ANGPTL6 (angiopoietin-like 6) is a hepatokine that functions as a metabolic regulator with pleiotropic effects on energy expenditure, glucose homeostasis, and vascular biology. Primary Function: ANGPTL6 acts as a compensatory metabolic factor that increases energy expenditure to counteract obesity and insulin resistance 1. Its expression is regulated by leptin, with hepatic ANGPTL6 upregulated during metabolic stress such as high-fat diet exposure 1. Mechanism: ANGPTL6 promotes endothelial cell migration and angiogenesis through ERK1/2 and AKT pathway activation 2. In normal pregnancies, cord ANGPTL6 correlates negatively with neonatal fat mass and positively with maternal glucose homeostasis; however, this relationship is disrupted in gestational diabetes 3. Disease Relevance: ANGPTL6 genetic variants are significantly associated with familial intracranial aneurysms, suggesting a critical role in vascular wall integrity 4. ANGPTL6 polymorphisms show associations with hypercholesterolemia risk in population studies 5. Elevated ANGPTL6 serves as an independent diagnostic and prognostic biomarker for hepatocellular carcinoma and AFP-producing gastric cancer 62. Serum ANGPTL6 levels increase in hypothyroidism, correlating with TSH and free T4 7. Clinical Significance: ANGPTL6 represents a potential therapeutic target for metabolic and vascular diseases, though human genetic associations show weak effects requiring further investigation 8.