Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile

Bile acids have recently emerged as potential neuroprotective agents that may modulate neurodegeneration. Most studies have focused on the single bile acid tauroursodeoxycholic acid (TUDCA) and its role as an anti-apoptotic agent. We studied other bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), and for liver X receptor (LXR), as potential neurotrophic agents. We used two in vitro model systems to identify the effects of bile acids and related pharmacological agents on neurite outgrowth using quantitative image analysis. We also identified early effects on gene expression using RNA sequencing analysis. We found that 20 uM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 uM retinoic acid (RA) with similar, but slightly less robust effects observed for chenodexoycholic acid (CDCA) at 20 uM and in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, TGR5 agonism was comparable to DCA stimulation, stronger than RA, and neither FXR nor LXR inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.