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. The authors show a brain-liver axis in which PVH Bdnf-e1-expressing neurons regulate hepatic bile acid metabolism. Findings provide new insights into the central regulation of liver metabolism and suggest a potential therapeutic target for MAFLD.