Metabolic syndrome is a group of medical conditions associated with obesity.They are a cluster of abnormalities that include extra fat deposited in the abdominal area, blood vessels, and liver.
Extra fat in the liver that is not caused by alcohol is called nonalcoholic fatty liver disease. There are two types of nonalcoholic fatty liver disease; one type is a simple fatty liver called nonalcoholic fatty liver and the other is nonalcoholic steatohepatitis.
The livers of patients with nonalcoholic steatohepatitis become inflamed in addition to the extra fat. When a fatty liver has chronic inflammation, it eventually forms scar tissue to replace dead liver cells, called fibrosis. If untreated, this condition will eventually develop into cirrhosis leading to liver failure. Liver failure requires transplantation of a new liver for the patiend to survive. Sometimes liver cancer will develop instead.
Nonalcoholic steatohepatitis is reaching epidemic numbers around the globe, especially among obese people. Millions of Americans have this condition. This is a silent process that doesn’t cause symptoms, and there is no laboratory test to detect it except for a liver biopsy.
Hilda Ghadieh is a PhD graduate student at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program.
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Developing a drug for nonalcoholic steatohepatitis is very challenging because it is a very complex condition and we have limited understanding of how the disease develops and/or progresses. Moreover, there is no animal model that replicates all features of human nonalcoholic steatohepatitis, therefore searching for effective drugs is difficult. Thus, it is important for us to generate proper animal models to help understand this disease and test for the best treatments.
The most successful drugs are the ones that can target the three components of nonalcoholic steatohepatitis, fatty liver causing inflammation, which then turns into liver fibrosis.
I am training in the laboratory of Sonia Najjar to study this complex disease, because this is one of the leading laboratories in this field of research. One of the research projects in our laboratory has been to test current drugs to develop a safe and effective medicine for long term use in patients with nonalcoholic steatohepatitis.
Insulin resistance also leads to nonalcoholic fatty liver disease. Restoring insulin sensitivity is very important in this group of patients to maintain correct sugar levels in the blood. Insulin action is determined by how much is released from your pancreas and how much is removed by your liver.
You can think of normal insulin levels as the heat in your home that controls your thermostat. Too much heat and the thermostat turns off, not enough heat and the thermostat turns on, similar to plasma insulin levels regulating its own action. However, if you have a chronically abnormal increase in blood insulin levels, this will eventually lead to insulin resistance because cells in your body stop responding to insulin.
My investigations focus on a protein called CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1). This protein is highly expressed in your liver and it plays a major role in removing insulin from your bloodstream. We have found that patients with fatty liver, insulin resistance, and obesity have marked reduction in CEACAM1 protein levels.
We have a mouse model that does not express CEACAM1 in any organ. When fed a regular diet, this mouse model has extra fat in the liver, along with inflammation and fibrosis. Importantly, when fed a high-fat diet, this mouse model develops all of the key features of human nonalcoholic steatohepatitis. Having a mouse model deficient in CEACAM1 is a very good tool to study fatty liver disease and to investigate commercially available drugs for treatment.
First on our list of drugs to investigate was exenatide, a drug that is used to treat patients with type 2 diabetes (adult onset) by causing insulin release from the pancreas. Exenatide helps to maintain insulin sensitivity and thus corrects sugar levels in these patients.
We wanted to know if exenatide can promote insulin removal from the blood by increasing CEACAM1 expression in the liver. We also wanted to know if this method of controlling insulin levels could reverse fatty liver, inflammation and fibrosis.
To answer these questions, we first put normal mice and others lacking CEACAM1 expression on high fat diet for a month to make them obese. Then we treated them with exenatide during the second month of their high fat diet. We observed that exenatide was able to increase CEACAM1 expression in the liver, restoring the metabolic diseases that were because of high fat intake in normal mice but not in the mice lacking CEACAM1.
Thus, exenatide maintains normal blood insulin level by increasing CEACAM1 expression in the liver. In other words, insulin release from the pancreas and clearance by the liver should go hand in hand to maintain insulin sensitivity. Moreover, the increase in CEACAM1 expression also restored fat accumulation, inflammation and fibrosis in the livers of normal mice.
Collectively, these data indicate the importance of CEACAM1 as a promising therapeutic target in liver cells for the prevention and/or treatment of nonalcoholic steatohepatitis.It is our hope to develop a novel drug against nonalcoholic steatohepatitis that induces CEACAM1 expression to limit fat accumulation in the liver.
Hilda Ghadieh is a PhD graduate student at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. She is completing her doctoral studies in the molecular medicine track in the lab of Sonia Najjar, John J. Kopchick PhD fellow, endowed eminent research chair, professor of department of biomedical sciences, Heritage College of Osteopathic Medicine, Ohio University. For details email Hilda.Ghadieh@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.
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