LBP resists hepatic oxidative stress by regulating LD homeostasis

Abstract Lipopolysaccharide-binding protein (LBP), an acute-phase protein, is expressed in inflammatory response and stress 1,2 , but its intracellular function is still unclear. Here, we uncover the profound paradigm of LBP as an antioxidant by coupling lipid droplet (LD) metabolism and redox signal, which protects hepatocytes from lipid peroxidation. LBP is upregulated and identified in LDs of hepatocytes after 24h fasting. Hepatic knock-in of LBP causes severe steatosis and LD accumulation on a high-fat diet. We showed that the C-segment groove of LBP conferred triglyceride (TG) capture activity, resulting in the LD-translocation of LBP and increasing the LD stability. Thus, a combination of LBP and unsaturated TG prevents lipid peroxidation under oxidative stress, whereas LBP was shuttled-out from LD after N-Acetyl-L-cysteine (NAC) treatment to promote phospholipid synthesis and lipolysis. Moreover, we found that LBP as a redox regulator of PRDX4, can sense the oxidative stress of cells and achieve precise control of LDs homeostasis. Stresses, like chronic jet lag and forced swimming test, caused LBP upregulation and steatosis, which can be rescued by NAC treatment in vivo. Taken together, our findings reveal a noncanonical mechanism of LBP as a hub for adapting to a stress-changing environment and maintaining intracellular homeostasis through physical collection of lipids and PRDX4 in-and-out LDs.