Targeting Uric Acid as a Therapeutic for NASH

点击翻译按钮获取中文摘要

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. The most common risk factors associated with NAFLD are obesity, type 2 diabetes and dyslipidemia, with 80-90% of obese adults developing NAFLD. Simple steatosis is generally inert pathologically but in the presence of inflammation, defined as non-alcoholic steatohepatitis (NASH), is a gateway to more severe forms of liver disease including cirrhosis and liver failure. As waistlines continue to expand, NAFLD is now considered the next global epidemic, as it is associated with increased risk of metabolic syndrome, cardiovascular disease and cancer. Two of the largest untargeted metabolome studies revealed uric acid (UA) as the most significant metabolite associated with obesity and is a better predictor than the next six metabolites combined. UA is generated solely from xanthine oxidase (XO) during the catabolism of purines. Recent publications and preliminary data herein reveal that XO activity is increased in conjunction with UA in obesity and in clinical and experimental NAFLD. During this catabolism of purines by XO, toxic reactive oxygen species (ROS) are generated that can damage biomolecules and contribute to injury. Indeed, the current dogma is that ROS generated from XO are directly responsible for this enzyme’s injurious role in inflammation and injury. However, this dogma ignores the fact that UA also is a toxic species that induces inflammation, mitochondrial dysfunction and ROS generation in other diseases. Whether or not UA plays a similar deleterious role in NAFLD remains unclear. Elucidating whether ROS or UA is the predominant XO-derived toxic metabolite in NAFLD pathogenesis fills critical gaps in knowledge and reveals new therapeutic options. A longitudinal mouse study revealed that a fast food diet (FFD) consisting of high- fat, -fructose and - cholesterol recapitulates the NASH phenotype observed clinically. It is believed that fructose metabolism activates the purine catabolism pathway (via XO) resulting in the culmination of UA although the exact mechanism is unclear. Therefore, we will test the hypothesis this fast food diet leads to hyperuricemia and promotes the progression of NAFLD to NASH. To test this hypothesis, these aims will be tested: (1)- Determine whether hyperuricemia is causally responsible for mitochondrial stress, insulin resistance and hepatic steatosis in experimental NAFLD/NASH; and (2)-Determine whether pharmacologically targeting XO is sufficient enough to slow the progression from NAFLD to NASH. Understanding the pathophysiology of hyperuricemia and whether it directly causes mitochondrial dysfunction resulting in the progression of NAFLD to NASH will fill critical knowledge gaps. Additionally, successful outcomes will determine if inhibiting XO (novel target) with febuxostat is sufficient enough to protect against NAFLD/NASH or a one drug-multiple target approach using nitro-oleic acid will provide better responses for diseases that display complex, multifactorial pathogenesis such as NASH.