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Ketogenesis And Ketone Bodies In Glucose Biology Essay

Ketone bodies are produced in low rates when an individual is eating normally. The production increases when the physiological status is normal, signaling a carbohydrate shortage. Keeping a regular production allows the heart and skeletal muscles to rely on ketone bodies for energy, and the brain to rely on glucose1. In normal individuals, the oxidation and synthesis of ketone bodies are active during long periods of starvation2.

Ketone bodies are specifically acetoacetate, β-hydroxybutyrate, and acetone2. Their functions provide energy to the skeletal muscle, heart, brain in the fetus and newborn, kidneys and mitochondria. A brief overview involves acetoacetate, and the reduced form β-hydroxybutyrate, being synthesized from acetyl-CoA in the mitochondria of liver. Towards the end of the pathway, acetone from spontaneous decarboxylation of acetoacetate is formed2. From here ketone bodies are oxidized as a fuel source and distributed to their functional areas1.

Synthesized ketone bodies are known as ketogenesis. This occurs in the liver and is irreversible due to the enzyme not present in the liver, which catalyzes acetoacetate to acetoacetyl-CoA. Ketone bodies are then exported from the liver and taken up in the brain, skeletal muscle and cardiac muscle2. Ketogenesis is related to fatty acid β-oxidation, in that the acetyl-CoA converted in acetoacetate is produced in fatty acid β-oxidation3.

Ketogenesis causes a lower glucose concentration and an increased lipid mobilization5. The Kreb cycle energy yield decreases and less acetyl CoA is transported into mitochondria1. The occurrence of ketogenesis can be found when a person is starving or diet switching from carbohydrates to poor amounts resulting in lots of lipids4. This can lead to gastrointestinal problems such as diarrhea and vomiting. Renal glucosuria and loss of glucose can also occur7.

Starvation does not necessarily mean the person is literally starving themselves. A person could be dieting or a diabetic limiting how many carbohydrates they consume. Low carbohydrate diets occasionally deplete carbohydrates altogether, creating a shortage of energy storages “leading to the breakdown of fat4. Known to be a healthy reaction within the body, ketogenesis is “associated with cells using fat for energy in place of carbohydrate stores4.” Ketogenesis is the process that releases ketone bodies when carbohydrate stores are exhausted and fat is broken down into energy4.

The first day or two of starvation, the brain begins to preserve glucose when large quantities of acetoacetate are used by the heart and tissues1. When the body is on its 3rd day, three-fourths of the brain energy sources are ketone bodies because the glucose requirement decreases by 50%. This is provided by a balance of ketogenesis and utilization of ketone bodies also being decreased. Within a few weeks to months, the brain will process ketone bodies for energy by up to 75%, as a source instead of glucose3. Glucose and glycogen work to prevent a temporary increase of ketogenesis. Glucose uses oxalacetate combined with fatty acid fragments to prevent ketogenesis. If fatty acid oxidation is blocked because of a deficiency in oxalacetate, then fatty acids cannot be metabolized and ketogenesis occurs1.

Ketosis will take effect, which is production of ketone bodies occurring quicker than the supply is needed. Acetone will then be found in the urine and breathe2. Ketoacidosis is what causes an increase of urination due to dehydration3.

Fatty acid oxidation begins with fatty acids being activated in the cytoplasm with acetyl CoA. Fatty acetyl-CoA ligase becomes the activated form consuming two ATP in the process. Acyl-caritine is an intermediate that generates the enzyme carnitine palmitoyltransferase I (CPT 1). The intermediate in then transported over with CPT II catalyzing the regeneration of fatty acyl-CoA. From here fatty acetyl CoA is transported into the mitochondrial membrane. Each time this process occurs 1 NADH, 1 FADH2 and 1 acetyl CoA are produced1.

“Mobilization and breakdown of stored fatty acids” generate acetyl CoA in the liver for synthesis of ketone bodies2. The signaling pathway begins with high amounts of acetyl-CoA, which is generated in the liver, when high rates of fatty acid oxidation occur. The acetyl-CoA that does not enter the Kreb Cycle takes part in the synthesis of ketogenesis1.

Reverse thiolase catalysis of fat oxidation takes two moles of acetyl-CoA and condenses it to form acetoacetyl-CoA. In the next step, under β-hydoxy-β-methylglutaryl-CoA (HMG-CoA) synthase, another acetyl-CoA is added to acetoacetyl-CoA making HMG-CoA. Within the mitochindra, HMG-CoA lyase converts HMG-CoA to acetoacetate7. Figure 1 depicts this set up for a visual understanding.

From here the pathway breaks into two different conversions. The third step involves acetyl- CoA being removed creating acetoacetate. Followed by the fourth step of acetoacetate being reduced to 3-hydroxybutyrate3. Spontaneous decarboxylation takes acetoacetate and creates acetone, or β-hydroxybutyrate dehydrogenase converts acetoacetate to β-hydroxybutyrate1. Like Figure 1, Figure 2 gives a visual understanding of these last two steps.

Figure 1

Figure 2

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When glucose demands become less and the acetone levels decrease, the pathway prevents itself to be converted back to acetyl-CoA. From here acetone is released by breathing out or from urination3. Figure 5 provides another way to explain this pathway break down.

Production of β-hydroxybutyrate becomes necessary when glycogen increases, carbohydrate utilizations is deficient, causing oxaloacetate levels and the Kreb Cycle flux to both decrease. This triggers the release of ketone bodies to the heart and skeletal muscles. Glucose will then be focused on only supplying the brain with energy1.

