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In the liver, galactose-1-phosphate is converted to glucose-1-phosphate, before finally being converted to glucose-6-phosphate1. As shown below, glucose 6-phosphate can then be used in either glycolysis or glycogenesis, depending on the person's current energy state.
Unlike galactose, fructose cannot be used to form phosphorylated glucose. Instead, fructose-1-phosphate is cleaved in the liver to form glyceraldehyde 3-phosphate (glycolysis intermediate, you will learn more about this pathway in section 6.23). This occurs through multiple steps, as depicted below. Figure 6.213 Conversion of fructose-1-phosphate to glyceraldehyde 3-phosphate
Within hepatocytes or myocytes (muscle cells), glucose-6-phosphate can be used either for glycogenesis (glycogen synthesis) or glycolysis (breakdown of glucose for energy production). If the person is in an anabolic state, they will use glucose-6-phosphate for storage. If they are in a catabolic state, they will use it for energy production. In an anabolic state, glucose-6-phosphate will be used for glycogen synthesis for storage. In catabolic state, it will be used for energy production.
As discussed earlier, glycogen is the animal storage form of glucose. If a person is in an anabolic state, such as after consuming a meal, most glucose-6-phosphate within the myocytes (muscle cells) or hepatocytes (liver cells) is going to be stored as glycogen. The structure is shown below as a reminder.
body, there is 3-4 times more glycogen stored in muscle than in the liver2. We have limited glycogen storage capacity. Thus, after a high-carbohydrate meal, our glycogen stores will reach capacity. After glycogen stores are filled, glucose will have to be metabolized in different ways for it to be stored in a different form.
The synthesis of glycogen from glucose is a process known as glycogenesis. Glucose-6-phosphate is not inserted directly into glycogen in this process. There are a couple of steps before it is incorporated. First, glucose-6-phosphate is converted to glucose-1-phosphate and then converted to uridine diphosphate (UDP)-glucose. UDP-glucose is inserted into glycogen by either the enzyme, glycogen synthase (alpha-1,4 bonds), or the branching enzyme (alpha-1,6 bonds) at the branch points3. Figure 6.222 Glycogenesis
The process of liberating glucose from glycogen is known as glycogenolysis. This process is essentially the opposite of glycogenesis with two exceptions: (1) there is no UDP-glucose step, and (2) a different enzyme, glycogen phosphorylase, is involved. Glucose-1-phosphate is cleaved from glycogen by the enzyme, glycogen phosphorylase, which then can be converted to glucose-6-phosphate as shown below3.
References & Links http://en.wikipedia.org/wiki/File:Glycogen.png Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.
Thus, from a molecule of glucose, the harvesting step produces a total of four ATPs and two NADHs. Subtracting the harvesting from the investment step, the net output from one molecule of glucose is two ATPs and two NADHs. The figure below shows the stages of glycolysis, as well as the transition reaction, citric acid cycle, and electron transport chain that are utilized by cells to produce energy. They are also the focus of the next 3 sections. Figure 6.236 Glycolysis, transition reaction, citric acid cycle, and the electron transport chain2
If a person is in a catabolic state, or needs energy, how pyruvate will be used depends on whether adequate oxygen levels are present. If there are adequate oxygen levels (aerobic conditions), pyruvate moves from the cytoplasm, into the mitochondria, and then undergoes the transition reaction. If there are not adequate oxygen levels (anaerobic conditions), pyruvate will instead be used to produce lactate in the cytoplasm. We are going to focus on the aerobic pathway to begin with, then we will address what happens under anaerobic conditions in the anaerobic respiration section.
The transition reaction is the transition between glycolysis and the citric acid cycle. The transition reaction converts pyruvate (3 carbons) to acetyl CoA (2 carbons), producing carbon dioxide (CO2) and an NADH as shown below. The figure below shows the transition reaction with CoA and NAD entering, and acetyl-CoA, CO2, and NADH being produced.
References & Links https://simple.wikipedia.org/wiki/Mitochondria#/media/File:Animal_mitochondrion_diagram_en_(edit).svg http://en.wikipedia.org/wiki/Image:Citric_acid_cycle_with_aconitate_2.svg http://en.wikipedia.org/wiki/Image:Coenzym_A.svg
Acetyl-CoA is a central point in metabolism, meaning there are a number of ways that it can be used. We are going to continue to consider its use in an aerobic, catabolic state (need energy). Under these conditions, acetyl-CoA will enter the citric acid cycle (aka Krebs Cycle, TCA Cycle). The following figure shows the citric acid cycle.
The citric acid cycle begins by acetyl-CoA (2 carbons) combining with oxaloacetate (4 carbons) to form citrate (aka citric acid, 6 carbons). A series of transformations occur before a carbon is given off as carbon dioxide and NADH is produced. This leaves alpha-ketoglutarate (5 carbons). Another carbon is given off as CO2 to form succinyl CoA (4 carbons) and produce another NADH. In the next step, one guanosine triphosphate (GTP) is produced as succinyl-CoA is converted to succinate. GTP is readily converted to ATP, thus this step is essentially the generation of 1 ATP. In the next step, an FADH2 is produced along with fumarate. Then, after more steps, another NADH is produced as oxaloacetate is regenerated.
