Lipocalin 2 Induces Neuroinflammation through Liver‐Brain Axis in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is chronic liver disorder characterized by accumulation of excess fat in liver due to consumption of high fat/lipid diets. A multiple hit paradigm that include lipotoxicity, environmental and genetic causes for prolonged period often leads to nonalcoholic steatohepatitis (NASH) with scarring and inflammation in liver that consequently causes irreversible hepatic damage. Both clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with several ectopic manifestations like type 2 diabetes, cardiovascular disease, chronic kidney disease and more recently neuroinflammation and neurodegeneration. Notably, mechanisms of neuroinflammation in underlying NAFLD are poorly understood. In this report we identified adipokine Lipocalin 2 (Lcn2) induced neuroinflammation by acting through liver‐brain axis in diet induced murine NAFLD/NASH model. We found that Lcn2 is overexpressed in liver and in portal circulation that activated 24p3R (Lipocalin2 receptor) in brain and induced the release of high mobility group box 1 (HMGB1) from brain cells. Released HMGB1 acted as a preferential ligand to Toll like receptor 4 (TLR 4) and induced oxidative stress by activation of NOX‐2 signaling. NOX2 downstream signaling activated NF‐kB by phosphorylation of p65 protein. Activation of p65 and NOX‐2 led to NLRP‐3 inflammasome activation which subsequently released proinflammatory cytokines IL‐6 and IL‐1β from brain cells. Furthermore, we show that elevated Lcn2 level from neurons in underlying NAFLD caused a non disruptive blood brain barrier dysfunction by over production of TNFα, IL‐1β and MMP 9 without alteration of tight junction proteins Claudin 5 and Occludin. Based on the above, the above findings identify Lcn2 as a potent molecule inducing neuroinflammation in underlying NAFLD.Support or Funding InformationNIH#P01ES028942‐01 to Dr. Saurabh Chatterjee