Circulating Liver-Derived and CD36+ Extracellular Vesicles Correlate With Ectopic Liver Fat and Markers of Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease and Decrease During Weight Loss Intervention.

Metabolic dysfunction-associated steatotic liver disease (MASLD) lacks applicable and non-invasive biomarkers for diagnosis. The fatty acid transporter, CD36 is central for ectopic liver fat accumulation in MASLD. Extracellular vesicle (EV) secretion is modulated by lipotoxicity and since circulating EVs expectedly represent phenotype of their cell of origin, EVs hold significant biomarker potential. Using high-resolution flow cytometry, we compared levels of liver-derived (ASGR1+-EVs) and CD36+-expressing EVs (CD36+-EV) in individuals with obesity and MASLD (n = 36) with individuals with obesity (n = 25) or lean (n = 27) without MASLD. These EV-populations were assessed for all groups at baseline and during weight loss intervention for the MASLD group. In the MASLD group at baseline, ASGR1+-EVs were significantly increased compared with lean individuals, while CD36+-EVs were significantly increased compared with either control group. During intervention, levels of both ASGR1+-EVs, CD36+-EVs and ASGR1+CD36+-EVs were significantly decreased in the MASLD group already at 1 month and further reduced after 5 months. Finally, we found that CD36+-EV levels correlated with liver fat content, total body fat, and markers of liver fibrosis. Our study is the first to report levels of circulating ASGR1+-EVs and CD36+-EV in MASLD. We hereby expand knowledge about EVs in developing MASLD, while advancing their biomarker potential.