Through glycolysis, the transition reaction, and the citric acid cycle, multiple NADH and FADH2 molecules are produced. Under aerobic conditions, these molecules will enter the electron transport chain to be used to generate energy through oxidative phosphorylation as described in the next section.
The electron transport chain contains a number of electron carriers. These carriers take the electrons from NADH and FADH2, pass them down the chain of complexes and electron carriers, and ultimately produce ATP. More specifically, the electron transport chain takes the energy from the electrons on NADH and FADH2 to pump protons (H+) into the intermembrane space. This creates a proton gradient between the intermembrane space (high) and the matrix (low) of the mitochondria. ATP synthase uses the energy from this gradient to synthesize ATP. Oxygen is required for this process because it serves as the final electron acceptor, forming water. Collectively this process is known as oxidative phosphorylation. The following figure and animation do a nice job of illustrating how the electron transport chain functions.
The first video does a nice job of illustrating and reviewing the electron transport chain. Note that it uses 3 ATP/NADH and 2 ATP/FADH2 so the totals from each cycle are different from those listed above. The second video is a great rap video explaining the steps of glucose oxidation.
Notice that the vast majority of ATP is generated by the electron transport chain. If we do the math, 28/32 X 100 = 87.5% of the ATP from a molecule of glucose is generated by the electron transport chain. Remember that this is aerobic and requires oxygen to be the final electron acceptor. If 3 ATP/NADH and 2 ATP/FADH2 are used instead of 2.5 ATP/NADH and 1.5 ATP/FADH2 that were used above, total ATP and percentage of ATP produced by the electron transport chain would be different. But the takeaway message remains the same. The electron transport chain by far produces the most ATP from one molecule of glucose.
This leads to a problem in glycolysis because NAD is needed to accept electrons, as shown below. Without the electron transport chain functioning, all NAD has been reduced to NADH and glycolysis cannot continue to produce ATP from glucose.
However, anaerobic respiration only produces 2 ATP per molecule of glucose, compared to 32 ATP for aerobic respiration. The biggest producer of lactate is the muscle. Through what is known as the Cori cycle, lactate produced in the muscle can be sent to the liver. In the liver, through a process known as gluconeogenesis, glucose can be regenerated and sent back to the muscle to be used again for anaerobic respiration forming a cycle as shown below.
References & Links https://simple.wikipedia.org/wiki/Mitochondria#/media/File:Animal_mitochondrion_diagram_en_(edit).svg http://en.wikipedia.org/wiki/File:CellRespiration.svg https://en.wikipedia.org/wiki/Pyruvic_acid#/media/File:Pyruvic-acid-2D-skeletal.png https://en.wikipedia.org/wiki/Lactic_acid#/media/File:Lactic-acid-skeletal.svg https://commons.wikimedia.org/wiki/File:CoriCycle-noLang.svg#/media/File:CoriCycle-eng.svg
Despite performing the same function, at the adipose level, the enzymes are primarily active for seemingly opposite reasons. In the fed state, LPL on the endothelium of blood vessels cleaves lipoprotein triglycerides into fatty acids so that they can be taken up into adipocytes, for storage as triglycerides, or myocytes where they are primarily used for energy production. This action of LPL on lipoproteins is shown in the two figures below. Figure 6.312 Lipoprotein lipase cleaves fatty acids from the chylomicron, forming a chylomicron remnant.
HSL is an important enzyme in adipose tissue, which is a major storage site of triglycerides in the body. HSL activity is increased by glucagon and epinephrine ("fight or flight" hormone), and decreased by insulin. Thus, in hypoglycemia (such as during a fast) or a "fight or flight" response, triglycerides in the adipose are cleaved, releasing fatty acids into circulation that then bind with the transport protein albumin. Thus, HSL is important for mobilizing fatty acids so they can be used to produce energy. The figure below shows how fatty acids can be taken up and used by tissues such as the muscle for energy production1.
To generate energy from fatty acids, they must be oxidized. This process occurs in the mitochondria, but long chain fatty acids cannot diffuse across the mitochondrial membrane (similar to absorption into the enterocyte). Carnitine, an amino acid-derived compound, helps shuttle long-chain fatty acids into the mitochondria. The structure of carnitine is shown below.
As shown below, there are two enzymes involved in this process: carnitine palmitoyltransferase I (CPTI) and carnitine palmitoyltransferase II (CPTII). CPTI is located on the outer mitochondrial membrane, CPTII is located on the inner mitochondrial membrane. The fatty acid is first activated by adding CoA (forming acyl-CoA), then CPTI adds carnitine. Acyl-Carnitine is then transported into the mitochondrial matrix with the assistance of the enzyme translocase. In the matrix, CPTII removes carnitine from the activated fatty acid (acyl-CoA). Carnitine is recycled back into the cytosol to be used again, as shown in the figure and animation below. Even though carnitine is important for this action, taking supplemental carnitine will not increase fatty acid oxidation. This is due to the fact that the amount of carnitine available is not limiting fatty acid oxidation.
