25,8 Ketone Bodies

776 CHAPTER25 Lipid Metabolism 25,8 Ketonebodies AIM: To list the three ketone bodiesond the conditionsthot cousetheir production. Under certain circumstances, body cells do not have enough glucose even for brain cellsto use as an energysource. This happens most often in star- Liver cells produce ketone vation or in untreated diabetes.In starvation, no supply of glucose is avail- bodies when glucose is in short able; in diabetes, glucose is present in the blood, but it cannot penetrate supply. cell membranes. A lack of glucosecauses the cells of many organs to step up the beta oxidation of fatty acids. However, when glucose levels are lor,r4there is not enough oxaloacetateavailable to condense with acetyl CoA in the first step of the citric acid cycle.This is so becauseoxaloacetate comes from the car- boxylation of pyruvate, and pyruvate comes from the breakdo',nmof glucose in glycolysis. At low glucose levels, therefore, the concentration of acetyl CoA produced by the beta oxidation of fatty acids builds up. Under these conditions, the liver manufactures three special compounds from the excessaceryl CoA-the ketone bodies. Ketone bodies may be oxidized by many tissuesto meet energy needs. Th,eketonebodies are acetoaceticacid, B-hydroxybutyric acid, and acetone.We can see from their structural formulas that one of these compounds, p-hydroxybutyric acid, is inaccurately named as a ketone body, since it does not contain a ketone group. oo ooHo iltl rrlll cH3-c-cH2-c-oH cH.-c-cH., cH.-c-cH2-c-oH H Acetoaceticacid Acetone B-Hydroxybuty'ric acid (not a ketone) The liver does not use ketone bodies for energy production but releases them into the bloodstream. From the bloodstream, the ketone bodies reach other tissues-mainlythe brain, the heart, and skeletal muscle. The only ketone body that is in a form that can be used directly to produce energy is acetoaceticacid. The acetoaceticacid is converted to its thioesterwith CoA. o o o o tl CH3-C-CH2-C-OH + HS-CoA -+ CH:-C-CH2-C-S-CoA + H2O Acetoaceticacid AcetoacetylCoA The thioester that is formed, acetoacetylCoA, may look familiar. If you recall our discussion of beta oxidation, you will see that acetoacetyl CoA is the same compound that is formed at the end of the fatty acid spiral. Tissue cells can cleavethe acetoacewl CoA back to two molecules of acewl CoA. oo o iltl CH3-C-CH2-C-S-CoA + HS-CoA - 2CHt-C-S-CoA AcetoacetylCoA 25.9 Ketosis 777 The acetyl CoA is then oxidized to carbon dioxide in the citric acid cycle, thereby providing NADH and FADH2for ATP production by cellular respi- ration. The thioester of the ketone body B-hydroxybutyric acid is also formed in cells, but the hydroxyl group of the acid portion of the ester must be oxidized to a ketone. Acetoacetyl CoA, useful for energy production, is formed as a result of this oxidation. oHo oo ttl lttl CH3-C-CH2-C-S-CoA --Z----+ CH3-C-CH2-C-S-CoA I NAD* NADH- H- H p-HydroxybutyrylCoA Acetoacetyl CoA Acetone, the third ketone body, is not used as an energy source. 25.9 Ketosis AIMS: To characterizethe following ospectsof ketosis: ketonemio,ketonurio, acetonebreath, ond ketoocidosis. To describehow the effectsof ketosisare counteroctedby mechonismswithin the body ond by the odministrotionof externol ogents. In normal metabolism,some ketone bodies are continuouslyproduced and broken dor,rrnin energy production. The normal blood level of ketone bod- Prolonged ketosis stawes cells ies seldom exceeds3 mg/100 mL of blood. In diabetes,however, the liver for oxygen. produces large quantities of ketone bodies, releasing them into the bloodstream for delivery to other tissues.This causesa substantial increasein the level of ketone bodies in the blood of untreated diabetics. A leuel of ketone bodies greater than about 20 mg/100 mL of blood is called ketonemia ("ketonesin the blood"). Tissue cells cannot use all