Immunoregulation of Intrahepatic Bone Marrow Monocyte–Derived Macrophages by Dietary Nitrate Prevents Nonalcoholic Fatty Liver Disease

Although nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of liver disease worldwide, no efficient treatment has been approved yet. We investigated whether oral nitrate administration prevents development of diet-induced NAFLD in two mouse models. Nitrate exerted its protective effect mainly through rebalancing of pro- and anti-inflammatory bone marrow monocyte–derived macrophages (MoMFs) in the liver. Using an NAFLD model in relatively germ-free mice and bone marrow–transplanted mice with a heritable Slc17a5 mutation, we showed that nitrate can prevent NAFLD by direct regulation of MoMFs through sialin, besides via the classical nitric oxide pathway. In vitro studies revealed that nitrate directly regulates mouse and human macrophages through the sialin-Sema4A pathway. Our work demonstrated for the first time nitrate's ability to prevent NAFLD by directly modulating the homeostasis of hepatic pro- and anti-inflammatory macrophages, which indicates a novel strategy for potential clinical application in NAFLD. Overall design: The monocytes mRNA profiles of M1 and M2 , Slc17a5 siRNA-M1 and Slc17a5 siRNA-M2 were stimulated with or without nitrate