As shown below, the first step of fatty acid oxidation is activation. A CoA molecule is added to the fatty acid to produce acyl-CoA, converting ATP to AMP (adenosine monophosphate). Thus, activation uses the equivalent of 2 ATP molecules (since it typically cleaved to ADP)4.
Fatty acid oxidation is also referred to as beta-oxidation because 2 carbon units are cleaved off at the beta-carbon position (2nd carbon from the acid end) of an activated fatty acid. The cleaved 2 carbon unit forms acetyl-CoA and produces an activated fatty acid (acyl-CoA) with 2 fewer carbons, acetyl-CoA, NADH, and FADH2. To completely oxidize the 18-carbon fatty acid above, 8 cycles of beta-oxidation have to occur. This might seem like one too few cycles (18 divided by 2 is nine), but the last cycle will split the 4 carbon fatty acid into 2 acetyl-CoAs, meaning that it only takes 8 cycles to completely cleave the fatty acid. Overall beta oxidation of an 18 carbon fatty acids will produce:
Subtract 2 ATP (ATP-->AMP) required for activation of the fatty acid: 122-2 = 120 Net ATP Compared to glucose (32 ATP) you can see that there is far more energy stored in a fatty acid. This is because fatty acids are in a more reduced form and thus, they yield 9 kcal/g instead of 4 kcal/g like carbohydrates4.
References & Links http://en.wikipedia.org/wiki/File:Carnitine_structure.png https://simple.wikipedia.org/wiki/Mitochondria#/media/File:Animal_mitochondrion_diagram_en_(edit).svg 3.https://en.wikipedia.org/wiki/Carnitine_palmitoyltransferase_I#/media/File:Acyl-CoA_from_cytosol_to_the_mit ochondrial_matrix.svg 4. Berg JM, Tymoczko JL, Stryer L. (2002) Biochemistry. New York, NY: W.H. Freeman and Company.
De novo in Latin means "from the beginning." Thus, de novo lipogenesis is the synthesis of fatty acids, beginning with acetyl-CoA. Acetyl-CoA has to first move out of the mitochondria, where it is then converted to malonyl-CoA (3 carbons). Malonyl-CoA then is combined with another acetyl-CoA to form a 4 carbon fatty acid (1 carbon is given off as CO2). The addition of 2 carbons is repeated through a similar process 7 times to produce a 16 carbon fatty acid1.
In cases where there is not enough glucose available for the brain (very low carbohydrate diets, starvation), the liver can use acetyl-CoA, primarily from fatty acids (but also certain amino acids), to synthesize ketone bodies (ketogenesis). The structures of the three ketone bodies; acetone, acetoacetic acid, and beta-hydroxybutyric acid, are shown below.
After they are synthesized in the liver, ketone bodies are released into circulation where they can travel to the brain. The brain converts the ketone bodies to acetyl-CoA that can then enter the citric acid cycle for ATP production, as shown below.
If there are high levels of ketones secreted, it results in a condition known as ketosis or ketoacidosis. The high level of ketones in the blood decreases the blood’s pH, meaning it becomes more acidic. It is debatable whether mild ketoacidosis is harmful, but severe ketoacidosis can be lethal. One symptom of this condition is fruity or sweet smelling breath, which is due to increased acetone exhalation.
Simplifying this, acetyl-CoA is converted to acetoacetyl-CoA (4 carbons) before forming 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is converted to mevalonate by the enzyme HMG-CoA reductase. This enzyme is important because it is the rate-limiting enzyme in cholesterol synthesis.
Rate-limiting enzymes limit the rate at which a metabolic pathway proceeds. The pharmaceutical industry has taken advantage of this knowledge to lower people's LDL levels with drugs known as statins. These drugs inhibit HMG-CoA reductase and thus decrease
The cholesterol guidelines have changed dramatically from the previous focus on LDL and HDL target levels. Now statins are prescribed at set therapeutic doses based on assessed cardiovascular risk rather than based off LDL and HDL target levels. It is also recommended that only statins that have been shown to decrease cardiovascular disease risk be used, some have only been shown to improve LDL/HDL levels. The link below is to the online calculator that can be used to estimate an individual's risk. The body synthesizes approximately 1 g/day, whereas it is recommended that we consume less than 0.3 g/day. A number of tissues synthesize cholesterol, with the liver accounting for ~20% of synthesis. The intestine is believed to be the most active among the other tissues that are responsible for the other 80% of cholesterol synthesis5.