Extrahepatic tissues, the heart and skeletal muscle, utilized ketone bodies by converting β-hydroxybutyrate into acetoacetyl-CoA, through the reverse of ketogenesis, known as ketone utilization1. For this can be seen in Figure 6.

The first step in ketone utilization is the reversal of β-hydroxybutyrate, with the enzyme β-hydroxybutyrate dehydrogenase releasing 1 NADH, while creating acetoacetate. The second step involves the enzyme β-ketoacyl CoA transferase turning acetoacetate into Acetoacetate- CoA. Figure 3 is a mechanism that may help with identifying the conversion. During the transfer of acetoacetate to acetoacetate CoA, succinyl donates CoA to the reaction. The last step to ketone utilization takes acetoacetyl CoA and with the addition of β-ketothiolase to create two separate acetyl CoA1. Figure 4 shows this mechanism.

Acetoacetate + Succinyl- CoA  Acetoacetyl CoA + Succinate Figure 3

Acetoacetyl CoA + Thiolase(HS-CoA)  2 acetyl CoA Figure 4

Figure 5

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The metabolism for ketogenesis is the fatty acids metabolism. Fatty Acid Metabolism is dependable on carbohydrate metabolism and protein metabolism. The pancreas is the organ that senses dietary state and glucose concentration in the blood. The concentrations detected by blood trigger the release of insulin or glucose. The liver however, has a substrate that works as a regulatory mechanism1.

Figure 6

<http://themedicalbiochemistrypage.org/fatty-acid-oxidation.html>

Chylomicrons absorb fat where triglycerides can be found. From here, extra cellular lipase releases the fatty acids5. Two more sources of fatty acids come from adipose tissues, in the plasma membrane, and lipase triglycerides, specific for the liver intracellular triglycerides. Lipase are activated by four hormone controls; epinephrine, non-epinephrine, adipocytes and hepatocytes5. Hormone-sensitive lipase (HSL) is found within adipose tissues, which activates PKA-dependent phosphorylation, leading to fatty acids being released in the blood1.

ADP/ATP ratios are part of the energy charge of the cell. High ATP levels activate fatty acid synthesis and phosphatidic acid synthesis, while ADP increases β-oxidation and acetyl-CoA oxidation in the Kreb cycle. Lastly, carnitine acyl-transferase links the metabolisms of carbohydrates and fatty acids together. During this control mechanism β-oxidatation is avoided, fatty acids are synthesized creating a high energy charge, and carnitine-acyltransferase I is inhibited by maloyl-CoA. Malonyl-CoA-mediated inhibits CPT I preventing de novo5.

Substrate-level regulation is one of the ways to regulate ketogenesis. It regulates the release of free fatty acids from adipose tissue, and control the level of ketogenesis in the liver1. Two things can happen to fats when they enter the liver. The first is, fats may be converted to acetyl-CoA and then oxidized into the Kreb cycle3. This occurs when there is a need for ATP. Acetyl-CoA will be oxidized into CO2­ triggering this fate. Secondly, fats will be converted to glycerol forming triacylglycerols. Triacylglycerols will most likely to be produced when there is an abundance of glycerol-3-phosphate in the liver. Fat oxidation is regulated by phosphorylation. When glucagon triggers receptor phosphorylation goes into an active state, and inhibited when insulin triggers receptors5.

Eukaryotic cells are unable to convert acetyl-CoA to the formation of oxaloacetate, limiting catabolism from occurring. Since eukaryotic cells do not contain a glyoxylate shunt, high levels of acetyl-CoA are created when low glucose conditions exist preventing the Kreb cycle from occurring. The glyoxylate shunt works as a short cut to the Kreb cycle in prokaryotic cells converting isocitrate to oxaloacetate directly7.

Ketoacidosis is typically found in diabetics and alcoholics, and when untreated could lead to death and kidney failure. Diabetic Ketoacidosis (DKA) is developed when a decline of circulating insulin results in a low supply of glucose. An increase in fatty acid oxidation follows an increase in circulating glucagon, and acetyl-CoA production is increased followed by an increase in ketone bodies. The ketone bodies production exceeds the tissues’ ability to oxidize causing the pH in blood to drop causing it to turn acidic; therefore, the inability for oxygen and hemoglobin to bind4. This means the pH level of the blood drops before 7 causing the blood to become acidic1.

DKA contributes to hyperglycaemia. And severe systemic acidosis and intracellular acidosis inhibits gluconeogenesis. Researchers have looked at rats and the symptoms of DKA. All have shown signs of difficulties showing livers of diabetic ketoacidotic rats had inhibited gluconeogenesis from lactate that normal animals had shown. It did show the pH in both the living liver and diabetic ketoacidotic liver had little DKA comparisons8.

There are three types of treatments in curing DKA. Just like when the immune system is fighting a cold, drinking lots of water to help keep the body and veins hydrated. This also helps with the removal of acetone, by flushing it out of the body. Replacement of electrolytes in the body such as potassium, chloride and sodium allows normal function of the heart and nerves. The last type of treatment is combined with the other two types. Insulin therapy uses the abundance of fluids and electrolytes to help drop the blood sugar levels. Once accomplished the blood is back to a neutral pH and insulin therapy ends.9

As a diabetic, the best way to prevent DKA is to watch your ketone levels, monitor blood sugar and insulin dosages. Also notice any signs of possible early detection, like if confusion, excessive thirst, vomiting, fatigue and shortness of breath. However, keeping up with your diabetes will also detect any signs when something out of the ordinarily happens.9

DKA is one illness that can come from ketogenesis if a person carried a defect elsewhere. Ketogenesis works with the fatty acid metabolism along with the cholesterol metabolism to provide energy to the brain, heart and other vital tissues.

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