Emerging data highlight the critical role for the innate immune system in the progression of
nonalcoholic fatty liver disease (
NAFLD).
Connexin 32 (Cx32), the primary liver
gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of
steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human
NAFLD in a histologically characterized cohort of 362 patients with
NAFLD. We also studied the hepatic expression of the genes and
proteins known to interact with Cx32 (known as the connexome) in patients with
NAFLD. Last, we used three independent dietary mouse models of
nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of
steatohepatitis and
fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the
NAFLD activity score and
fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the
NAFLD activity score and
fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with
NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury,
inflammation, and
fibrosis in three murine models of
nonalcoholic steatohepatitis by limiting initial diet-induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with
steatohepatitis and
fibrosis in patients with
NAFLD. We also identify novel genes associated with
NAFLD and suggest that Cx32 plays a role in promoting
NAFLD development. (Hepatology Communications 2018;2:786-797).