Genetic inactivation of the LIGHT (TNFSF14) cytokine in mice restores glucose homeostasis and diminishes hepatic steatosis.

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes mellitus. Progression of NAFLD is mediated, among other things, by activation of inflammatory pathways. In the present study, the role of the proinflammatory cytokine LIGHT (TNFSF14) was explored in NAFLD and type 2 diabetes mellitus in mice deficient for the cytokine.

Methods: Light-deficient (Light) mice and WT controls were fed a regular chow diet (RCD) or a high-fat high-cholesterol diet (HFHCD) for 16 weeks. The expression of LIGHT and its receptors, herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), was investigated in both dietary regimens. Glucose tolerance, insulin sensitivity, non-alcoholic fatty liver (NAFL), systemic and tissue inflammation, and metabolic gene expression were explored in Light and WT mice fed an RCD and an HFHCD. The effect of Light deficiency was also evaluated in hepatic tissue and in inflammation in HFHCD-fed Irs2 mice with impaired insulin signalling.

Results: Light deficiency did not have an effect on metabolism, in NAFL or in tissue and systemic inflammation, in RCD-fed WT mice. HVEM and LTβR were markedly increased in livers of HFHCD-fed WT mice compared with RCD-fed WT controls. In WT mice under HFHCD, Light deficiency improved glucose tolerance and insulin sensitivity. Non-alcoholic fatty liver disease activity (NAS) score, hepatic CD3 T lymphocytes and F4/80 macrophages were decreased in HFHCD-fed Light mice compared with HFHCD-fed WT controls. Consistent with a potential role of adipose tissue in hepatic homeostasis, Light mice exhibited augmented anti-inflammatory F4/80CD206 adipose tissue macrophages and reduced proinflammatory F4/80CD11c adipose tissue macrophages. Moreover, adipose tissue explants from Light mice showed diminished secretion of monocyte chemoattractant protein 1 (MCP1), TNF-α and IL-17 cytokines. Circulating Light leucocytes consistently displayed augmented levels of the patrolling Ly6C monocytes, decreased Th9 T cell subset and diminished plasma TNF-α and IL-6 levels. Similarly, Light deficiency in Irs2 mice, which display impaired insulin signalling, also reduced NAFL as well as systemic and adipose tissue inflammation. Analysis of hepatic gene expression in Light mouse livers showed reduced levels of Zbtb16, the transcription factor essential for natural killer T (NKT) cell function, and two genes related to NAFLD and fibrosis, Klf6 and Tlr4.

Conclusions/interpretation: These results indicate that Light deficiency in HFHCD improves hepatic glucose tolerance, and reduces hepatic inflammation and NAFL. This is accompanied by decreased systemic inflammation and adipose tissue cytokine secretion and by changes in the expression of key genes such as Klf6 and Tlr4 involved in NAFLD. These results suggest that therapies to block LIGHT-dependent signalling might be useful to restore hepatic homeostasis and to restrain NAFLD.