The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease
| Autor: | Nathan R. Souchet, Aparna Mahadevan, Natasza A. Kurpios, Gerald E. Duhamel, Alessandra K. Taboada, Bhargav D. Sanketi, Ge Tao, Shing Hu, Gloria H. Bae, Carolyn S. Sevier, Joseph Choi, Isaac F. Elysee |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Lacteal Duodenum Morphogenesis Biology General Biochemistry Genetics and Molecular Biology Article Pathogenesis Mice medicine Animals Intestinal Mucosa Lymphangiogenesis Transcription factor Lymphatic Vessels Homeodomain Proteins PITX2 Fatty liver Biological Transport medicine.disease Lipid Metabolism Dietary Fats Lipids Cell biology Intestines Lymphatic system medicine.anatomical_structure Female Signal Transduction Transcription Factors |
| Zdroj: | Cell reports |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. Graphical Abstract In brief Lacteals drive dietary lipid absorption, but how they form remains mostly unknown. Hu et al. demonstrate how the Pitx2 gene directs lacteal development through the adjacent muscle lineage and protects against fatty liver disease. This holds promise for combating intestinal diseases and identifying regulators of alternative fat absorption pathways. |
| Databáze: | OpenAIRE |
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