| Abstract: | Serotonin (5-HT) is one of the key bioamines of nonalcoholic fatty liver disease (NAFLD). Its mechanism via autonomic neural signal pathways remains unexplained; hence, we evaluated the involvement of 5-HT and related-signaling pathways via autonomic nerves in NAFLD. Diet-induced NAFLD animal models were developed using wild-type and melanocortin 4 receptor knockout (MC4RKO) mice, and the effects of autonomic neural axis on NAFLD physiology, 5-HT and its receptors (Htrs), and lipid metabolism-related genes were assessed applying hepatic nerve blockade. Hepatic neural blockade retarded the progression of NAFLD by reducing 5-HT in the small intestine, hepatic Htr2a, and hepatic lipogenic genes expression, and HTR2A antagonist reproduced these effects. The effects were milder in MC4RKO, and brain 5-HT and Htr2c expression did not correlate with peripheral neural blockade. Our study demonstrates that the autonomic liver-gut neural axis is involved in the etiology of diet-induced NAFLD and that 5-HT and HTR2A are key factors, implying that the modulation of the axis and use of HTR2A antagonists are potentially novel therapeutic strategies for NAFLD treatment. |
