Research Article Details
| Article ID: | A12459 |
| PMID: | 30446669 |
| Source: | Nat Commun |
| Title: | 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. |
| DOI: | 10.1038/s41467-018-07287-7 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D248 | Obeticholic Acid | Chemical drug | DB05990 | NR1H4 activator; NR1H4 agonist; FXR agonist | Enhance lipid metabolism | Approval rejected | Details |
| D010 | Amoxicillin | Chemical drug | DB01060 | -- | -- | Under clinical trials | Details |
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |