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.

In the era of antiviral therapy, the prognostic significance of serum hepatitis B virus (HBV) DNA level as a biological gradient substantially diminished, as most patients can achieve complete virological response (CVR). We aimed to investigate the predictive roles of liver stiffness (LS) for liver-related events (LREs) among patients with CVR. We analyzed 192 patients with chronic HBV infection who achieved CVR (defined as HBV DNA <20 IU/ml) through entecavir therapy. LS values at CVR were measured using transient elastography. LREs were defined as any cirrhotic complication, hepatocellular carcinoma, and liver-related mortality. The median age of the patients was 49 years, and 134 (69.8%) were male. The median LS value at CVR was 8.8 kPa. During follow-up, LREs occurred in 25 (13.0%) patients. When the population was stratified into three groups (13.0 kPa), cumulative LRE incidences increased significantly in association with LS values (log-rank test, P=0.001). Patients with an LS value >13.0 kPa (hazard ratio (HR)=12.336, 95% confidence interval (CI) 1.335–114.010; P=0.027) and 8.0–13.0 kPa (HR=8.832, 95% CI 1.092–71.432; P=0.041) were at significantly greater risk compared with those with an LS value <8.0 kPa. On multivariate analysis, age and LS values were seen to be independent predictors (all P<0.05). When LS values were incorporated into the REACH-B scoring model instead of serum HBV DNA level, a better predictive performance was seen compared with a conventional approach (areas under the receiver operating characteristic curve, 0.814 vs. 0.629, respectively). LS values at CVR are useful for predicting forthcoming LRE development. Thus, in the era of potent antiviral therapy, tailored surveillance strategies might be established based upon LS values at CVR.