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

Abstract

Intestinal 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.

Brain-gut-liver axis: Chronic psychological stress promotes liver injury and fibrosis via gut in rats

“…The direct consequence of impaired intestinal barrier function is that harmful substances, such as LPS, enter into the circulatory system (Forlano et al, 2022). LPS can cause disorders to the immune system within the liver via "gut-liver" axis and mediate the inflammatory cascade, up-regulate Fas antigen expression in liver cells, activate Kupffer cells and hepatic stellate cells, thereby accelerating liver apoptosis, promoting the formation of the extracellular matrix, leading to liver injury and progression of liver fibrosis (Muschen et al, 1998;Henao-Mejia et al, 2012;Kumar et al, 2017;Castillo-Dela Cruz et al, 2019;Hu et al, 2020;Hu et al, 2021;Forlano et al, 2022). Additionally, some studies have found that anxiety can also increase LPS levels in feces and blood of rats (Jang et al, 2018).…”