the ketone bodies produced. But the liver does not stop production, and eventually, a surplus builds up. At a leuel of about 70 mg/100 mL of blood, ketone bodies are excretedin the urine. This condition is ketonuria ("ketonesin the urine'). At high levels of ketone bodies in the blood, acetone is excretedby the lungs. The sweet, minty smell of acetone breath b ecomesapp arent. The conditions of ketonuria, ketonemia, and acetone breath together are symptoms of ketosis (also calledketoacidosis)-blood acidosis caused by an excessofthe ketonebody acids,acetoacetic acid, and B-hydroxybutyric acid. Diabetic ketosis involves the same problem as respiratory acidosis and lactic acidosis.This is the problem: The ketone body acids in the blood will lower the blood pH unlessenough bicarbonateions are presentto act as buffers (proton sponges). + HCo3- :- H2CO3 /..---->H- from ketone Proton Bicarbonate Carbonic bodr acid ion acid The pH of the blood is maintained at 7.40 as long as the kidneys can regeneratenew bicarbonate ions. In severecases of diabetic ketosis, how- 778 CHAPTER25 LipidMetabolism ever, the kidne.vscannot supply enough bicarbonate ions to keep up with the production of ketonebodies. More ketonebodies are produced, insuffi- cient bicarbonate ions are available, and the blood pH drops. This sequencehas a disastrouseffect. Hemoglobin can pick up oxygenonly in an environment with a low concentration of protons. The lower the pH of the blood, the higher is the concentration of protons, and the less oxygen can be transportedby hemoglobin. Brain cellsbecome starvedfor oxygen. If this lack of oxygen continues, coma and death will follow. The first step in the treatment of patients with diabeteswho are exhibit- ing ketosis is usually the administration of insulin. This should restore normal glucosemetabolism and reduce the formation of ketone bodies.Like glycosuria, ketonuria results in the loss of a large volume of body water, often causing dehydration. In diabetic patients with severe dehydration and ketosis, fluids and buffering power are restored by intravenous administration of solutions containing sodium bicarbonate. 25,10Cholesterol synthesis AIM: Toshow how the synthesisof cholesterolond ketone bodies illustrotesthe comportmentolizationsf cellulor Processes. Cholesterol is formed in the cytoplasm of liver cells. Biochemists have sho'nmthat the 27 carbons of the carbon skeleton of this important steroid The carbon skeleton ofcholes- come entirely from acetylCoA (Fig.25.5). The total biosynthesisof I mole- terol is formed from acetvl CoA. cule of cholesteroluses up 15 moleculesof acetylCoA and involvesat least 13 separatechemical reactions. A few of the main stepsin cholesterolsgr- thesisare shovrmin Figure25.6. The synthesis of cholesterol in the cl.toplasm and the synthesis of ketone bodiesin mitochondria are excellentexamples of the compartmen- talization of cellular processes.The cytoplasm lacks the enzl'rnesneeessary to synthesize ketone bodies from acetyl CoA; the mitochondrion lacks the enzyrnes necessary to synthesize cholesterol from acetyl CoA. Compart- mentalization is often important in balancing the s1'nthetic and energy needsof cells.\Mhen a cell needsenergy, most of the acerylCoA produced in its mitochondria is oxidized in the citric acid cycle.\Mhen large amounts of acetyl CoA are being oxidized, lesseramounts can be furnished to the cltoplasm. The decreasedlevel of acetyl CoA in the cltoplasm slows dornmor c'-a-tc'-a Figure25.5 ct I The incorporationof the acetyl t-a-' carbonsof acetylCoA into the a-c--j-c'-a carbonskeleton of cholesterol. CH3-C-S-CoACl lll Thecarbons of cholesterol 1 1 -".c''frc--.-c-c c shownin colorcome from the 5Y -===-->a methyl group of acetylCoA. The -L'-a-C--a'-C remainderof the carbonscome from the carbonylgroup (-C=O)..

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