Grant: CIHR Fellowship

Obesity, fatty liver and diabetes are modern metabolic disorders that affect millions of people worldwide. These disorders are typically associated with inflammation that disrupts how the liver handles cholesterol. Emerging evidence reveals that proteins called transcription factors that bind to DNA and control gene expression, in particular transcription factors that are normally involved in the innate immune response, modulate liver cholesterol handling. A recent study has tied one such protein, IRF2BP2, to elevated plasma total cholesterol and LDL-cholesterol, the so-called "bad cholesterol" because it increases the risk of heart disease and stroke. IRF2BP2, works with its partner interferon regulatory factor 2 (IRF2) to reduce the inflammatory actions caused by interferons. Interferons are known to cause fat accumulation in the liver (steatosis) and to suppress the synthesis of cholesterol by the liver. The main objective here is to understand how IRF2BP2 works to control fat and cholesterol balance in the liver. We hypothesize that IRF2BP2 regulates gene expression in the liver and controls the response to metabolic and other stressors. We made a LKO mouse model to study IRF2BP2 function in the liver. We found that loss of this protein made mice more susceptible to high fat diet induced steatosis and chemically-induced liver injury. Global analysis of gene expression using microarrays indicates that several molecules important for fat metabolism are affected by IRF2BP2 loss in the liver of LKO mouse. Our study will determine how IRF2BP2 controls fat and cholesterol balance in the liver and how the liver responds to injury (hepatitis) and metabolic stress (steatosis). Our study will reveal the link between a protein that regulates innate immunity and metabolism in non-immune liver cells, and provide information about the mechanism of metabolism disorders that may lead to new therapies that target this new direction.