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Serotonin signals through a gut-liver axis to regulate hepatic steatosis.

Published on Dec 1, 2018in Nature Communications11.878
路 DOI :10.1038/s41467-018-07287-7
Wonsuk Choi2
Estimated H-index: 2
(KAIST),
Jun Namkung4
Estimated H-index: 4
(KAIST)
+ 17 AuthorsHail Kim20
Estimated H-index: 20
(KAIST)
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasing in worldwide prevalence, closely tracking the obesity epidemic, but specific pharmaceutical treatments for NAFLD are lacking. Defining the key molecular pathways underlying the pathogenesis of NAFLD is essential for developing new drugs. Here we demonstrate that inhibition of gut-derived serotonin synthesis ameliorates hepatic steatosis through a reduction in liver serotonin receptor 2A (HTR2A) signaling. Local serotonin concentrations in the portal blood, which can directly travel to and affect the liver, are selectively increased by high-fat diet (HFD) feeding in mice. Both gut-specific Tph1 knockout mice and liver-specific Htr2a knockout mice are resistant to HFD-induced hepatic steatosis, without affecting systemic energy homeostasis. Moreover, selective HTR2A antagonist treatment prevents HFD-induced hepatic steatosis. Thus, the gut TPH1-liver HTR2A axis shows promise as a drug target to ameliorate NAFLD with minimal systemic metabolic effects.
  • References (47)
  • Citations (7)
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References47
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#1Jun Namkung (KAIST)H-Index: 4
#2Ko Eun Shong (KAIST)H-Index: 3
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The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed ...
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#1Richard L. Young (University of Adelaide)H-Index: 28
#2Amanda L. Lumsden (Flinders University)H-Index: 10
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Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity. We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4鈥塳cal/min for 30鈥塵in) in non-diabetic obese (BMI 44鈥壜扁4鈥塳g/m2, N鈥=鈥14) ...
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NAFLD is growing in prevalence worldwide, and has emerged as a leading cause of end-stage liver disease in many countries. In this Review, the authors describe the global epidemiology of NAFLD, discuss associated risk factors and outline challenges for screening and management.
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The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to be 25-30% of the population, and is the most common cause of elevated liver enzymes in Korea. NAFLD is a 鈥渉ot potato鈥 for pharmaceutical companies. Many clinical trials are underway to develop a first-in-class drug to treat NAFLD. However, there are several challenging issues regarding the diagnosis of NAFLD. Currently, liver biopsy is the gold standard method for the diagnosis of NAFLD and steatohepatitis. Ideally, glob...
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Metabolic homeostasis in the organism is assured both by the nervous system and by hormones. Among a plethora of hormones regulating metabolism, serotonin presents a number of unique features. Unlike classical hormones serotonin is produced in different anatomical locations. In brain it acts as a neurotransmitter and in the periphery it can act as a hormone, auto- and/or paracrine factor, or intracellular signaling molecule. Serotonin does not cross the blood鈥揵rain barrier; therefore the two maj...
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AIM: Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter and hormone, modulates many physiological functions including body temperature. We investigated neural mechanisms involved in the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) and BAT thermogenesis evoked by 5-HT. METHODS: Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats. RESULTS: Cooling-evoked increases in BAT SNA were inhibite...
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Abstract The rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase (TPH). There are two independent serotonin systems in the body characterized by two isoforms of TPH, TPH1 and TPH2. While TPH2 synthesizes serotonin in the brain, TPH1 is expressed in the gut and in other peripheral tissues and supplies platelets in the circulation with serotonin. This duality of the serotonin system is enforced by the blood-brain barrier which is impermeable for serotonin. In the brain serotonin ...
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Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease, which influences the health of people worldwide. However, the specific mechanism of the disease remains unknown, and effective treatments are still lacking. It was reported that Nuclear enriched abundant transcript 1 (NEAT1) obviously was up-regulated in NAFLD model. But the role and underlying mechanism of NEAT1 in NAFLD is unclear. Methods HepG2 cells were treated by free fatty acids (FFA) and C57BL/6J mice...
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