Lipocalin‐2 Protects Against Diet‐Induced Nonalcoholic Fatty Liver Disease by Targeting Hepatocytes

Abstract

Hepatocytes are the major source of hepatic lipocalin-2 (LCN2), which is up-regulated in response to inflammation, injury, or metabolic stress. So far, the role of hepatocyte-derived LCN2 in the development of nonalcoholic fatty liver disease (NAFLD) remains unknown. Herein we show that overexpression of human LCN2 in hepatocytes protects against high fat/high cholesterol/high fructose (HFCF) diet-induced liver steatosis and nonalcoholic steatohepatitis by promoting lipolysis and fatty acid oxidation (FAO) and inhibiting <i>de novo</i> lipogenesis (DNL), lipid peroxidation, and apoptosis. LCN2 fails to reduce triglyceride accumulation in hepatocytes lacking sterol regulatory element-binding protein 1. In contrast, <i>Lcn2^-/-</i> mice have defective lipolysis, increased lipid peroxidation and apoptosis, and exacerbated NAFLD after being fed an HFCF diet. In primary hepatocytes, <i>Lcn2</i> deficiency stimulates <i>de novo</i> lipogenesis but inhibits FAO. <i>Conclusion:</i> The current study indicates that hepatocyte LCN2 protects against diet-induced NAFLD by regulating lipolysis, FAO, DNL, lipid peroxidation, and apoptosis. Targeting hepatocyte LCN2 may be useful for treatment of NAFLD.