6. Activation vs. inhibition of the gluconeogenic enzymes pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK). Pyruvate can also be converted to OA by PC (reaction 6F). However, this reaction is indirectly inhibited by insulin in several ways. First, insulin activates PDH as just discussed, thereby diverting pyruvate away from the PC reaction. Additionally, PC is allosterically activated by high levels of intramitochondrial acetyl CoA. Insulin keeps intramitochondrial levels of acetyl CoA low by activation of cytosolic DNL, which promotes removal of acetyl CoA via citrate from the mitochondria. Another key mechanism is to prevent β-oxidation of FFAs within the mitochondria, which generates high levels of acetyl CoA. By stimulating DNL, insulin also increases levels of cytosolic malonyl CoA, which inhibits transport of FFAs into the mitochondria (reaction 12D). Also, inhibitory actions of insulin on glucagon secretion and on lipolysis of TG within adipocytes prevents release of FFAs by adipose tissue and their import into hepatocytes.
In contrast, during the fasting phase, low insulin coupled with high glucagon and/or catecholamines stimulate release of FFAs from adipocytes (see later), which increases the flow of FFAs into hepatocytes. Glucagon also phosphorylates and activates the enzyme malonyl decarboxylase, which converts malonyl CoA back to acetyl CoA (reaction 9F). Enhanced malonyl CoA decarboxylase, along with generally low DNL due to low insulin, reduces malonyl CoA levels and thus removes the inhibition on the CPT1 transporter. This allows FFAs to enter the mitochondria and undergo β-oxidation (reaction 13F), generating high levels of intramitochondrial acetyl CoA, activating PC (reaction 6F) and also allosterically inhibiting PDH (reaction 6D).). The enzymes involved in β-oxidation are activated by PKA signaling. Glucagon also activates the transcription factor PPARα, which further induces expression of enzymes involved in β-oxidation. Fibrate drugs activate PPARα, promoting oxidation of intrahepatic TG and ameliorating insulin resistance.
Insulin also represses gene expression of the gluconeogenic enzyme PEPCK (reaction 7F), which converts pyruvate (by way of malate transferase out of the mitochondria) to phosphoenolpyruvate. PEPCK is primarily regulated at the level of transcription. Similar to its actions on G6Pase, FOXO1 stimulates transcription of PEPCK during the fasting phase, and insulin/Akt kinase signaling inactivates FOXO1 during the digestive phase. Glucagon and catecholamines also increase PEPCK gene expression through PKA-CREB signaling during the fasting phase.
Skeletal Muscle and Adipose Tissue Metabolism: Digestive vs. Fasting Phases 1.