Beta-Klotho Protein Expression in Healthy Human Tissues and Liver Biopsies From Patients With MASLD or MASH

Background and Aims: Biologics based on the structure of fibroblast growth factor (FGF) 19 and 21 show strong beneficial effects in the treatment of metabolic dysfunction–associated steatotic liver disease (MASLD), including compensated cirrhosis. Studies in rodents indicated that the effectiveness of these drugs relies on the presence of transmembrane protein beta-klotho (KLB). However, the tissue expression profile of KLB and its regulation in liver disease remain poorly characterized. Here, we aim to investigate KLB protein expression in healthy human tissues and liver biopsies from patients with MASLD. Methods: Following extensive antibody validation, immunohistochemical analyses were conducted on paraffin-embedded human tissue samples to determine KLB protein tissue distribution. Subcellular localization of KLB was examined in cell lines expressing KLB either ectopically or endogenously. Additionally, KLB protein levels were quantified in 28 liver biopsies from patients with MASLD within the ANCHOR cohort study and correlated with histological MASLD features and clinical patient characteristics. Results: KLB protein expression was observed in the liver, bile ducts, gallbladder, stomach, colon, adipose tissue, and pancreas. Localization studies revealed that KLB was predominantly localized to the plasma membrane in both ectopic and endogenous contexts. KLB was also detected in liver biopsies from patients with MASLD/metabolic dysfunction–associated steatohepatitis and remained expressed at advanced stages of MASLD. Lower levels of hepatic KLB protein were significantly associated with higher levels of lobular inflammation (P = .0168) but not with histology- or magnetic resonance imaging–derived scores of steatosis or fibrosis. Conclusion: This study provides insight into target organs for FGF-based drugs and demonstrates that hepatic KLB remains expressed throughout MASLD stages, supporting the use of FGF-based drugs in early and advanced stages of MASLD.