The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.
Cell Rep
; 37(8): 110030, 2021 11 23.
Article
em En
| MEDLINE
| ID: mdl-34818545
ABSTRACT
Intestinal lacteals are essential lymphatic channels for absorption and transport of dietary lipids and drive the pathogenesis of debilitating metabolic diseases. However, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover an 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 system-dependent lipid transport. Surprisingly, activation of lymphatic system-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. Our study reveals the molecular mechanism linking gut lymphatic function to the earliest symmetry-breaking Pitx2 and highlights the important relationship between intestinal lymphangiogenesis and the gut-liver axis.
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Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Gorduras na Dieta
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Proteínas de Homeodomínio
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Intestinos
Limite:
Animals
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article