Fatty liver disease and the pathogenic paradox
In the normal liver, insulin suppresses glucose production, which lowers blood glucose levels. At the same time, it stimulates lipogenesis (the synthesis of fatty acids). With the development of obesity, insulin loses its ability to control glucose production. Paradoxically, however, it continues to drive lipogenesis, leading to non-alcoholic fatty liver disease (NAFLD). The Biddinger lab is working to understand how insulin retains its ability to drive lipogenesis. In parallel, we are studying how diet, particularly the excessive consumption of fructose, may contribute. It is our hope that these studies will lead us to more effective therapies for NAFLD, which is rapidly becoming one of the most common causes of liver disease in our nation
Obesity and the related disorders of metabolic syndrome and Type 2 diabetes lead to cardiovascular disease. Indeed, cardiovascular disease is the most important cause of death in diabetic patients. We have found that insulin resistance, a central feature of obesity, is sufficient to cause high cholesterol levels in the blood and atherosclerosis. The Biddinger lab is currently dissecting, at the molecular level, the mechanisms by which insulin resistance produces atherosclerosis.
Over 100 years ago, Sir William Osler documented the association between obesity and gallstones. Since then, many studies have confirmed the increased prevalence of gallstones in obese individuals, but how obesity could cause gallstones remained a mystery. In 2008, we showed that insulin resistance, a central feature of obesity, promotes gallstone formation by increasing biliary cholesterol secretion and altering the composition of the bile such that it becomes more likely to form gallstones. The Biddinger lab is now taking on further studies to identify the specific regulatory molecules which mediate the effects of insulin on biliary lipid metabolism.
Over the past century, our intake of fructose has dramatically increased. This is correlated with increases in obesity, fatty liver disease, and other disorders. This has led to the suggestion that fructose intake should be limited. But is fructose itself harmful? The Biddinger lab, using a combination of metabolomics, genetic and transcriptional profiling approaches, is trying to determine the specific metabolic effects of fructose. It is our expectation that this will lead to more rational dietary advice.
Sudha Biddinger, MD/PhD
Harvard Medical School
Children's Hospital Boston