Section 2.22 described how proteins are synthesized. Thus, this section will focus on how proteins and amino acids are broken down. There are four protein metabolic pathways that will be covered in this section:
The first step in catabolizing, or breaking down, an amino acid is the removal of its amine group (-NH3). Amine groups can be transferred or removed through transamination or deamination, respectively.
Keto acids (also known as carbon skeletons) are what remains after amino acids have had their nitrogen group removed by deamination or transamination. Transamination is used to synthesize nonessential amino acids.
Our body has a method to safely package ammonia into a less toxic form to be excreted. This safer compound is urea, which is produced by the liver using 2 molecules of ammonia (NH3) and 1 molecule of carbon dioxide (CO2). Most urea is then secreted from the liver and incorporated into urine in the kidney to be excreted from the body, as shown below.
References http://en.wikipedia.org/wiki/File:Transaminierung.svg http://en.wikipedia.org/wiki/File:DesaminierungCtoU.png http://en.wikipedia.org/wiki/File:Symptoms_of_hyperammonemia.svg http://commons.wikimedia.org/wiki/File:Liver.svg
Gluconeogenesis is the synthesis of glucose from noncarbohydrate sources. Certain amino acids can be used for this process, which is the reason that this section is included here instead of the carbohydrate metabolism section. Gluconeogenesis is glycolysis in reverse with an oxaloacetate workaround, as shown below. Remember oxaloacetate is also an intermediate in the citric acid cycle. Figure 6.421 Gluconeogenesis is glycolysis in reverse with an oxaloacetate workaround1 Not all amino acids can be used for gluconeogenesis. The ones that can be used are termed glucogenic (red), and can be converted to either pyruvate or a citric acid cycle intermediate. Other amino acids can only be converted to either acetyl-CoA or acetoacetyl-CoA, which cannot be used for gluconeogenesis. However, acetyl-CoA or acetoacetyl-CoA can be used for ketogenesis to synthesize the ketone bodies, acetone and acetoacetate. Thus, these amino acids are instead termed ketogenic (green).
Fatty acids and ketogenic amino acids cannot be used to synthesize glucose. The transition reaction is a one-way reaction, meaning that acetyl-CoA cannot be converted back to pyruvate. As a result, fatty acids can't be used to synthesize glucose, because beta-oxidation produces acetyl-CoA. Even if acetyl-CoA enters the citric acid cycle, the carbons from it will eventually be completely oxidized and given off as CO2. The net result is that these carbons are not readily available to serve as keto-acids or carbon skeletons for amino acid synthesis. Some amino acids can be either glucogenic or ketogenic, depending on how they are metabolized. These amino acids are referred to as glucogenic and ketogenic (pink).
Proteins that are damaged or abnormal are tagged with the protein ubiquitin. There are multiple protein subunits involved in the process (E1-E3), but the net result is the production of a protein (substrate) with a ubiquitin tail, as shown below. Figure 6.431 Ubiquitination of a protein (substrate)1 This protein then moves to the proteasome for degradation. Think of the proteasome like a garbage disposal. The ubiquitinated "trash" protein is inserted into the garbage disposal where it is broken down into its component parts (primarily amino acids). The following video illustrates this process nicely.
Ethanol is passively absorbed by simple diffusion into the enterocyte. Ethanol metabolism occurs primarily in the liver, but 10-30% is estimated to occur in the stomach2. For the average person, the liver can metabolize the amount of ethanol in one drink (1/2 ounce) per hour3. There are three ways that alcohol is metabolized in the body.
Alcohol dehydrogenase (ADH) - This is the major ethanol-metabolizing enzyme that converts ethanol and NAD to acetaldehyde and NADH, respectively. Aldehyde dehydrogenase (ALDH) uses NAD, CoA, and acetaldehyde to create acetyl-CoA and to produce another NADH. The action of ADH is shown in the figure below.
Microsomal ethanol oxidizing system (MEOS) - When a person consumes a large amount of alcohol the MEOS, is the overflow pathway, which also metabolizes ethanol to acetaldehyde. It is estimated that the MEOS metabolizes 20% of ethanol3, and it differs from ADH in that it uses ATP to convert reduced nicotinamide adenine dinucleotide phosphate (NADPH + H+) to NADP+. The action of the MEOS is shown in the figure above. At high intakes or with repeated exposure, there is increased synthesis of MEOS enzymes resulting in more efficient metabolism, also known as increased tolerance. ADH levels do not increase based on alcohol exposure. MEOS also metabolizes a variety of other compounds (drugs, fatty acids, steroids) and alcohol competes for the enzyme's action. This can cause the metabolism of drugs to slow and potentially reach harmful levels in the body3. Females have lower stomach ADH activity and body H2O concentrations. As a result, a larger proportion of ethanol reaches circulation, thus, in general, females have a lower tolerance for alcohol. About 50% of Taiwanese, Han Chinese, and Japanese populations have polymorphisms in ALDH which cause the enzyme to have low activity6. This leads to acetaldehyde buildup and undesirable symptoms such as: flushing, dizziness, nausea, and headaches2. The following short video explains what happens when the MEOS system gets involved in alcohol metabolism. References & Links http://en.wikipedia.org/wiki/File:Ethanol_flat_structure.png Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Whitney E, Rolfes SR. (2008) Understanding nutrition. Belmont, CA: Thomson Wadsworth. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. https://en.wikipedia.org/wiki/Acetaldehyde#/media/File:Acetaldehyde-2D-flat.svg Zakhari, S. (2006) Overview: How Is Alcohol Metabolized by the Body? (2006) Alcohol Research and Health. 29 (4) 245-254.
