Effects of BLT1 inhibition in a mouse model of liver fibrosis

Nonalcoholic steatohepatitis (NASH) is a prevalent disease that can ultimately progress to more severe forms of disease including liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death. A key feature of NASH is lobular inflammation, which is a major driver of disease progression, and both innate and adaptive immune mechanisms support and perpetuate hepatic inflammation in NASH. Previous studies have demonstrated that the pro-inflammatory leukotriene B4 (LTB4) is a potent chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased lipid accumulation in the liver. Accordingly, the LTB4-BLT1 axis is a potential therapeutic target for the treatment of liver steatosis and insulin resistance by modulating inflammation.The goal of this study is to validate the therapeutic efficacy of BLT1 inhibition in a NASH mouse model. 8 Week old male C57BL/6J mice were fed a choline-deficient L-amino acid defined high fat diet (CDAA-HFD) with 60 kcal% fat with 0.1% methionine and no added choline (Research Diets, A06071302). After 4 weeks, one group remained on CDAA-HFD and the other was started on CDAA-HFD with a 90 mg/kg dose of BLT1i for 8 weeks.