LKB1 in Intestinal Epithelial Cells Regulates Bile Acid Metabolism by Modulating FGF15/19 Production

Abstract

BACKGROUND & AIMS: Liver kinase B1 (LKB1) is a master upstream protein kinase involved in nutrient sensing and glucose and lipid metabolism in many tissues; however, its metabolic role in intestinal epithelial cells (IEC) remains un-clear. In this study, we investigated the regulatory role of LKB1 on bile acid (BA) homeostasis.& nbsp;METHODS: We generated mice with IEC-specific deletion of LKB1 (LKB1(delta IEC)) and analyzed the characteristics of IEC development and BA level. In vitro assays with small interfering RNA, liquid chromatography/mass spectrometry, meta-genomics, and RNA-sequencing were used to elucidate the regulatory mechanisms underlying perturbed BA homeostasis.& nbsp;RESULTS: LKB1 deletion resulted in abnormal differentiation of secretory cell lineages. Unexpectedly, BA pool size increased substantially in LKB1(delta IEC)& nbsp;mice. A significant reduction of the farnesoid X receptor (FXR) target genes, including fibroblast growth factor 15/19 (FGF15/19), known to inhibit BA syn- thesis, was found in the small intestine (SI) ileum of LKB1(delta IEC)& nbsp;mice. We observed that LKB1 depletion reduced FGF15/19 protein level in human IECs in vitro. Additionally, a lower abundance of bile salt hydrolase-producing bacteria and elevated levels of FXR antagonist (ie, T-bMCA) were observed in the SI of LKB1(delta IEC)& nbsp;mice. Moreover, LKB1(delta IEC)& nbsp;mice showed impaired conversion of retinol to retinoic acids in the SI ileum. Subsequently, vitamin A treatment failed to induce FGF15 production. Thus, LKB1(delta IEC)& nbsp;mice fed with a high-fat diet showed improved glucose tolerance and increased energy expenditure.& nbsp;CONCLUSIONS: LKB1 in IECs manages BA homeostasis by con- trolling FGF15/19 production.