Understanding the different metabolic pathways is an important step. However, an integrated understanding of the interconnectedness and tissue specificity of metabolism is where this knowledge really becomes powerful. To this end, you will first learn how the different pathways integrate with one another and then talk about the metabolic capabilities of the different tissues in the body. We will then discuss what happens metabolically during different conditions or when consuming certain diets.
Carbohydrate pathways are orange Triglyceride/fatty acid pathways are purple Protein/amino acid pathways are green Nonclassified pathways are gray Figure 7.11 Integrated macronutrient and alcohol metabolism1
Notice that acetyl-CoA is the central metabolite in integrated metabolism that connects many different pathways. For example, carbohydrates can be broken down to acetyl-CoA that can then be used to synthesize fats and ultimately triglycerides.
The liver is the organ that has the greatest macronutrient metabolic capability; there are a number of metabolic functions that only the liver performs. However, there are two major macronutrient metabolic processes, lactate synthesis and ketone body breakdown, that the liver will not normally perform, as shown in the figure below.
Glucose-6-phosphatase is important because it removes the phosphate from glucose-6-phosphate so that glucose can be released into circulation. Kidneys have glucose-6-phosphatase and can perform gluconeogenesis. However, it is estimated that 90% of glucose formed from gluconeogenesis is produced by the liver; the remaining 10% is produced by the kidney(s). It is also important to note that the muscle does not have this enzyme, so it cannot release glucose into circulation3. References & Links http://en.wikipedia.org/wiki/File:CellRespiration.svg Phypers B, Pierce JMT. (2006) Lactate physiology in health and disease. Continuing Education in Anaesthesia Critical Care & Pain, 6(3). Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.
Because the liver is so important in metabolism, the term extrahepatic has been defined to mean "located or occurring outside of the liver1". We are next going to consider extrahepatic tissue metabolism.
Figure 7.32 Removing the pathways that only or mostly occur in the liver3 We are left with metabolic capabilities that are listed and shown below. Glycogen synthesis and breakdown Glycolysis Fatty acid synthesis and breakdown Triglyceride synthesis and breakdown Protein synthesis and breakdown
We will use this figure as the base for metabolic capabilities of the different extrahepatic tissues to compare what pathways other tissues can perform versus all the pathways performed by extrahepatic tissues.
Muscle is a major extrahepatic metabolic tissue. It is the only extrahepatic tissue with significant glycogen stores. However, unlike the liver, the muscle cannot secrete glucose after it is taken up (no glucose-6-phosphatase). Thus, you can think of the muscle as being selfish with glucose. It either uses it for itself initially or stores it for its later use.
It probably does not surprise you that the major function of the adipose is to store energy as triglycerides. Compared to extrahepatic tissues as a whole, in the adipose the following pathways are not performed or are not important: Glycogen synthesis and breakdown Lactate synthesis Ketone body breakdown Fatty acid breakdown Protein synthesis and breakdown Citric acid cycle (not much since it is not an active tissue needing energy)
Fatty acid synthesis only occurs in the adipose and liver. In the adipose, fatty acids are synthesized and most will be esterified into triglycerides to be stored. In the liver, some fatty acids will be esterified into triglycerides to be stored, but most triglycerides will be incorporated into VLDL so that they can be used or stored by other tissues.
Fatty acid breakdown does not occur to any great extent in the brain because of the low activity of an enzyme in the beta-oxidation pathway limits the pathway’s activity1. Compared to the extrahepatic tissues as a whole, in the brain the following pathways are not performed or are not important:
References & Links Yang SY, He XY, Schulz H (1987) Fatty acid oxidation in rat brain is limited by the low activity of 3-ketoacyl-coenzyme A thiolase. J BIol Chem 262 (27): 13027-13032. http://en.wikipedia.org/wiki/File:CellRespiration.svg
You have learned about the pathways and the tissue metabolic capabilities, so now you are going to apply that knowledge to four conditions: fed state, fasting, the Atkins diet, and the Ornish/Pritikin diet, as ways to illustrate how you can use this knowledge. In the fed state, we are going to be considering what is happening metabolically after consuming all 3 macronutrients. In fasting, we’re going to be considering what is happening metabolically during a prolonged period without food. The Atkins diet is a carbohydrate-restricted diet, so we are going to consider what happens metabolically when someone is eating a diet that essentially only contains protein and lipids over an extended period of time. Finally the Ornish/Pritikin diet is a very low fat diet, so we’re going to consider what happens metabolically when someone is eating a diet that is essentially only carbohydrates and protein over an extended period of time. For each of these conditions, we’re going to consider what is happening in the liver, muscle, adipose, and brain. Now that you should have an understanding of the glycemic response and macronutrient metabolism, you should be able to understand the broader effects of insulin and glucagon that are summarized in the following tables. Knowing what hormone is elevated in the different conditions helps you to understand the metabolism that occurs in different conditions.
