Implications for Farnesoid X Receptor Signaling on Bile Acid Metabolism as a Potential Therapeutic Strategy for Nonalcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by massive ectopic triglyceride accumulation in the liver in the absence of other chronic liver disease or significant alcohol consumption. NAFLD is the most common chronic liver disease in developed and developing countries, affecting 20-30% of the adult population and more than 80% of obese individuals around the world. NAFLD refers to a wide spectrum of liver disorders, ranging from simple fatty liver (steatosis) to nonalcoholic steatohepatitis (NASH) and liver cirrhosis. NAFLD begins with simple steatosis, which can progress to NASH, which involves hepatic steatosis with inflammation, fibrosis, and hepatocyte injury. NASH may further progress to liver cirrhosis, eventually leading to hepatocellular carcinoma and liver failure. In addition, NAFLD is strongly associated with insulin resistance, type 2 diabetes, coronary heart disease, and atherosclerosis. To date, treatment options for NAFLD are limited and are directed primarily at weight loss, lifestyle modifications, or pharmacological improvement of the risk factors that are commonly associated with metabolic syndrome. Although no pharmacological treatment has currently been approved for NAFLD/NASH, therapies with insulin sensitizers, such as pioglitazone and metformin, and antioxidants such as vitamin E are among the best-established approaches. However, these approaches have conservative efficacy (pioglitazone and metformin in patients with type 2 diabetes and vitamin E in non-diabetic patients) and long-term safety issues (vitamin E treatments have increased mortality, and pioglitazone is associated with various adverse effects, including weight gain, fluid retention, and osteoporosis), complicating their clinical use. In this review, we provide an overview of the role of bile acids and their signaling in NAFLD and provide new insights into the possible approach of targeting bile acid-related pathways in the treatment of this serious global health problem. Implications for Farnesoid X Receptor Signaling on Bile Acid Metabolism as a Potential Therapeutic Strategy for Nonalcoholic Fatty Liver Disease Hyekyung Yang, Cheol-Young Park* Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea