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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #75: Regulation of Glucose Metabolism in Liver Part 11 of 11

Pyruvate dehydrogenase and lipogenesis

The generation of pyruvate via glycolysis and L-PK brings the chapter full circle. Tracer experiments in humans estimate PDH flux to be very small in the postabsorptive liver [36,37]. However, in the fed state activation of hepatic lipogenesis requires activation of PDH flux to generate acetyl-CoA from carbohydrate. PDH consists of three subunits (E1 – E3) that catalyze the sequential decarboxylation, acetyl-CoA formation and reduction of NAD+ to NADH, respectively. These subunits exist in a super-complex of more than 200 of these subunits called the PDH complex (PDC) [92]. During fasting, PDH activity is kept suppressed by pyruvate dehydrogenase kinase (PDK) which phosphorylates one or more of three serine residues on the E1 subunits [33]. PDK is associated to the E2 subunit of the PDC and its activity is acutely regulated by its own substrates and products (ATP/ADP) as well as the substrates and products of PDH (NADH/NAD+ and acetyl-CoA/CoA). Upon carbohydrate ingestion, PDH is reactivated by dephosphorylation of these sites through the actions of pyruvate dehydrogenase phosphatases (PDP), which are also components of the E2 subunits of the PDC and broadly regulated by Ca2+ and Mg2+. The main regulation of PDH phosphorylation appears to be through modification of PDK activity [33]. Upon carbohydrate ingestion, fatty acid oxidation is suppressed, PDK is deactivated, and PDPs dephosphorylate to relieve the suppression of PDH.

In coordination with the conversion of pyruvate to acetyl-CoA, high glucose activates ChREBP and induces the expression ACC and FAS, which facilitates the conversion of acetyl-CoA to lipids. During this process, ACC catalyzed carboxylation of acetyl-CoA to malonyl-CoA suppresses fat oxidation through allosteric inhibition of CPT-1 [43]. In normal physiology, elevated glucose is always accompanied by high insulin, which suppresses the genes of fat oxidation and induces SREBP. SREBP, in turn, promotes the expression of lipogenic genes and enhances the conversion of acetyl-CoA to lipids [93].


The liver has been studied for its metabolic characteristics for more than 200 years. The liver’s ability to produce or utilize glucose is the foundation of glycemic control. During fasting, liver releases glucose from glycogen stores and uses gluconeogenesis to produce glucose from pyruvate, lactate, amino acids, and glycerol. During prolonged fasting, gluconeogenesis is upregulated to compensate depleted glycogen levels and prevent major changes in blood glucose concentration. Upon feeding, liver rapidly converts to an organ that utilizes more glucose than it produces. Postprandial glucose uptake by liver replenishes glycogen and provides substrate for lipid synthesis for long-term energy storage. A large proportion of glycogen is formed by “indirect” synthesis, a process driven by the simultaneous activity of glycolysis and gluconeogenesis. Lipids are synthesized from acetyl-CoA derived from the activation of glycolysis and PDH. These elegant shifts in metabolism are regulated by transcription, posttranslational modification, allosteric and the substrate regulation of several key enzymes in the gluconeogenic and glycolytic pathway. Glucagon and other counterregulatory hormones activate transcription factors and co-activators that induce the expression and stability of gluconeogenic enzymes, while insulin opposes these effects and stimulates glucose uptake. Defects in any of these mechanisms can lead to loss of glycemic regulation.

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