In this condition, assume a person just consumed a meal containing carbohydrates, protein and fat. As a result, this person is in an anabolic state with high blood glucose levels, meaning the pancreas will secrete insulin. The liver will take up glucose and synthesize glycogen until its stores are filled. After these stores are full, glucose can be broken down through glycolysis to pyruvate, then form acetyl-CoA in the transition reaction. Because we are in the fed or anabolic state, acetyl-CoA will be used for ATP generation, but some acetyl-CoA will also be used for fatty acid synthesis. Chylomicron remnants will also be taken up and fatty acids from them will also be used for triglyceride synthesis (along with fatty acids synthesized) to contribute to the pool of triglycerides found in the liver. Triglycerides from this pool will be packaged into VLDL and secreted from the liver. Amino acids will also be taken up and used for protein synthesis as needed. Because there is plenty of glucose, gluconeogenesis and ketone body synthesis will not be operating to any great extent. The muscle will take up glucose and synthesize glycogen until those stores are filled. Some glucose will go through glycolysis to produce pyruvate, then form acetyl-CoA in the transition reaction. The acetyl-CoA will enter the citric acid cycle, and NADH and FADH2 produced will enter the electron transport chain to generate ATP. Fatty acids that are cleaved from chylomicrons, VLDL, IDL, and LDL are also going to be taken up. These fatty acids will be used to synthesize triglycerides for storage. Whatever amino acids are taken up will be used for protein synthesis. The muscle will not be secreting anything in this condition. The adipose is going to take up glucose that will enter glycolysis, pyruvate will be produced, then acetyl-CoA will be produced in the transition reaction. Because we are in the fed or anabolic state, the acetyl-CoA will be used for fatty acid synthesis. Fatty acids will also be taken up from being cleaved from chylomicrons, VLDL, IDL, and LDL. These fatty acids from both synthesis and cleavage are primarily going to be used to synthesize triglycerides for storage. The adipose will not be secreting anything under this condition.
In this condition a person has been fasting for an extended period of time (18 hours or longer). As a result, the person is in a catabolic state with low blood glucose levels, which leads the pancreas to secrete glucagon. The liver will break down glycogen to secrete glucose for other tissues to use until its stores are exhausted. Amino acids and lactate (Cori cycle) from muscle will be used for gluconeogenesis to synthesize glucose that will also be secreted. Glycolysis will not be occurring to any great extent to spare glucose for use by other tissues. From the breakdown of amino acids, there will be an increase in the synthesis and secretion of urea from the liver to safely rid the body of ammonia from the amino acids. Fatty acids that are received from the adipose will be broken down to acetyl-CoA. The acetyl-CoA will then enter the citric acid cycle, and NADH and FADH2 produced will enter the electron transport chain to generate ATP. The acetyl-CoA will also be used to synthesize ketone bodies that are secreted for tissues, such as the brain, that cannot directly use fatty acids as a fuel. The muscle will break down glycogen to glucose until glycogen stores are exhausted, and receive limited glucose from the liver that enters glycolysis, forming pyruvate. Most pyruvate will be converted to lactate to spare glucose (Cori cycle). Limited pyruvate will enter the transition reaction to form acetyl-CoA. Once there isn’t enough glucose for the muscle to use, fatty acids taken up from the adipose and from breakdown of muscle triglyceride stores will be broken down to acetyl-CoA. Acetyl-CoA will then enter the citric acid cycle, and NADH and FADH2 produced will enter the electron transport chain to generate ATP. Amino acids from protein breakdown and lactate (Cori cycle) will be secreted to be used by the liver for gluconeogenesis.
