Increased incidence of non‐alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis

Abstract

Up to 10% of women take selective serotonin reuptake inhibitors (SSRI) during pregnancy. Children exposed to SSRIs in utero have an increased risk of being overweight suggesting that fetal exposure to SSRIs can cause permanent metabolic changes. We have previously shown in rats that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations including increased hepatic triglyceride content; a hallmark of non‐alcoholic fatty liver disease (NAFLD). Therefore, the aim of this study was to identify the mechanism(s) underlying the fluoxetine‐induced increase in intrahepatic triglyceride content. Female nulliparous Wistar rats were given vehicle or fluoxetine (10 mg/kg/day) orally for 2 weeks prior to mating until weaning. At 6 months of age, we assessed whether SSRI exposure altered components of the hepatic triglyceride biosynthesis pathway in the offspring and examined the molecular mechanisms underlying these changes. Male SSRI‐exposed offspring had a significant increase in the steady‐state mRNA levels of Elovl6 and Dgat1 and core components of the NLRP3 inflammasome (apoptosis‐associated speck‐like protein containing a caspase activation recruitment domain [ASC] and caspase‐1). Augmented expression of Asc in the SSRI‐exposed offspring coincided with increased histone acetylation in the proximal promoter region. Given that we have previously demonstrated that antenatal exposure to SSRIs can lead to fatty liver in the offspring, this raises concerns regarding the long‐term metabolic sequelae of fetal SSRI exposure. Moreover, this study suggests that elevated hepatic triglyceride levels observed in the SSRI‐exposed offspring may be due, in part, to activation of the NLRP3 inflammasome and augmentation of de novo lipogenesis.

Tannic acid, a novel histone acetyltransferase inhibitor, prevents non-alcoholic fatty liver disease both in vivo and in vitro model

“…In the present study, in vitro and in vivo HAT assays clearly showed the TA inhibits HAT-induced histone acetylation. The acetylation of histone H3K9 is well known as an epigenetic marker for NAFLD [47], [50], and, as previously remarked, acetylation of proteins is associated with dynamic cellular activities in the liver [46]. In addition, we showed that TA attenuated the lipid accumulation-induced increase in acetylation levels of total proteins and histones H3K9 and H3K36 in vitro and in vivo.…”

Resveratrol Reduces Glucolipid Metabolic Dysfunction and Learning and Memory Impairment in a NAFLD Rat Model: Involvement in Regulating the Imbalance of Nesfatin-1 Abundance and Copine 6 Expression

“…FLX and DNP are other two positive control drugs used in this study to observe the behavioral performance of rats. However, lipid metabolism abnormalities have been reported in patients with depression treated with FLX (41) and patients with AD treated with DNP (42), and increased incidence of NAFLD has been found in male rat offspring exposed to FLX during the fetal and neonatal periods (43). In the present study, they showed no effect on the increased plasma glucose and lipid concentrations and the morphological and functional impairments in the liver of NAFLD rats.…”

Serum Bile Acid, Vitamin E, and Serotonin Metabolites Are Associated With Future Liver‐Related Events in Nonalcoholic Fatty Liver Disease

“…( 33 ) In rat models, fetal and neonatal exposure to fluoxetine increased the incidence of NAFLD; changes in the inflammasome and hepatic lipogenesis were observed and were considered possible mechanisms. ( 34 ) Interestingly in our analysis, controlling for serotonergic medications did not cause this metabolite to lose statistical significance, suggesting that exogenous serotonin is not the cause of this observed association between serotonin metabolites and liver‐related events. Given that serotonin modulation is already possible through existing therapies, better understanding of the relationship between serotonin and NAFLD could have direct applications to patient care.…”