Fluoxetine-induced hepatic lipid accumulation is linked to elevated serotonin production

Abstract

Fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor antidepressant, has been shown to increase hepatic lipid accumulation, a key factor in the development of non-alcoholic fatty liver disease. Interestingly, fluoxetine has also been reported to increase peripheral serotonin synthesis. As emerging evidence suggests that serotonin may be involved in the development of non-alcoholic fatty liver disease we sought to determine if fluoxetine-induced hepatic lipid accumulation is mediated via altered serotonin production. Fluoxetine treatment increased lipid accumulation in association with increased mRNA expression of tryptophan hydroxylase 1 (<i>Tph1, serotonin biosynthetic enzyme) and intracellular serotonin content. Serotonin alone had a similar effect to increase lipid accumulation. Moreover, blocking serotonin synthesis reversed the fluoxetine-induced increases in lipid accumulation. Collectively, these data suggest that fluoxetine induced lipid accumulation can be mediated, in part, by elevated serotonin production. These results suggest a potential therapeutic target to ameliorate the adverse metabolic effects of fluoxetine exposure.

Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ12,14PGJ2

“…Long‐term SSRI use is associated with increased weight gain, dyslipidemia, and new‐onset type 2 diabetes (Ferguson, 2001; Jerrell, 2010; Raeder et al, 2006; Sussman & Ginsberg, 1998; Yoon et al, 2013). Moreover, animal and cell culture experiments have shown that fluoxetine exposure increases hepatic triglyceride content and lipid accumulation, hallmarks of NAFLD (Ayyash & Holloway, 2021; De Long et al, 2015; Feng et al, 2012; Lu et al, 2020; Pan et al, 2018; Xiong et al, 2014). While the mechanisms by which fluoxetine leads to hepatic steatosis are not fully elucidated, there is evidence that altered prostaglandin production may be a key mediator of fluoxetine‐induced lipid accumulation.…”

“…Long-term SSRI use is associated with increased weight gain, dyslipidemia, and new-onset type 2 diabetes (Ferguson, 2001;Jerrell, 2010;Raeder et al, 2006;Sussman & Ginsberg, 1998;Yoon et al, 2013). Moreover, animal and cell culture experiments have shown that fluoxetine exposure increases hepatic triglyceride content and lipid accumulation, hallmarks of NAFLD (Ayyash & Holloway, 2021;Feng et al, 2012;Lu et al, 2020;Pan et al, 2018;Xiong et al, 2014).…”

“…F597100; N = 5 independent experiments) to assess lipid accumulation and involvement of the prostaglandin biosynthetic pathway as described below. The 10μM concentration of fluoxetine and 24h time point used has been shown to result in increased lipid accumulation in the H4‐II‐E‐C3 (Ayyash & Holloway, 2021) and primary rat hepatocytes (Feng et al, 2012; Xiong et al, 2014).…”

Intestinal Dysbiosis, the Tryptophan Pathway and Nonalcoholic Steatohepatitis

“…Fluoxetine induced hepatic lipid accumulation through upregulation of TPH1 expression and subsequent increased blood concentration of 5-HT. 57 …”

Serotonergic Regulation of Hepatic Energy Metabolism

“…Patients who received TCAs (imipramine, tianeptine) [62,63] and SNRIs (venlafaxine, duloxetine) developed hepatic steatosis [64,65]. A clinical study showed that fluoxetine, an SSRI, increased serum triglyceride levels and hepatic lipid accumulation [66,67]. A clinical trial on the cardiometabolic benefits of lorcaserin, a 5-HT2C receptor agonist, showed that lorcaserin significantly improved fatty liver in obese adults, and the effect remained significant even after controlling for fat mass and change in body weight [68].…”