A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

Nonogaki, Katsunori; Kaji, Takao; Murakami, Masuo

doi:10.4172/neuropsychiatry.1000358

Cited by 4 publications

(9 citation statements)

References 24 publications

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Section: Discussionmentioning

confidence: 95%

“…We have previously reported that treatment with PCPA for 3 days suppresses daily food intake, body weight gain and the increases in plasma FGF21 levels and insulin levels in C57BL6J mice fed a high-fat diet [19]. Moreover, treatment with PCPA significantly increases expression of hepatic Nrf2 and decreases expression of hepatic FGF21 in mice fed a high-fat diet [19]. Despite decreases in daily food intake and body weight, treatment with PCPA had different effects on plasma FGF21 levels and expression of hepatic FGF21 and Nrf2 in mice fed a high-fat diet and Research Katsunori Nonogaki Figure 1: Plasma FGF21 levels (A) and hepatic FGF21 expression (B) in 9 wk-old db/db mice and C57BL6J mice.…”

Section: Discussionmentioning

confidence: 98%

“…Thus, the different effect of PCPA on hepatic FGF21 production are independent of changes in daily food intake and body weight, and could be due to the differences in blood glucose levels and hepatic gluconeogenesis. Although mice fed a high-fat diet for 9 weeks display normal blood glucose levels [19], db/ db mice displayed remarkable hyperglycemia. Although plasma FGF21 levels and hepatic FGF21 expression are increased in obese mice fed a high-fat diet, they were decreased in diabetic db/db mice associated with increased hepatic gluconeogenesis.…”

Section: Figurementioning

confidence: 99%

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A Tryptophan Hydroxylase Inhibitor Increases Hepatic FGF21 Production and Decreases Hepatic Gluconeogenesis Independently of Insulin in db/db Mice

Nonogaki¹,

Kaji²,

Murakami³

2018

Neuropsychiatry

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Background The aim of our study is to determine circulating fibroblast growth factor (FGF21) levels in obese and diabetic db/db mice, and role of serotonin (5-HT) in the regulation of hepatic FGF21 expression and circulating FGF21 levels in relation to hepatic gluconeogenesis in obese and diabetic db/db mice. Methods and results Plasma FGF21 levels and expression of hepatic FGF21 were significantly decreased in obese and diabetic db/db mice compared with age-matched C57BL6J mice. Treatment with p-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor, for 3 days significantly increased plasma FGF21 levels, and decreased body weight and hyperglycemia in db/db mice while having no significant effect on plasma insulin levels. In addition, treatment with PCPA significantly increased expression of hepatic FGF21 and decreased expression of hepatic nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in db/db mice, while having no significant effects on expression of hepatic peroxisome proliferator-activated receptor (PPAR) α, PPAR γ, and activating transcription factor 4. Moreover, treatment with PCPA significantly decreased phosphoenolpyruvate carboxykinase, glucose 6-phosphatase, fructose 1,6-bisphosphate1, Nur77, forkhead box protein O1 and peroxisome proliferatoractivated receptor γ coactivator-1α, which are involved in hepatic gluconeogenesis, in db/db mice. Conclusions These findings suggest that hepatic FGF21 production is decreased in db/db mice, and that a tryptophan hydroxylase inhibitor increases expression of hepatic FGF21 production and decreases hepatic gluconeogenesis and hyperglycemia independently of insulin in db/db mice.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 98%

Section: Figurementioning

confidence: 99%

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A Tryptophan Hydroxylase Inhibitor Increases Hepatic FGF21 Production and Decreases Hepatic Gluconeogenesis Independently of Insulin in db/db Mice

Nonogaki¹,

Kaji²,

Murakami³

2018

Neuropsychiatry

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“…Similar to what we observed in our study, the TPH1 inhibitor (LX‐1031) has been shown to ameliorate irritable bowel syndrome and chronic diarrhea through reduced 5‐HT levels . Moreover, a study has shown that p‐CPA decreases liver FGF21 expression/levels of fibroblast growth factor 21 in a mouse model of high‐fat diet, suggesting the potential role of 5HT in modulating LF in nonalcoholic fatty liver disease/nonalcoholic steatohepatitis patients …”

Section: Discussionmentioning

confidence: 99%

“…(45) Moreover, a study has shown that p-CPA decreases liver FGF21 expression/levels of fibroblast growth factor 21 in a mouse model of high-fat diet, suggesting the potential role of 5HT in modulating LF in nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis patients. (46) We next performed in vitro experiments aimed to demonstrate that the autocrine/paracrine action of serotonin on biliary proliferation/liver fibrosis is not attributed to secondary in vivo effects, but rather to a direct interaction with both cholangiocytes and HSCs.…”

Section: Discussionmentioning

confidence: 99%

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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Translation Reprogramming as a Novel Therapeutic Target in MAFLD

et al. 2022

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Approved pharmacotherapies for metabolic‐dysfunction‐associated fatty liver disease (MAFLD) are lacking. Novel approaches and therapeutic targets that are likely to translate to clinical benefit are required. Targeting components of the translation machinery hold promise as a novel therapeutic approach that can overcome the well‐known disease heterogeneity, as dysregulation of mRNA translation is a common feature independent of the MAFLD drivers. In this perspective, recent advances in understanding the role of mRNA translation in MAFLD are discussed, with a particular focus on the potential implications and challenges to “translate” these findings to the clinic, and an overview of similar recent efforts in other diseases is provided.

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A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

Abstract: Background:

Cited by 4 publications

References 24 publications

A Tryptophan Hydroxylase Inhibitor Increases Hepatic FGF21 Production and Decreases Hepatic Gluconeogenesis Independently of Insulin in db/db Mice

A Tryptophan Hydroxylase Inhibitor Increases Hepatic FGF21 Production and Decreases Hepatic Gluconeogenesis Independently of Insulin in db/db Mice

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

Translation Reprogramming as a Novel Therapeutic Target in MAFLD

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