High-fat-induced nonalcoholic fatty liver potentiates vulnerability to and the severity of viral hepatitis in a C3H/HeN mouse model

Abstract

Although the concomitance of nonalcoholic fatty liver disease (NAFLD) and viral hepatitis is soaring, there is not much knowledge about the impact of NAFLD on viral hepatitis. Here, we aimed to investigate how NAFLD influences the pathogenesis of viral hepatitis. Wild-type C3H/HeN mice with NAFLD induced by high-fat diet were infected with murine hepatitis virus 3 (MHV-3) and sacrificed at Days 4, 8, 12, and 16 post infection. Although there was no difference in the survival rate between mice with and without NAFLD, individuals with steatosis suffered more severe and prolonged liver injury demonstrated by transaminases and histology examination. The intrahepatic viral load was higher in NAFLD group during early infection, although it declined ultimately. On the contrary, the serum antiviral antibody titer remained in a lower level in mice with NAFLD throughout the investigation. In NAFLD group, the production of proinflammatory cytokines (tumor necrosis factor α, interleukin 1β, interleukin 6, and interleukin 17A) and the frequencies of antiviral immune cells (NKG2D⁺ NK cells and CD69⁺ cytotoxic T lymphocytes [CTLs]) were profoundly increased. Parallelly, the production of anti-inflammatory cytokine (interleukin 10) and inhibitory checkpoint expression (NKG2A on NK cells and programmed cell death-1 on CTLs) were also significantly elevated to maintain homeostasis. However, the upregulation of interleukin 22, a protective cytokine was deficient in NAFLD group post MHV-3 infection. Conclusively, hepatic lipid metabolic abnormalities disturb antiviral immunity and increase the vulnerability to and severity of viral hepatitis.

Keywords: antiviral immunity; high-fat diet; murine hepatitis virus 3; nonalcoholic fatty liver disease; viral hepatitis.