Pyruvate Dehydrogenase as a Therapeutic Target for Nonalcoholic Fatty Liver Disease

Excess caloric intake combined with a sedentary lifestyle in the general population has greatly increased the prevalence of obesity and nonalcoholic fatty liver disease (NAFLD), which is defined as the accumulation of excess fat in the liver in the absence of alcohol abuse or other attributable causes such as infection with hepatitis C. Furthermore, NAFLD increases the risk for insulin resistance, type 2 diabetes (T2D), and cardiovascular disease, while currently having no approved therapy to counteract its pathology. Thus, increasing efforts to understand the mechanisms responsible for NAFLD have been pursued in preclinical studies, in the hopes of developing novel therapies that can prevent the progression of insulin resistance and/or T2D. The pathology of NAFLD is multifactorial, with proposed mechanisms including inflammation, oxidative stress, and mitochondrial dysfunction to name a few. The latter remains a subject of ongoing debate, but may be attributed to impaired hepatic fatty acid oxidation, thereby increasing the accumulation of triacylglycerol within hepatocytes. More recent studies have also demonstrated that the mitochondrial dysfunction in NAFLD may also encompass impairments in glucose oxidation, despite oxidative energy production having minimal contribution to overall glucose/pyruvate metabolism in the liver. Accordingly, strategies to reverse this defect in glucose oxidation can ameliorate hepatic steatosis and improve glucose homeostasis. We will review herein the evidence supporting impaired hepatic glucose oxidation as a mechanism of NAFLD, while discussing the validity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation, as a potential target for NAFLD. In addition, we will discuss potential mechanisms of action by which increased hepatic PDH activity and subsequent glucose oxidation can reverse the pathology of obesity-induced NAFLD, as well as opportunities to target this pathway with clinical agents.