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

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.

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT1A receptor activation in raphe pallidus

“…High fat fed mice have increased levels of 5-HT in serum 76 and in BAT, 54 and inhibition of peripheral 5-HT synthesis reduces their adiposity, metabolic dysfunction, 54,77 and hepatic steatosis. 78 This effect was at least partially attributed to increased β3-adrenergic induction of UCP1mediated, BAT thermogenesis. 54 BAT SNA is impaired in rats maintained chronically on a high fat diet, 79,80 similar to the reduction in BAT thermogenesis in obese humans.…”

“…High fat fed mice have increased levels of 5‐HT in serum and in BAT, and inhibition of peripheral 5‐HT synthesis reduces their adiposity, metabolic dysfunction, and hepatic steatosis . This effect was at least partially attributed to increased β3‐adrenergic induction of UCP1‐mediated, BAT thermogenesis .…”

The Relationship Between the Serotonin Metabolism, Gut-Microbiota and the Gut-Brain Axis

“…Choi et al [65] demonstrated that the portal blood serotonin concentrations are selectively increased by high-fat diet feeding in mice, and they have endocrine effects on the liver. In fact, nutrient infusion induces 5-HT production in the human gut while the liver is the first organ to encounter gut-derived serotonin via the portal vein.…”

Influence of Gastrointestinal Hormones on the Development of Obesity and Non-Alcoholic Fatty Liver Disease in Children

“…У роботі J. Namkung et al за допомогою генетичних і фармакологічних моделей інгібування серотоніну у мишей досліджувались функціональні зв'язки між стеатозом печінки і гормоном. Було показано, що серотонін має прямий вплив на накопичення ліпідів в печінці, а пригнічення його синтезу в кишечнику полегшує прояви стеатозу печінки [28,29]. Однак, досліджень в цьому напрямку у людей ще [30].…”

“…Отже, збільшення рівня гормону в ЦНС сприяє зменшенню споживання їжі і маси тіла, а гіперпродукція серотоніну в кишечнику, як вважають, призводить до ожиріння [27]. У дослідженнях на мишах концентра ція серотоніну в портальній вені підвищувалася при харчуванні продуктами з високим вмістом жиру [28]. У роботі A. Ojeda-Rodríguez et.…”