LXR and INSIG Act as Differentiators in the Regulation of the Gene Expression of G6PDH and FAS Under Insulin Resistant Conditions

Abstract

Diabetes, a chronic metabolic disease that affects nearly 10% of the world's population can lead to very serious complications such as renal failure, liver cirrhosis, and heart attacks. The most common type is Type 2 diabetes and is diagnosed when a person has elevated amounts of blood glucose due to insulin resistance. This resistance to insulin leads to problems with glucose transport into tissues for subsequent metabolism. Over the years it has been shown that insulin regulates the expression of several key enzymes in both carbohydrate and fatty acid metabolic pathways via the phosphatidyl inositol 3-kinase (PI3K) pathway. Previously, using glucosamine, a precursor of the hexosamine biosynthetic pathway, we had established a model of insulin resistance in primary rat hepatocytes in culture. Using this primary cell culture model, we showed that under insulin resistant conditions, the expression of glucose 6 phosphate dehydrogenase (G6PDH), a key enzyme in carbohydrate metabolism and fatty acid synthase (FAS), a key enzyme in fat metabolism were differently regulated but the mechanism of this differentiation was unclear. Under this model of insulin resistance, we now show that this differential regulation is due to the liver X receptor (LXR) and insulin induced gene (INSIG).