Brain control of hepatic bile acid homeostasis through Bdnf exon I-positive neurons in the paraventricular hypothalamus

Bile acids (BAs) are produced in the liver and regulate whole-body cholesterol balance. Whether and how the brain regulates liver function, including BA homeostasis, remains largely unexplored. Here we show that a subpopulation of liver-connected Bdnf-e1-expressing hypothalamic neurons regulates BA metabolism in the liver.

Bdnf-e1 mutant mice (Bdnf-e1−/−) exhibit a decreased BA synthesis, elevated cholesterol levels and phenotypes resembling metabolic dysfunction-associated fatty liver disease (MAFLD). These are accompanied by impaired sympathetic innervation in the liver. Transsynaptic and retrograde-tracing identify a group of liver-connected neurons in paraventricular hypothalamic nucleus (PVH) co-expressing Bdnf-e1 mRNA and the BDNF receptor TrkB.

Deletion of the Bdnf gene in PVH reduces hepatic bile acid synthesis, while activating BDNF-TrkB signaling in PVH effectively rescues the deficits in bile acid synthesis and MAFLD phenotypes of Bdnf-e1−/− mice. Collectively, these results reveal a brain-liver axis, and identify a specific role of PVH Bdnf-e1-expressing neurons in regulating hepatic bile acid metabolism. We thank all members from Bai Lu lab at Tsinghua University for support and constructive advice.

This research was funded by the National Key Research and Development Program of China (2017YFE0126500), the National Natural Science Foundation of China (20221300592, 81861138013, 81501105, 31730034), Shanghai Academy of Natural Sciences, to B.L. These authors contributed equally: Mengfei Sun, Haochen Zhu. School of Pharmaceutical Sciences, Tsinghua University, Beijing, China Tsinghua-Peking Center for Life Sciences, Beijing, China School of Medicine, Tsinghua University, Beijing, China Institute for Immunology and School of Basic Medical Sciences, Beijing Key Laboratory of Immunological Research of Allergy (LIRA), Tsinghua Medicine, Tsinghua University, Beijing, China SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, China Institute of Biomedical Sciences, Fudan University, Shanghai, China Shanghai Academy of Natural Sciences, Shanghai, China The authors declare no competing interests.

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