Circulating and hepatic levels of growth differentiation factor 15 in patients with metabolic dysfunction‐associated steatotic liver disease

Abstract

AbstractAimIncreased growth differentiation factor 15 (GDF15) may reflect impaired metabolic health and an inflammatory state in metabolic dysfunction‐associated steatotic liver disease (MASLD). We investigated the role of GDF15 in histologically verified MASLD in a meal test (discovery) cohort (n = 20) and a prospective (validation) cohort with 2 years of follow‐up (n = 276).MethodsParticipants were evaluated clinically and histologically in both cohorts. Fibrosis severity was classified as no/mild (F0/F1) or significant (F2–4). Plasma GDF15 was measured by enzyme‐linked immunosorbent assays and the SOMAScan platform. Hepatic GDF15 mRNA expression was analyzed by RNA in situ hybridization and bulk RNA‐sequencing. In addition, we used data from public single‐nucleus RNA‐sequencing datasets.ResultsIn both cohorts, plasma GDF15 was increased in MASLD compared with healthy controls (p < 0.0001) with the highest levels in patients with significant fibrosis (area under the curve 0.83; 95% confidence interval [CI], 0.76–0.91). The GDF15 levels were unaffected by a standardized meal and there was no difference in peripheral or hepatic venous concentrations. After 2 years, the increase in GDF15 levels was reduced in patients treated with glucagon‐like peptide receptor agonists (GLP‐1‐RA) compared to patients receiving lifestyle advice (−28%; 95% CI, −44 to −8; p = 0.01). Plasma GDF15 was associated with circulating insulin‐like growth factor 1 and related proteins. Hepatic GDF15 mRNA was mainly expressed in hepatocytes and in cholangiocytes in fibrotic areas and was increased in MASLD (p = 0.02) with the highest expression in the group with steatohepatitis (p = 0.009).ConclusionsIncreased hepatic and circulating GDF15 are found in MASLD. Treatment with GLP‐1‐RA may reduce GDF15, possibly reflecting beneficial metabolic and inflammatory effects.