Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Haub, Synia; Ritze, Yvonne; Ladel, Inga; Saum, Karolin; Hubert, Astrid; Spruss, Astrid; Trautwein, Christian; Bischoff, Stephan C.

doi:10.1124/jpet.111.181834

Cited by 58 publications

(63 citation statements)

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“…5-HT, which is produced at high amounts in the GI tract, is involved in the regulation of intestinal motility and possibly permeability [7,17,29]. Hence, we quantified 5-HT concentration, TPH1 mRNA expression, as well as 5-HT transporter (SERT), and 5-HT 3A R protein content in the duodenum of mice (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…Protein was prepared and antibodies were applied as described earlier [17]. Semi-quantitative real-time PCR analyses were performed using SsoFast EvaGreen Supermix (BioRad Laboratories, Munich, Germany) and were carried out in an iCycler (BioRad Laboratories, Munich, Germany) with 40 cycles of a two-step PCR (denaturation 95°C for 35 s, denaturation 95°C for 5 s, annealing/extension 62°C for 10 s).…”

Section: Methodsmentioning

confidence: 99%

“…Semi-quantitative real-time PCR analyses were performed using SsoFast EvaGreen Supermix (BioRad Laboratories, Munich, Germany) and were carried out in an iCycler (BioRad Laboratories, Munich, Germany) with 40 cycles of a two-step PCR (denaturation 95°C for 35 s, denaturation 95°C for 5 s, annealing/extension 62°C for 10 s). MyD88, TNF-α and β-actin primer sequences were used as previously described [17]. Tryptophan hydroxylase 1 (THP1) primer sequence: forward CAT CAG CCG AGA ACA GTT GA; reverse TTC GGA TCC ATA CAA CAG CA.…”

Section: Methodsmentioning

confidence: 99%

“…For example, serotonin (5-HT) derived from enterochromaffin cells, has been recognized as a potent pro-inflammatory mediator [16] and major regulator of intestinal permeability [14]. Interestingly, we could show that 5-HT is up-regulated in mice fed a fructose-rich diet and that liver steatosis induced by such a diet can be attenuated by suppressing 5-HT signaling [17]. The precursor of 5-HT is the amino acid tryptophan (TRP), which is also known to be a regulator of intestinal motility [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice

et al. 2013

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BackgroundSaturated fatty acids are thought to be of relevance for the development of non-alcoholic fatty liver disease and obesity. However, the underlying mechanisms are poorly understood. In previous studies we found that food-derived carbohydrates such as fructose alter the intestinal serotonergic system while inducing fatty liver disease in mice. Here, we examined the effect of fatty acid quantity (11% versus 15%) and quality (saturated, monounsaturated, or polyunsaturated fatty acids) on hepatic fat accumulation, intestinal barrier and the intestinal serotonergic system.MethodsC57BL/6 mice had free access to diets enriched with one of the three fatty acids or standard diet, for 8 weeks. In an additional experiment mice were fed diets enriched with saturated, monounsaturated fatty acids or standard diet supplemented with tryptophan (0.4 g/(kg.d), 8 weeks) or not. Hepatic fat accumulation, small intestinal barrier impairment and components of the serotonergic system were measured with RT-PCR, western blot or immunoassays. For statistical analysis t-test and one-way ANOVA with Tukey’s post hoc test and Bartlett’s test for equal variances was used.ResultsHepatic triglycerides, liver weight and liver to body weight ratio were significantly changed depending on the fat quality but not fat quantity. In contrast, fat quantity but not quality decreased the expression of the tight junction proteins occludin and claudin-1 in the small intestine. These changes seemed to result in enhanced portal vein endotoxin concentrations and fatty liver disease after feeding diet enriched with saturated and monounsaturated fatty acids but not polyunsaturated fatty acids. Neither fatty acid quantity nor quality significantly influenced the intestinal serotonergic system. Similarly, tryptophan supplementation had no impact on small intestinal barrier or fatty liver disease.ConclusionIn conclusion, diets rich in saturated or monounsaturated fatty acids promote the development of fatty liver disease in mice, likely by a dysfunction of the small intestinal mucosal barrier.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice

et al. 2013

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“…Besides this, Haub et al have suggested that serotonin may raise the fat concentration of the liver [29]. Comparing lean control mice, there is an increase of duodenal Htr3a protein expression and plasma serotonin levels in ob/ob mice.…”

Section: Serotonin and Lipid In The Liver And The Circulationmentioning

confidence: 97%

Energy Homeostasis by the Peripheral Serotonergic System

Watanabe

Rose²,

Kanayama

et al. 2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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Energy homeostasis is maintained by balancing energy intake and energy expenditure. In addition to the central nervous system, several hormones play a key role in energy homeostasis in the whole body. In particular, serotonin is regarded as one of the key regulators of energy homeostasis. Serotonin is unique in that it is able to act in both the brain as a neurotransmitter and the peripheral tissue as a gastrointestinal hormone. In the brain, serotonin is thought of as a pharmacological target for anti-obesity treatments because it greatly inhibits meal size and body weight gain. In contrast, serotonin in the periphery has not been targeted as a strategy for anti-obesity treatment, even though almost all of the serotonin produced in the body is produced in the peripheral tissue. Recently, the peripheral serotonergic signal has been shown to regulate glucose and lipid metabolism through autocrine and paracrine signals in energy homeostasis-related tissues, including the pancreatic β cell, liver, white adipose tissue, brown adipose tissue, and skeletal muscle. Thus, it is possible that the serotonergic system in the peripheral tissue is a new therapeutic target for metabolic disease, including obesity and diabetes. Here, we summarize the role of peripheral serotonin in the regulation of energy homeostasis.

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Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

Kyritsi

Chen²,

O’Brien³

et al. 2019

Hepatology

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Background and Aims Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO‐A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5‐hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile‐duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. Approach and Results While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout (Mdr2–/–) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO‐A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2–/–‐ mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2–/–‐ mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2–/– mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2–/– mice, respectively. 5HT levels increase in Mdr2–/– mice and in PSC human patients compared to their controls and decrease in serum of Mdr2–/– mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2–/– mice. In vitro, cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO‐A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. Conclusions Modulation of the TPH1/MAO‐A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.

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Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Cited by 58 publications

References 32 publications

Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice

Role of serotonin in fatty acid-induced non-alcoholic fatty liver disease in mice

Energy Homeostasis by the Peripheral Serotonergic System

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

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