In this condition, assume a person has just started into phase I of the Atkins Diet and he/she has just consumed a meal of all protein and fat with no carbohydrates. As a result, this person is in an anabolic state, but blood glucose levels are low, meaning the pancreas will secrete glucagon. Liver glycogen stores will be broken down to secrete glucose for other tissues. Glycolysis will not be occurring to any great extent, in order to spare glucose for other tissues. Using amino acids from digestion and lactate from muscle (Cori Cycle), gluconeogenesis will synthesize glucose (minimal) that will also be secreted. From the breakdown of amino acids, there will be an increase in the synthesis and secretion of urea from the liver to safely rid the body of ammonia from the amino acids. Amino acids will also be used for protein synthesis. Fatty acids will be cleaved from chylomicron remnants and broken down to acetyl-CoA and used to synthesize ketone bodies that are secreted for tissues, such as the brain, that cannot directly use fatty acids as a fuel. Fatty acids from them will also be used for triglyceride synthesis to contribute to the pool of triglycerides found in the liver. Triglycerides from this pool will be packaged into VLDL and secreted from the liver. The muscle will break down glycogen to glucose, and receive glucose from the liver that enters glycolysis, forming pyruvate. After glycogen is used up, most pyruvate produced by glycolysis is converted to lactate to spare glucose (minimal). Limited pyruvate will enter the transition reaction to form acetyl-CoA. The acetyl-CoA will then enter the citric acid cycle, and NADH and FADH2 produced will enter the electron transport chain to generate ATP. Once there is not enough glucose for the muscle to use, fatty acids will be cleaved from and taken up from chylomicrons, VLDL, IDL, and LDL and broken down to acetyl-CoA in beta-oxidation. The acetyl-CoA will then enter the citric acid cycle, and NADH and FADH2 produced will enter the electron transport chain to generate ATP. Amino acids taken up will be used for protein synthesis, and lactate will be secreted for the liver to use for gluconeogenesis (Cori cycle). In the adipose, fatty acids that are cleaved from chylomicrons, VLDL, IDL, and LDL are also going to be taken up. These fatty acids will be used to synthesize triglycerides for storage. With glucagon levels high in this condition, hormone-sensitive lipase would be active. However, since this is an anabolic state, the net effect would be uptake of fatty acids after cleavage by lipoprotein lipase. The adipose will not be secreting anything under this condition.
In this condition, assume a person is on the Ornish/Pritikin diet and just consumed a meal containing carbohydrates, with minimal but adequate amount of protein and no fat. As a result, this person is in an anabolic state with high blood glucose levels, meaning the pancreas will secrete insulin. The liver will take up glucose and synthesize glycogen until its stores are filled. After these stores are full, glucose will be broken down through glycolysis to pyruvate, then form acetyl-CoA in the transition reaction. Because we are in the fed or anabolic state, acetyl-CoA will be used for fatty acid synthesis, and the fatty acids will be used for triglyceride synthesis. These triglycerides will be packaged into VLDL and secreted from the liver. Amino acids will also be taken up and used for protein synthesis as needed. Because there is plenty of glucose, gluconeogenesis and ketone body synthesis will not be operating to any great extent. The muscle will take up glucose and synthesize glycogen until those stores are filled. Some glucose will go through glycolysis to produce pyruvate, then form acetyl-CoA in the transition reaction. The acetyl-CoA will enter the citric acid cycle, and NADH and FADH2 produced will enter the electron transport chain to generate ATP. Fatty acids (minimal) that are cleaved from VLDL, IDL, and LDL are also going to be taken up. These fatty acids will be used to synthesize triglycerides for storage. Whatever amino acids are taken up will be used for protein synthesis. The muscle will not be secreting anything in this condition. The adipose is going to take up glucose that will enter glycolysis, pyruvate will be produced, then acetyl-CoA will be produced in the transition reaction. Because we are in the fed or anabolic state, the acetyl-CoA will be used for fatty acid synthesis. Fatty acids will also be cleaved from VLDL, IDL, and LDL. Fatty acids from both sources are going to be taken up and primarily used to synthesize triglycerides for storage. The adipose will not be secreting anything under this condition.
Adipose only takes up two things: glucose and fatty acid Glucose only when it is consumed (fed state, Ornish, 100% carbohydrates) Fatty acids in every condition except fasting Adipose only secretes fatty acids during fasting Muscle only takes up three things: glucose, fatty acid, amino acid Fatty acids in all; minimal in: Ornish and 100% protein Glucose in all; minimal in: 1) fasting; 2) no/low carbohydrate (Atkins, 100% carbohydrates, 100% triglyceride) Amino acids only when it is consumed in a meal (no other source) Muscle only secretes two things: amino acid and lactate Amino acids secreted when protein is not in diet (fasting, 100% carbohydrates, 100% triglyceride) Lactate secreted in: 1) fasting; 2) no/low carbohydrate diets (fasting, Atkins, 100% protein, 100% triglyceride, note these are the same conditions when minimal glucose is taken up) Liver takes up four things: glucose, fatty acids (from chylomicron remnants), amino acids, lactate Amino acid in all; source: food or from muscle Glucose only when it is consumed (fed state, Ornish, 100% carbohydrates) Fatty acids in: 1) fasting (adipose); 2) when it is consumed (fed state, Atkins, 100 triglyceride) Lactate (Cori cycle) in: 1) fasting; 2) no/low carbohydrate diets (Atkins, 100% protein, 100% triglyceride) Liver secretes four things: VLDL, glucose, urea, ketone bodies VLDL in all scenarios: 1) chylomicron remnants (triglycerides consumed) or 2) glucose ->acetyl-CoA -> FA Glucose is secreted in 100% protein and minimal in: 1) fasting; 2) Other no/low carbohydrate diets (Atkins, 100% triglycerides) Urea is secreted in 1) fasting; 2), high protein/carbohydrate restricted diets (Atkins, 100% protein) Ketone bodies in: 1) fasting, and 2) no/low carbohydrate diets (Atkins, 100% protein, 100% triglyceride)
Micronutrients consist of vitamins and minerals. In this chapter, an overview of vitamins and minerals will be presented followed by a description of the dietary reference intakes (DRIs), which are used as benchmarks of micronutrient intake.
