandings of these processes.

References

1. Mocciaro G, George AL, Allison M, et al. Oxidised apolipoprotein peptidome characterizes metabolic dysfuntion-associated steatotic liver disease. Liver Int. 2025;45(2):e16200. doi:10.1111/liv.16200

2. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335-1347.doi:10.1097/HEP.0000000000000004