Insulin enhances the activity of pyruvate dehydrogenase (PDH) complex, which converts pyruvate to acetyl CoA. This acetyl CoA can then enter the TCA cycle by combining with oxaloacetate to form citrate. PDH phosphatase, activated by Akt kinase, is responsible for the dephosphorylation and activation of PDH (reaction 6D).

During the digestive phase, a portion of acetyl CoA is transferred from the mitochondria to the cytosol in the form of citrate. In the cytosol, the enzyme ATP-citrate lyase converts citrate back to acetyl CoA and oxaloacetate (reaction 8D). Insulin increases the gene expression of ATP-citrate lyase through the transcription factor SREBP1C. Acetyl CoA in the cytoplasm can then participate in fatty acid synthesis. The initial step involves the conversion of acetyl CoA to malonyl CoA by the enzyme acetyl-CoA carboxylase (reaction 9D). Insulin stimulates the gene expression of acetyl-CoA carboxylase through the transcription factor SREBP1C. Additionally, insulin promotes the dephosphorylation of acetyl-CoA carboxylase, thereby activating the enzyme. Malonyl CoA is further converted to palmitoyl CoA, a 16-carbon fatty acid, through repetitive additions of acetyl groups by the fatty acid synthase (FASN) complex (reaction 10D). The gene expression of FASN is enhanced by insulin through the transcription factor SREBP1C. Insulin also stimulates the activity of palmitoyl-CoA desaturase, which produces unsaturated fatty acids, and glycerol phosphate–fatty acyl transferases that esterify free fatty acids (FFAs) to form intrahepatic triglycerides (TGs).

The production of NADPH, required for palmitate synthesis, mainly occurs through the pentose phosphate pathway (PPP). In the first reaction of the PPP, glucose-6-phosphate dehydrogenase (G6PD) converts glucose-6-phosphate (G6P) to 6-phosphogluconolactone (reaction 4D). Insulin increases the gene expression of G6PD through the transcription factor SREBP1C.

By promoting the steps leading to malonyl CoA generation, insulin indirectly inhibits the oxidation of FFAs. Malonyl CoA inhibits the activity of CPT-I, which transports FFAs from the cytosol into the mitochondria (reaction 12D). Consequently, FFAs synthesized through de novo lipogenesis (DNL) cannot be transported into the mitochondria for β-oxidation (reaction 13F). Thus, increased levels of malonyl CoA prevent the futile cycle of FFA synthesis and oxidation.

The liver converts FFAs into TGs (reaction 11D), which are either stored within the liver or transported to adipose tissue and muscle as very-low-density lipoproteins (VLDL). Insulin acutely promotes the degradation of apoB-100, the apoprotein of VLDL. This mechanism prevents the liver from secreting VLDL when the blood is rich in chylomicrons during a meal. Consequently, the lipids produced in response to insulin during a meal are released as VLDL during the interdigestive and fasting phases, serving as a crucial source of energy for skeletal and cardiac muscle.
Activating pyruvate dehydrogenase (PDH) complex. PDH converts pyruvate to acetyl CoA, which can then enter the TCA cycle upon condensation with oxaloacetate (OA) to form citrate. Insulin increases PDH activity through Akt kinase activation of PDH phosphatase, which in turn dephosphorylates and activates PDH (reaction 6D).
5.
Increasing synthesis of intrahepatic TG. During the digestive phase, some acetyl CoA is transferred from the mitochondria to the cytosol in the form of citrate, which is then converted back to acetyl CoA and oxaloacetate by the cytosolic enzyme ATP-citrate lyase (reaction 8D). Insulin increases ATP-citrate lyase gene expression through transcription factor SREBP1C. Once in the cytoplasm, acetyl CoA can enter fatty acid synthesis. The first step involves conversion of acetyl CoA to malonyl CoA by the enzyme acetyl-CoA carboxylase (reaction 9D). Insulin stimulates acetyl-CoA carboxylase gene expression through the transcription factor SREBP1C. Insulin also promotes dephosphorylation of acetyl-CoA carboxylase, which activates the enzyme. Malonyl CoA is converted to the 16-carbon fatty acid palmitoyl CoA by repetitive additions of acetyl groups (contributed by malonyl CoA) by the fatty acid synthase (FASN) complex (reaction 10D). FASN gene expression is enhanced by insulin through the transcription factor SREBP1C. Insulin also stimulates palmitoyl-CoA desaturase, which produces unsaturated fatty acids, and glycerol phosphate–fatty acyl transferases that esterify FFAs to G3P to form intrahepatic TG.
Palmitate synthesis requires the coenzyme NADPH. A major source of NADPH is the pentose phosphate pathway (PPP; see
Fig. 39.12 ). The first reaction converts G6P to 6-phosphogluconolactone by the enzyme glucose-6-phosphate dehydrogenase (G6PD; reaction 4D). Insulin increases G6PD gene expression through the transcription factor SREBP1C.
By activating steps that lead to generation of malonyl CoA, insulin indirectly inhibits oxidation of FFAs. Malonyl CoA inhibits the activity of CPT-I, which transports FFAs from the cytosol into the mitochondria (reaction 12D). As a result, FFAs that are synthesized by DNL cannot be transported into mitochondria, where they undergo β-oxidation (reaction 13F). Thus increased malonyl CoA prevents the futile cycle of FFA synthesis to FFA oxidation.
FFAs are converted to TGs by the liver (reaction 11D) and are either stored in the liver or transported to adipose tissue and muscle in the form of VLDL (see later). Insulin acutely promotes degradation of the VLDL apoprotein apoB-100. This keeps the liver from secreting VLDL during a meal when the blood is rich with chylomicrons. Thus the lipid made in response to insulin during a meal is released as VLDL during the interdigestive and fasting phases and provides an important source of energy to skeletal and cardiac muscle.