Glucagon regulates lipolysis and fatty acid oxidation through inositol triphosphate receptor 1 in the liver

Abstract

Glucagon promotes hepatic glucose production, lipolysis and amino acid catabolism. Inhibition of glucagon activity, or glucagon resistance, not only lowers blood glucose levels, but also induces non-alcoholic fatty liver disease and hyperaminoacidemia.

Figure 1

Stimulation of hepatic lipolysis by glucagon. Binding of glucagon to its cell surface receptor activates adenylate cyclase and phospholipase C. Activation of protein kinase A by cyclic adenosine monophosphate (cAMP) is sufficient to promote glycogenolysis and to activate hormone‐sensitive lipase. Activation of both protein kinase A and phospholipase C is required for type‐1 inositol triphosphate (IP3) receptor (INSP3R1) to release Ca²⁺ from the endoplasmic reticulum, and to activate calmodulin‐dependent kinase II (CaMKII). INSP3R1 is required to promote hepatic lipolysis, fatty acid oxidation and gluconeogenesis through activation of adipose triglyceride lipase.

Figure 2

(a) Glucagon action and (b) the consequence of glucagon suppression. Glucagon stimulates not only glycogenesis and gluconeogenesis, but also lipolysis and amino acid catabolism. Suppression of glucagon might have beneficial effects to lower blood glucose levels. However, inhibition of lipolysis should lead to the development of non‐alcoholic fatty liver disease (NAFLD) and glucagon resistance. Hyperaminoacidemia should also develop by suppression of glucagon.