The mood stabilizers lithium and valproate disrupt hepatic and intestinal farnesoid X receptor signalling and increase bile synthesis in the rat

Abstract

The mood stabilizers lithium and valproate are psychotropic medications widely used in clinical practice. Despite their proven benefits, many individuals stop their treatment due to the adverse effects. Chronic diarrhoea is a common reason for discontinuation of these drugs; however, the underlying mechanisms are unknown. Excessive loss of bile acids (BA) into the colon is a major cause of diarrhoea. Therefore, we aimed to investigate the effects of these drugs on BA metabolism. We measured BA levels in the liver, plasma and faeces of Sprague-Dawley rats treated with lithium or valproate for 4 weeks. Next, we analysed changes in the expression of genes and proteins involved in BA production and enterohepatic circulation. Lithium and valproate markedly increased BA levels across all body sites. This was accompanied by the up-regulation of hepatic cytochrome P450 7A1 (Cyp7a1), the rate-limiting enzyme in de novo BA synthesis. Under normal conditions, elevated levels of BAs suppress Cyp7a1 via activation of the hepatic farnesoid X receptor (Fxr)/small heterodimer partner (Shp) and intestinal Fxr/fibroblast growth factor 19 (Fgf19) pathways. This signalling was disrupted in both treatment groups. The Fxr-mediated responses in the expression of Ntcp, Asbt, Ilbp and Ostα/β bile transporters were also affected by treatment. In conclusion, lithium and valproate disrupted farnesoid X receptor signalling at the hepatic and intestinal levels, inducing sustained overproduction of bile in rats. These findings provide novel insights into the peripheral effects of these drugs. Given that similar changes in bile circuits underlie the pathophysiology of primary BA diarrhoea in humans, this study suggests a potential mechanism behind chronic diarrhoea in patients undergoing lithium or valproate therapy.

Keywords: ASBT; CYP7A1; FGF19; FXR; bile acid diarrhoea; bile acids; lithium; liver proteome; mood stabilizer; valproate.