Saturated Fatty Acid Inhibits Viral Replication in Chronic Hepatitis B Virus Infection With Nonalcoholic Fatty Liver Disease by Toll-Like Receptor 4-Mediated Innate Immune Response
Source: Shanghai Key Laboratory of Children’s Digestion and Nutrition, Department of Gastroenterology, XinHua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Chronic Hepatitis B (CHB) infection is common in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). The replication level of Hepatitis B Virus (HBV) was inversely correlated with hepatic steatosis. Toll-Like Receptor (TLR) 4-mediated innate immunity plays a pivotal role in the occurrence of NAFLD and controls HBV replication.
This study aimed to investigate whether the TLR4-mediated innate immunity stimulates the pathogenesis of CHB in patients with NAFLD and to determine whether TLR4 plays a role in inhibiting HBV replication.
Materials and Methods:
The HBV transgenic mice were randomized into the HBV and HBV/NAFLD groups. HepG2.2.15 cells were treated with different concentrations (0 – 200 μM) of Stearic Acid (SA) to induce steatosis. The total RNA of the liver tissue was extracted for Real-Time Polymerase Chain Reaction (RT-PCR) detection, and immunohistochemistry or western blot was conducted for further validation. The Enzyme-Linked Immunosorbent Assay (ELISA) analysis was applied to evaluate the production of Interleukin 6 (IL-6), Tumor necrosis factor α (TNF-α) and Interferon β (IFN-β). Moreover, viral dynamics were analyzed using HBV DNA and HBV-related antigens (HBsAg and HBeAg).
Non-alcoholic fatty liver disease was induced in HBV-transgenic mice fed with High Fat Diet (HFD) for 8 - 24 weeks. Oil red-O staining positive droplets and the content of Triglyceride (TG) were increased in HepG2.2.15 cells treated with SA. TLR4, Myeloid differentiation factor 88 (MyD88), IL-6 and TNF-α expression levels were significantly higher in the HBV/NAFLD group and the steatotic HepG2.2.15 cells than those in their respective controls. Compared to the HBV group, significant reductions in serum levels of HBsAg, HBeAg, and HBV DNA titers occurred in the HBV/NAFLD group at 24 weeks, but the IFN-β level was remarkably increased. Similar data were also obtained from the steatoric HepG2.2.15 cells.
Saturated Fatty Acids (SFAs) served as a potential ligand for TLR4 and activated TLR4 signaling pathway, which might be involved in the pathogenesis. Thus, SFAs can accelerate the mechanism of inhibiting HBV replication in CHB with NAFLD.
Keywords: Diet, High-Fat; Stearic Acid; Toll-like receptor 4; Hepatitis B Virus; Nonalcoholic Fatty Liver Disease