Dysregulation of Kupffer Cells/Macrophages and Natural Killer T Cells in Steatohepatitis in LXRα Knockout Male Mice

Liver X receptor (LXR) alpha expression is mainly localized to metabolic tissues, such as the liver, whereas LXR beta is ubiquitously expressed. LXR alpha is activated by oxysterols and plays an important role in the regulation of lipid metabolism in metabolic tissues. In macrophages, LXRs stimulate reverse cholesterol transport and regulate immune responses. Although a high-cholesterol diet induces severe steatohepatitis in LXR alpha-knockout (KO) mice, the underlying mechanisms linking lipid metabolism and immune responses remain largely unknown. In this study, we investigated the role of LXR alpha in the pathogenesis of steatohepatitis by assessing the effects of a high-fat and high-cholesterol diet (HFCD) on hepatic immune cell proportion and function as well as lipid metabolism in wild-type (WT) and LXR alpha-KO mice. HFCD feeding induced severe steatohepatitis in LXR alpha-KO mice compared with WT mice. These mice had higher cholesterol levels in the plasma and the liver and dysregulated expression of LXR target and proinflammatory genes in both whole liver samples and isolated hepatic mononuclear cells. Flow cytometry showed an increase in CD68(+)CD11b(+) Kupffer cells/macrophages and a decrease in invariant natural killer T cells in the liver of HFCD-fed LXR alpha-KO mice. These mice were more susceptible to lipopolysaccharide-induced liver injury and resistant to inflammatory responses against alpha-galactosylceramide or concanavalin-A treatment. The findings provide evidence for activation of bone marrow-derived Kupffer cells/macrophages and dysfunction of invariant natural killer T cells in LXR alpha-KOmouse liver. These findings indicate that LXRa regulates hepatic immune function along with lipid metabolism and protects against the pathogenesis of nonalcoholic steatohepatitis.