Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention

Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort.

We quantified a broad cardiometabolic proteome (>300 proteins) in 67 individuals randomized in a 2×2 factorial design to alternate day fasting and exercise before and after the 3-month intervention to identify proteomic signatures of hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction). Then, we analyzed the cross-sectional relationship of overlapping proteins (≈170) with hepatic attenuation (a computed tomographic technique linked to steatosis) in 707 participants from a community cohort. Principal component analysis demonstrated a proteomic signature associated with intrahepatic triglyceride content (Spearman rho=0.55, P<0.001) and insulin resistance (homeostatic model assessment for insulin resistance, Spearman rho=0.39, P=0.001). Changes in this proteomic signature were associated with changes in intrahepatic triglyceride content over the intervention period (beta=0.12, P<0.001). Moreover, cross-sectional analysis of overlapping proteins with hepatic attenuation in the community cohort showed generally, directionally consistent associations with hepatic steatosis.

These findings highlight the potential for broad proteomic profiling in small nutritional interventional studies with serial phenotyping alongside confirmatory large cohort epidemiology to prioritize targets of hepatic steatosis and cardiometabolic risk for mechanistic study.