Transcription factor Klf9 controls bile acid reabsorption and enterohepatic circulation in mice via promoting intestinal Asbt expression

Shuang Liu1, Man Liu1, Meng-lin Zhang1, Cui-zhe Wang2, Yin-liang Zhang1, Yu-jie Zhang1, Chun-yuan Du1, Su-fang Sheng1, Wei Wang3, Ya-tong Fan1, Jia-ni Song1, Jin-can Huang1, Yue-yao Feng1, Wei Qiao1, Jin-long Huang1, Yu-hui Li1, Lu Zhou4, Jun Zhang2, Yong-sheng Chang1
1 Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300052, China
2 Department of Basic Medicine, Shihezi University School of Medicine, Shihezi 832000, China
3 Key Laboratory of Biotechnology of Hubei Province, Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, Hubei University, Wuhan 430062, China
4 Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
Correspondence to: Lu Zhou:, Jun Zhang:, Yong-sheng Chang:,
DOI: 10.1038/s41401-021-00850-x
Received: 10 September 2021
Accepted: 21 December 2021
Advance online: 1 February 2022


Bile acid (BA) homeostasis is regulated by the extensive cross-talk between liver and intestine. Many bile-acid-activated signaling pathways have become attractive therapeutic targets for the treatment of metabolic disorders. In this study we investigated the regulatory mechanisms of BA in the intestine. We showed that the BA levels in the gallbladder and faeces were significantly increased, whereas serum BA levels decreased in systemic Krüppel-like factor 9 (Klf9) deficiency (Klf9−/−) mice. These phenotypes were also observed in the intestine-specific Klf9-deleted (Klf9vil−/−) mice. In contrast, BA levels in the gallbladder and faeces were reduced, whereas BA levels in the serum were increased in intestinal Klf9 transgenic (Klf9Rosa26+/+) mice. By using a combination of biochemical, molecular and functional assays, we revealed that Klf9 promoted the expression of apical sodium-dependent bile acid transporter (Asbt) in the terminal ileum to enhance BA absorption in the intestine. Reabsorbed BA affected liver BA synthetic enzymes by regulating Fgf15 expression. This study has identified a previously neglected transcriptional pathway that regulates BA homeostasis.
Keywords: Klf9; Asbt; bile acid; Fgf15

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