Serotonergic Regulation of Hepatic Energy Metabolism

Abstract

The liver is a vital organ that regulates systemic energy metabolism and many physiological functions. Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease and end-stage liver failure. NAFLD is primarily caused by metabolic disruption of lipid and glucose homeostasis. Serotonin (5-hydroxytryptamine [5-HT]) is a biogenic amine with several functions in both the central and peripheral systems. 5-HT functions as a neurotransmitter in the brain and a hormone in peripheral tissues to regulate systemic energy homeostasis. Several recent studies have proposed various roles of 5-HT in hepatic metabolism and inflammation using tissue-specific knockout mice and 5-HT-receptor agonists/antagonists. This review compiles the most recent research on the relationship between 5-HT and hepatic metabolism, and the role of 5-HT signaling as a potential therapeutic target in NAFLD.

Keywords: Liver; Non-alcoholic fatty liver disease; Serotonin.

Fig. 1

5-Hydroxytryptamine (5-HT) receptors and signaling pathways. The 5-HT1 and 5-HT5 receptors are Gi/Go-protein coupled receptors that inhibit adenylate cyclase (AC) and thus suppress the cyclic adenosine monophosphate (cAMP) downstream pathways. 5-HT2 receptors are Gq/G11-protein coupled receptors that activate phospholipase C, resulting in the activation of the inositol triphosphate (IP3) and diacylglycerol (DAG) downstream pathways. The only ligand-gated ion channel that can regulate membrane potential is the 5-HT3 receptor. The Gs-protein coupled receptors 5-HT4, 5-HT6, and 5-HT7 activate AC.

Fig. 2

Metabolic functions of 5-hydroxytryptamine (5-HT) in liver. Most peripheral 5-HTs are derived from enterochromaffin cells of the gut. 5-HT regulates hepatic fibrosis in hepatic stellate cells (HSCs) by activating HSC-produced transforming growth factor (TGF)-signaling. Through the 5-HT2B receptor, 5-HT promotes gluconeogenesis in hepatocytes by increasing the activity of fructose 1,6-bisphosphatase (FBPase) and glucose 6-phosphatase (G6pase). 5-HT2B receptor signaling also inhibits glucose uptake by promoting the breakdown of glucose transporter 2 (GLUT2). The activation of the sterol-regulatory-element-binding protein 1 (SREBP1) signaling pathway by the 5-HT2A receptor increases lipogenesis in the liver. ERK1/2, extracellular signal–regulated protein kinase.