The asymmetric Pitx2 regulates intestinal muscular-lacteal development and protects against fatty liver disease

Abstract

SUMMARYIntestinal lacteals are the essential lymphatic channels for absorption and transport of dietary lipids and drive pathogenesis of debilitating metabolic diseases. Yet, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover a novel intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer, ASE, alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic-dependent lipid transport. Surprisingly, activation of lymphatic-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. In summary, our studies reveal the molecular mechanism linking gut lymphatic development to the earliest symmetry-breaking Pitx2 and highlight the important relationship between intestinal lymphangiogenesis and gut-liver axis. GRAPHICAL ABSTRACTHIGHLIGHTS∼ Gut lymphangiogenesis is linked to Pitx2-driven LR asymmetry∼ Lacteal-associated smooth muscle requires ASE∼ ASE deletion leads to redox imbalance in intestinal smooth muscle lineage∼ ASE is required for the normal route of dietary lipid transport∼ Pitx2ASE/ASE neonates develop diet-induced fatty liver disease