Nonalcoholic fatty liver disease (NAFLD) is characterized by fatty infiltration of the liver in the absence of alcohol consumption. This fatty infiltration in the liver is associated with increased insulin resistance. Which of the following represents the most likely target of excess hepatic fatty acids resulting in the insulin resistance associated with NAFLD?

Question

Quizplus · Accepted Answer

Excess hepatic fatty acids activate protein kinase C (PKC), which is associated with the development of insulin resistance in NAFLD.  Hepatic IR is induced by the excess accumulation of FFAs. Within the hepatocyte metabolites of the FFA, re-esterification process, including longchain acyl-CoAs and diacylglycerol (DAG), accumulate. Excess FFAs also participate in the relocation of several protein kinase C (PKC) isoforms, from the cytosol to the membrane compartment. These PKC isoforms include PKC-β2, PKC-δ, and PKC-θ. DAG is a potent activator of these PKC isoforms and the membrane-associated PKC will phosphorylate the intracellular portion of the insulin receptor on serine residues which results in impairment of insulin receptor interaction with downstream signaling proteins including insulin receptor substrate 1 (IRS1). Loss of IRS1 interaction with the receptor prevents interaction with phosphatidylinositol 3-kinase (PI3K) and its subsequent activation.

Nonalcoholic Fatty Liver Disease (NAFLD) Is Characterized by Fatty Infiltration