Abstract
BackgroundAlthough metabolic associate fatty liver disease (MAFLD) is associated with obesity, it can also occur in lean patients. MAFLD is more aggressive in lean patients compared to obese patients, with a higher risk of mortality. Specific biomarkers to diagnose differentially lean or overweight MAFLD are missing. Histones and nucleosomes are released in the bloodstream upon cell death. Here, we propose a new, fast, imaging and epigenetics based approach to investigate the severity of steatosis in lean MAFLD patients.ResultsA total of 53 non-obese patients with histologically confirmed diagnosis of MAFLD were recruited. Twenty patients displayed steatosis grade 1 (0–33%), 24 patients with steatosis grade 2 (34–66%) and 9 patients with steatosis grade 3 (67–100%). The levels of circulating nucleosomes were assayed using enzyme-linked immunosorbent assay, while individual histones or histone dimers were assayed in serum samples by means of a new advanced flow cytometry ImageStream(X)-adapted method. Circulating nucleosome levels associated poorly with MAFLD in the absence of obesity. We implemented successfully a multi-channel flow methodology on ImageStream(X), to image single histone staining (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2). We report here a significant depletion of the levels of histone variants macroH2A1.1 and macroH2A1.2 in the serum of lean MAFLD patients, either individually or in complex with H2B.ConclusionsIn summary, we identified a new circulating histone signature able to discriminate the severity of steatosis in individuals with lean MAFLD, using a rapid and non-invasive ImageStream(X)-based imaging technology.
Highlights
Metabolic associate fatty liver disease (MAFLD) is associated with obesity, it can occur in lean patients
metabolic associate fatty liver disease (MAFLD) is mostly correlated to obese patients, it can occur in lean patients: in Asian populations, 27% of lean individuals with normal Body mass index (BMI) present with MAFLD, which is unrelated to metabolic syndrome compared to people with high BMI (19% Vs. 61%) [7]; while in Europe and in the USA, a lower prevalence of lean MAFLD/ NASH, in this case, associated to the metabolic syndrome, was reported [7]
In an effort to identify new epigenetic liquid biopsies for MAFLD, we have recently shown a strong correlation between fatty liver index [FLI, a simple MAFLD predictor based on BMI, waist circumference, triglycerides and GGT [14]], and high level of circulating nucleosomes in obese patients with metabolic syndrome with MAFLD [15]
Summary
Metabolic associate fatty liver disease (MAFLD) is associated with obesity, it can occur in lean patients. MAFLD is considered more aggressive in lean patients compared to obese patients for liver disease progression, as assessed histologically [9] and longitudinally [10], with a higher risk of mortality [11]. Other studies challenged this view [12, 13]. In an effort to identify new epigenetic liquid biopsies for MAFLD, we have recently shown a strong correlation between fatty liver index [FLI, a simple MAFLD predictor based on BMI, waist circumference, triglycerides and GGT [14]], and high level of circulating nucleosomes in obese patients with metabolic syndrome with MAFLD [15]. The potential of circulating nucleosomes to serve as biomarkers, or “liquid biopsies” is, a promising area of research for early cancer detection and monitoring treatment responses
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