Adult-onset deficiency of β-klotho in the liver reveals a novel role in lipid homeostasis.

BACKGROUND: β-klotho (KLB), the obligate co-receptor for fibroblast growth factor (FGF) 19 and 21 signalling, has emerged as a therapeutic target for metabolic disease. Current understanding of KLB function is based largely on germline knockout mouse models, where developmental abnormalities obscure its function in adult physiology. Here, we used somatic hepatocyte-specific gene editing in adult mice to define hepatic KLB function. METHODS: Hepatocyte-specific KLB deficiency was induced by retro-orbital delivery of adeno-associated virus particles containing guide RNAs targeting Klb in adult male mice expressing Cas9 in the liver. Following transduction, mice were maintained on a 4-week chow diet or a 12-week high-fat diet, prior to comprehensive metabolic and biochemical phenotyping. RESULTS: Adult-onset hepatic KLB deficiency did not alter body weight or composition, indicating that reduced bodyweight in germline models reflects developmental effects. In line with previous studies, KLB deficiency resulted in derepressed bile acid synthesis, elevated faecal bile acid excretion, and a shift towards a more hydrophobic bile acid pool. Importantly, we also uncovered a role for hepatic KLB in regulating lipid homeostasis. Chow-fed KLB-deficient mice exhibited reduced circulating very-low-density lipoprotein levels (VLDL) with marked hepatic triglyceride accumulation, suggesting altered VLDL metabolism as a potential mechanism driving steatosis. CONCLUSIONS: Using an adult-onset liver-specific knockout model, we disentangled KLB function from developmental confounders and established KLB as a critical regulator of adult lipid and lipoprotein homeostasis. Our study redefines the physiological role of KLB in hepatic metabolism and has important implications for the interpretation of FGF19/KLB-directed therapies for metabolic diseases.