The KLB rs12152703 variant confers protection against hepatic inflammation in patients with MASLD by boosting Klotho-beta expression

Background & Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease worldwide, paralleling the rising prevalence of obesity. We previously reported that the rs17618244 variant in the Klotho-beta (KLB) gene, which encodes the hepatic obligate co-receptor of fibroblast growth factor receptor 4 (FGFR4), reduces hepatic and circulating KLB levels, leading to more severe MASLD in both children and adults. The present study aimed to evaluate the impact of another KLB variant, the intronic rs12152703 G>T polymorphism, on histological liver damage in patients with MASLD. Methods: The rs12152703 variant was genotyped in 1,311 patients with biopsy-proven MASLD, including 261 children, and its association with the disease spectrum was assessed. We also investigated the relationship between this variant and hepatic and circulating KLB expression. Finally, we evaluated in an in vitro model whether KLB overexpression in HepG2 cells affects lipid homeostasis and inflammation. Results: In multivariate analyses, the KLB rs12152703 variant was associated with lower serum aminotransferase levels and protection against steatosis, lobular inflammation, and steatohepatitis in the overall cohort (p <0.05). Hepatic and circulating KLB levels were increased in both adult and pediatric patients with MASLD carrying the variant (p <0.05). In vitro, KLB overexpression reduced intracellular lipid accumulation in free fatty acid-loaded HepG2 cells by modulating the expression of genes involved in lipid metabolism. Moreover, KLB induction counteracted lipopolysaccharide–induced activation of inflammatory genes and NF-κB (p65) phosphorylation. Conclusions: The KLB rs12152703 variant confers protection against lobular inflammation and is associated with increased hepatic and circulating KLB levels, in contrast to the at-risk rs17618244 variant. Consistently, KLB overexpression ameliorated steatosis and the pro-inflammatory state in lipid-loaded hepatocytes. These findings suggest that KLB may represent a novel druggable target for the treatment of severe MASLD. Impact and implications: This study highlights the protective effect of a genetic variant in the Klotho-beta (KLB) gene in attenuating hepatic inflammation and disease severity in both adults and children with metabolic dysfunction-associated steatotic liver disease. The favorable clinical associations appear to be mediated by increased circulating and hepatic KLB protein levels. Consistently, KLB overexpression alleviates lipid overload in hepatocytes by modulating the expression of genes involved in lipid metabolism. Together, these findings support the FGF19/KLB axis as a promising therapeutic target for the treatment of severe metabolic dysfunction-associated steatotic liver disease.