EFFECTS OF AMP-ACTIVATED PROTEIN KINASE ON INTESTINAL HEALTH

Xiaofei Sun

Intestinal health is based on a delicate homeostasis of epithelial proliferation and differentiation. Disruptions of intestinal homeostasis are associated with a broad range of pathological changes including metabolic disorders, inflammatory and autoimmune diseases and cancers. AMP-activated protein kinase (AMPK), a highly-conserved energy sensor, has a crucial role in mediating paracellular junctions, nutrient transporters, autophagy, apoptosis, inflammation and carcinogenesis. In this dissertation, the impacts of AMPK on intestinal epithelial differentiation, barrier function and colorectal tumorigenesis were investigated. We found that AMPK activation enhanced epithelial differentiation and improved the barrier function, while AMPK inhibition both in vivo and in vitro impaired intestinal barrier function, integrity and ultrastructure of tight junction. These changes were correlated with the expression of caudal type homeobox 2 (CDX2), the key transcription factor committing cells to intestinal epithelial lineage. CDX2 deficiency abolished intestinal differentiation promoted by AMPK activation. Mechanistically, AMPK induced CDX2 alteration was partially mediated by altered histone modifications in the Cdx2 promoter. We further found that AMPK deficiency in intestinal stem cells caused colonic hyperproliferation and pathological features, which was associated with the reduction of metabolites, acetyl-CoA and α-ketoglutarate, production and ten-eleven translocation hydroxylases activity. Furthermore, AMPK knockout in intestinal stem cells accelerated the development of colon tumorigenesis including the augmentation of tumor number, tumor size, and hyperplasia. The deteriorated colorectal tumorigenesis induced by AMPK ablation might result from the alteration of metabolites, as indicated by the reduced production of acetyl-CoA and α-ketoglutarate in colonic tissue. Metabolic remodeling further inactivated hydroxylases and promoted the inhibtion of colon cancer related genes. Finally, we found that purple potato extract (PPE) improved gut epithelial differentiation and barrier function, and AMPK ablation abolished the beneficial effects of PPE, in junction with the reduced expression of CDX2. In summary, 1) AMPK improves intestinal epithelial differentiation and barrier function via regulating CDX2 expression, 2) AMPK deficiency deteriorates colorectal tumorigenesis, 3) PPE promotes intestinal epithelial differentiation and barrier function by activating AMPK. Thus, AMPK provides an ideal therapeutic target for attenuating intestinal diseases.

EFFECTS OF AMP-ACTIVATED PROTEIN KINASE ON INTESTINAL HEALTH

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