| First Author | Jiang B | Year | 2022 |
| Journal | Mol Metab | Volume | 59 |
| Pages | 101462 | PubMed ID | 35247611 |
| Mgi Jnum | J:333708 | Mgi Id | MGI:7257366 |
| Doi | 10.1016/j.molmet.2022.101462 | Citation | Jiang B, et al. (2022) Serum amyloid A1 exacerbates hepatic steatosis via TLR4-mediated NF-kappaB signaling pathway. Mol Metab 59:101462 |
| abstractText | OBJECTIVE: Chronic inflammatory response plays a prominent role in obesity-related nonalcoholic 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 found 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 the activation of nuclear factor (NF)-kappaB 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 with an AAV8-shRNA-SAA1/2 showed a therapeutic effect on hepatic inflammation and NAFLD progression. CONCLUSIONS: These results demonstrate that SAA1 triggers hepatic steatosis and intrahepatic inflammatory response by forming a SAA1/TLR4/NF-kappaB/SAA1 feedforward regulatory circuit, which, in turn, leads to NAFLD progression. SAA1 may act as a potential target for the disease intervention. |
