The role of hepatic lipid accumulation in the development of insulin resistance in the liver

Insulin resistance (IR) is commonly defined as a lack of insulin effects on target tissues, due to impaired post-receptor signaling pathways. Generally, liver IR is manifested by uncontrolled glucose release to the blood stream (hyperglycemia). However, metabolic consequences of hepatic insulin resistance are more profound, involving also lipid imbalances. Accumulation of intracellular lipids such as diacylglycerols (DAG) and ceramides (CER) was found to interfere directly with the insulin signaling cascade, inducing hepatic IR. Molecular targets of elevated DAG and/or CER levels include activation of protein kinase C (PKC) and/or protein phosphatase that dephosphorylates Akt/PKB. In either case as a result insulin resistance develops, enhancing hyperglycemia and subsequent hyperinsulinemia, which in turn aggravate liver lipogenesis and fatty acid accumulation.