LEPROTL1 is a tetraspanning membrane protein that negatively regulates growth hormone (GH) receptor signaling, primarily in the liver 1. The protein functions by reducing GH receptor cell-surface expression through its involvement in intracellular protein trafficking, specifically the late endosome to vacuole transport pathway 2. LEPROTL1 cooperates with LEPROT to control hepatic GH sensitivity, particularly during periods of nutrient restriction 1. Gene silencing of LEPROTL1 in hepatocytes enhances GH signaling and increases cell-surface GH receptor levels, while transgenic overexpression impairs hepatic GH sensitivity as measured by STAT5 phosphorylation and reduced IGF1 levels 1. FGF21-mediated induction of LEPROTL1 during calorie restriction decreases GH binding and inhibits GH-stimulated growth in chondrocytes, providing a mechanistic link between nutritional signals and growth regulation 3. Beyond metabolic functions, non-coding mutations in LEPROTL1 occur frequently in bladder cancer and show promise as non-invasive urinary biomarkers for cancer detection and recurrence monitoring 4. Additionally, evidence suggests LEPROTL1 undergoes stop codon readthrough in humans, potentially generating functionally distinct protein variants 5. LEPROTL1 expression correlates with improved insulin sensitivity and metabolic pathway upregulation in skeletal muscle 6.