KLF15 regulates sulfur amino acid metabolism through Cystathionine gamma-lyase

High-protein diets increase hepatic sulfur amino acid metabolism, but the underlying transcriptional mechanisms remain unclear. This study investigated whether Krüppel-like factor 15 (KLF15) directly regulates cystathionine γ-lyase (CTH), a key enzyme linking methionine transsulfuration to hydrogen sulfide (H₂S) and taurine production. Promoter-reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation identified two functional KLF15-binding elements, designated 1-1 and 2-2, within the proximal Cth promoter. Mutation of either element attenuated KLF15-dependent promoter activation, whereas mutation of both largely abolished it. In vivo luciferase imaging further demonstrated that these elements were required for the hepatic transcriptional response to a high-protein diet. KLF15 loss of function reduced high-protein-diet-induced Cth expression and altered the hepatic sulfur amino acid profile. Methionine, cystathionine, and cystine accumulated, whereas taurine production and the high-protein-diet-induced increase in hepatic H₂S were attenuated. Gene expression analyses further indicated that KLF15 selectively regulates components of methionine, taurine, and H₂S metabolism rather than controlling the entire sulfur metabolic program. Collectively, these findings establish the high-protein diet-KLF15-CTH axis as a physiologically relevant transcriptional pathway that amplifies hepatic sulfur amino acid disposal and directs sulfur toward H₂S and taurine production.