Research Article Details
| Article ID: | A00041 |
| PMID: | 35247611 |
| Source: | Mol Metab |
| Title: | Serum Amyloid A1 Exacerbates Hepatic Steatosis via TLR4 Mediated NF-κB Signaling Pathway. |
| Abstract: | OBJECTIVE: Chronic inflammatory response plays a prominent role in obesity-related non-alcoholic fatty liver disease (NAFLD). However, the intrahepatic triggering mechanism of inflammation remains obscure. This study aimed to elucidate the role of serum amyloid A1 (SAA1), an acute-phase response protein, in the obesity-induced hepatic inflammation and NAFLD. METHODS: Male mice were fed a high fat diet (HFD) for 16 weeks and insulin resistance, hepatic steatosis and inflammation in mice were monitored. Murine SAA1/2 was genetically manipulated to investigate the role of SAA1 in NAFLD. RESULTS: We finds that SAA1 was increased in the NAFLD liver in both humans and mice. Knockout of SAA1/2 or knockdown of hepatic SAA1/2 promoted energy expenditure and alleviated HFD-induced metabolic disorder, hepatic steatosis and inflammation. Endogenous overexpression of SAA1 in hepatocytes by adeno-associated virus 8 (AAV8) transfection aggravated overnutrition-associated gain of body weight, insulin resistance, hepatic lipid accumulation, and liver injury, which were markedly alleviated by knockout of murine toll like receptor 4 (TLR4). Mechanistically, SAA1 directly bound with TLR4/myeloid differentiation 2 (MD2) to induce TLR4 internalization, leading to activation of nuclear factor (NF)-κB signaling and production of both SAA1 and other inflammatory cytokines including interleukin (IL)-6 and C-C chemokine ligand (CCL2) in hepatocytes. Administration of HFD mice by an AAV8-shRNA-SAA1/2 showed a therapeutic effect on hepatic inflammation and NAFLD progression. CONCLUSIONS/INTERPRETATION: These results demonstrate that SAA1 triggers hepatic steatosis and intrahepatic inflammatory response by forming a SAA1/TLR4/NF-κB/SAA1 feedforward regulatory circuit, which, in turn, leads to NAFLD progression. SAA1 may act as a potential target for the disease intervention. |
| DOI: | 10.1016/j.molmet.2022.101462 |
| 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 |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | 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 |