TQ1.The phenotype would be the same. In familial defective apolipoprotein (apo) B-100, LDL receptors are normal in number and function, but the ligand for the receptor is altered such that binding to the receptor is decreased. Decreased ligand–receptor binding results in increased levels of LDL in the blood with hypercholesterolemia. [Note: The phenotype would be the same in individuals with a gain-of-function mutation to PCSK9, the protease that decreases recycling of the LDL receptor, thereby increasing its degradation.] With the apo E-2 isoform, cholesterol-rich chylomicron remnants and intermediate-density lipoproteins would accumulate in blood. TQ2.Aspirin irreversibly inhibits cyclooxygenase (COX) and, therefore, the synthesis of prostaglandins (PG), such as PGI2 in vascular endothelial cells, and thromboxanes (TX), such as TXA2 in activated platelets. TXA2 promotes vasoconstriction and formation of a platelet plug, whereas PGI2 inhibits these events. Because platelets are anucleate, they cannot overcome this inhibition by synthesizing more COX. However, endothelial cells have a nucleus. Aspirin, then, inhibits formation of blood clots by preventing production of TXA2 for the life of the platelet. TQ3.The decrease in ATP (as the result of a decrease in O2 and, thus, a decrease in oxidative phosphorylation) causes an increase in adenosine monophosphate (AMP). AMP allosterically activates phosphofructokinase-1, the key regulated enzyme of glycolysis. The rise in glycolysis increases the production of ATP by substrate-level phosphorylation. It also increases the ratio of the reduced to oxidized forms of NAD. Under anaerobic conditions, pyruvate produced in glycolysis is reduced to lactate by lactate dehydrogenase as NADH is oxidized to NAD+. NAD+ is required for continued glycolysis. Because fewer ATP molecules are produced per molecule of substrate in substrate-level phosphorylation relative to oxidative phosphorylation, there is a compensatory increase in the rate of glycolysis under anaerobic conditions.
TQ4.High-density lipoprotein (HDL) functions in reverse cholesterol transport. It takes cholesterol from nonhepatic (peripheral) tissues (for example, the endothelial layer of arteries) and brings it to the liver (see figure on the next page). The ABCA1 transporter mediates the efflux of cholesterol to HDL. The cholesterol is esterified by extracellular lecithin–cholesterol acyltransferase (LCAT) that requires apo A-1 as a coenzyme. Some cholesteryl ester is transferred to very-low-density lipoproteins (VLDL) by cholesteryl ester transfer protein (CETP) in exchange for triacylglycerol. The remainder is taken up by a scavenger receptor (SR-B1) on the surface of hepatocytes. The liver can use the cholesterol from HDL in the synthesis of bile acids. Removal of cholesterol from endothelial cells prevents its accumulation (as cholesterol or cholesteryl ester), decreasing the risk of heart disease. [Note: In contrast, LDL carries cholesterol from the liver to peripheral tissues or back to the liver.]
Case 2: Answers to Review Questions
RQ1.Answer = A. Deficiency of glucose 6-phosphatase prevents the glucose 6phosphate generated by glycogenolysis and gluconeogenesis from being dephosphorylated and released into the blood (see figure below). Blood glucose levels fall, and a severe, fasting hypoglycemia results. [Note: JS’s symptoms appeared only recently because, at age 4 months, his feedings are less frequent.]