Factors affecting insulin-regulated hepatic gene expression

Obesity has become a major concern of public health. A common feature of obesity and related metabolic disorders such as noninsulin-dependent diabetes mellitus is insulin resistance, wherein a given amount of insulin produces less than normal physiological responses. Insulin controls hepatic glucose and fatty acid metabolism, at least in part, via the regulation of gene expression. When the liver is insulin-sensitive, insulin can stimulate the expression of genes for fatty acid synthesis and suppress those for gluconeogenesis. When the liver becomes insulin-resistant, the insulin-mediated suppression of gluconeogenic gene expression is lost, whereas the induction of fatty acid synthetic gene expression remains intact. In the past two decades, the mechanisms of insulin-regulated hepatic gene expression have been studied extensively and many components of insulin signal transduction pathways have been identified. Factors that alter these pathways, and the insulin-regulated hepatic gene expression, have been revealed and the underlying mechanisms have been proposed. This chapter summarizes the recent progresses in our understanding of the effects of dietary factors, drugs, bioactive compounds, hormones, and cytokines on insulin-regulated hepatic gene expression. Given the large amount of information and progresses regarding the roles of insulin, this chapter focuses on findings in the liver and hepatocytes and not those described for other tissues and cells. Typical insulin-regulated hepatic genes, such as insulin-induced glucokinase and sterol regulatory element-binding protein-1c and insulin-suppressed cytosolic phosphoenolpyruvate carboxyl kinase and insulin-like growth factor-binding protein 1, are used as examples to discuss the mechanisms such as insulin regulatory element-mediated transcriptional regulation. We also propose the potential mechanisms by which these factors affect insulin-regulated hepatic gene expression and discuss potential future directions of the area of research.