Abstract
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases, and it has become pervasive worldwide. Inflammation, including inflammation resulting from free fatty acid (FFA) activation of toll-like receptor (TLR) signaling, has been suggested to be an essential component of the pathophysiology of both insulin resistance and NAFLD. High fat (HF) diets promote an increased uptake and storage of FFAs and triglycerides in hepatocytes, which initiates inflammation and steatosis that induces lipotoxicity and an exacerbation of inflammation. In previous studies, we have established the efficacy of phenylmethimazole, a TLR3/4 inhibitor, to prevent and reverse HF diet-induced NAFLD, inflammation, and insulin resistance. A new library of small molecule compounds, including COB-214, was generated to identify even more potent inhibitors of inflammation. The objectives of this study were to evaluate the efficacy of COB-214 to delay and/or prevent hepatic steatosis, inflammation, and insulin resistance in a HF diet-induced model of NAFLD. C57BL/6J male mice were fed a HF diet (60 % fat, 20% protein, 70% carbohydrate) and divided into 3 groups (N=8 for each group): sham injection (stress control), DMSO (vehicle control), COB-214. Each treatment was administered once daily at a dosage of 1mg/kg for 16 weeks. Histological examination of liver sections from these mice using hematoxylin and eosin (H&E) revealed less hepatic lipid accumulation in mice treated with COB-214 when compared to mice in the sham- and DMSO-treated groups. Transcription of pro-inflammatory cytokines was down-regulated in both liver and mesenteric adipose tissue isolated from COB-214-treated mice when compared to sham- and DMSO-treated mice. Treatment with COB-214 prevented HF diet-induced insulin resistance measured by a 3-hour intraperitoneal glucose tolerance test (IPGTT) and 1.5-hour intraperitoneal insulin tolerance test (IPITT). Future directions include determining the efficacy of COB-214 to reverse HF diet-induced NAFLD, inflammation, and insulin resistance. At the conclusion of this study, we hope to have established the role of a novel class of small molecule inhibitors of inflammation in the treatment and prevention of NAFLD.