TQ5.Increased glycolysis results in increased availability of glycerol 3phosphate for hepatic TAG synthesis. Additionally, some of the pyruvate generated in glycolysis will be oxidatively decarboxylated to acetyl coenzyme A (CoA). However, the tricarboxylic acid cycle is inhibited by the rise in NADH, and the acetyl CoA is transported to the cytosol as citrate. The rise of acetyl CoA in the cytosol results in increased fatty acid (FA) synthesis. Recall that citrate is an allosteric activator of acetyl CoA carboxylase (ACC). The malonyl product of ACC inhibits FA oxidation at the carnitine palmitoyltransferase I step. Because mitochondrial FA oxidation generates the acetyl CoA substrate for hepatic ketogenesis, ketone body levels do not rise. The FA gets esterified to the glycerol backbone, resulting in an increase in TAG that gets sent out of the liver as components of very-low-density lipoproteins (VLDL). [Note: The hypoglycemia results in release of epinephrine and the activation of TAG lipolysis with release of free FA into the blood. The FA are oxidized, with the excess used in hepatic TAG synthesis.] The acetyl CoA is also a substrate for cholesterol synthesis. Thus, the increase in glycolysis results in the hyperlipidemia seen in JS (see figure below).
Case 3: Answers to Review Questions
RQ1.Correct answer = A. Diabetes is characterized by hyperglycemia. Chronic hyperglycemia can result in the nonenzymatic glycosylation (glycation) of hemoglobin (Hb), producing HbA1c. Therefore, measurement of glucose or
HbA1c in the blood is used to diagnose diabetes. In response to physiologic stress (for example, a urinary tract infection), secretion of counterregulatory hormones (such as the catecholamines) results in a rise in blood glucose. Glucose is a reducing sugar. It is type 2 diabetes (T2D) that is associated with obesity and a sedentary lifestyle and is caused by insensitivity to insulin (insulin resistance). T1D is caused by lack of insulin as a result of the autoimmune destruction of pancreatic β cells. Even individuals on a program of tight glycemic control do not achieve euglycemia. RQ2.Correct answer = E. The ketone bodies 3-hydroxybutyrate and acetoacetate are organic acids, and their ionization contributes to the proton load of the body. Ketone bodies are made in the mitochondria of liver cells using acetyl coenzyme A (CoA) generated primarily from the β-oxidation of fatty acids ([FA]; see figure on the next page). Because they are water soluble, they do not require a transporter. The liver cannot use them because it lacks the enzyme thiophorase, which moves CoA from succinyl CoA to acetoacetate for conversion to two molecules of acetyl CoA. It is the acetone released in the breath that can impart a fruity odor.
RQ3.Correct answer = A. Malonyl CoA, an intermediate of FA synthesis, inhibits FA β-oxidation through inhibition of carnitine palmitoyltransferase I. Lipolysis occurs when the insulin/counterregulatory hormone ratio decreases. Acetyl CoA, the product of FA β-oxidation, inhibits the pyruvate dehydrogenase (PDH) complex through activation of PDH kinase and activates pyruvate carboxylase. Acetyl CoA, then, pushes pyruvate to gluconeogenesis. β-Oxidation generates reduced nicotinamide adenine dinucleotide (NADH), the reducing equivalent required for gluconeogenesis. FA are not readily catabolized for energy by the brain.