The name vitamin comes from Casimir Funk, who in 1912 thought vital amines (NH3) were responsible for preventing what we know now are vitamin deficiencies. He coined the term vitamines to describe these compounds. Eventually it was discovered that these compounds were not amines and the 'e' was dropped to form vitamins1. Vitamins are classified as either fat-soluble or water-soluble. The fat-soluble vitamins are: Vitamin A Vitamin D Vitamin E Vitamin K
Before they even knew that vitamins existed, a scientist named E.V. McCollum recognized that a deficiency in what he called ‘fat-soluble factor A’ resulted in severe ophthalmia (inflammation of the eye). In addition, a deficiency in ‘water-soluble factor B’ resulted in beriberi (a deficiency discussed more later)1.
Factor A is what we now know as vitamin A. However, researchers soon realized that factor B actually consisted of two factors that they termed B1 and B2. Then they realized that there are multiple components in B2, and they began identifying the wide array of B vitamins that we know today1.
Minerals are a subset of elements that are essential for body functions that cannot be synthesized in the body. Some people refer to them as elements instead of minerals, and the names can be used interchangeably. However, in the nutrition community, they are more commonly referred to as minerals. Minerals can be divided up into three different categories:
There are two common ways to teach about vitamins and minerals in nutrition classes. The traditional way is to start with fat-soluble vitamins and go down through the vitamins alphabetically (i.e. vitamin A, vitamin D, vitamin E, vitamin K). However, this method leads students to learn about vitamins and minerals more individually instead of how they work together. For instance, it makes sense to cover calcium with vitamin D, and iron with copper and zinc. We are going to cover vitamins and minerals based on their function rather than covering them by whether they are a water-soluble vitamin or trace mineral. The hope is that you will gain a more integrative understanding of vitamins and minerals from this approach. Here are the different functional categories that you are going to learn about. Notice that some micronutrients fit into more than one functional category. Each vitamin and mineral is presented in one section, with some mention of its overlap in other section(s) in certain cases.
Dietary Reference Intakes (DRIs) are more than numbers in the table, even though that is often how many people view them. The link below takes you to the tables that many people commonly associate with the DRIs. These tables have been updated to include the revised RDAs for vitamin D and calcium.
DRIs are a collective term to refer to these components: profe Estimated Average Requirement (EAR) Recommended Dietary Allowance (RDA) Adequate Intake (AI) Tolerable Upper Intake Level (UL) Chronic Disease Risk Reduction Intakes (CDRR)
The RDA is the measure that professionals use to assess the quality of people's diets. It is the requirement estimated to meet the needs of 97.5% of the population. But the RDA is calculated using the EAR. Therefore, the EAR needs to be set before an RDA can be set. There must be applicable research in order to set an EAR. An EAR is the estimated requirement for 50% of the population (hence the average in its name), as shown in the figure below. On the left vertical axis is the risk of inadequacy, and on the bottom of the figure is the observed level of intake that increases from left to right. We will talk about the right axis label in a later figure. Notice that for the EAR, the risk of inadequacy is 0.5 (50%) whereas the RDA the risk of inadequacy is
The figure below shows the EAR on the normal distribution and splits out the different standard deviations as percents. Notice that for 50% of the population, their adequate intake is below the EAR and 50% of the population their adequate intake is above the EAR.
The following figure shows the distribution and how the percentages and standard deviation changes from the EAR. Only 2.5% of the population will have a need above the RDA for a particular nutrient. As you can see, the EAR is adequate for 50% (0.5) of the population and is lower than the RDA. The RDA is adequate for 97.5% (0.025) of the population, and higher than the EAR. Figure 8.43 The RDA meets the needs for 97.5% of the population For nutrients lacking the research evidence needed to set an EAR, an AI is set instead of an EAR/RDA (thus, there will never be an AI and RDA for the same population class). An AI is a level that appears to be adequate in a defined population or subgroup. Since an EAR/RDA has not been set, it is not known how an AI quantity compares to a RDA/EAR as shown in the figure below, but since an RDA is based on research there is more confidence in it as an indicator than an AI. Figure 8.44 The AI compared to the other DRI components, the question mark and dotted line are meant to indicate that it is not known exactly where the AI would fall relative to and EAR/RDA if they were set. The dotted EAR/RDA is meant to indicate that these are not set when an AI is set. The last of the DRIs is the Tolerable Upper Intake Level (UL). This is the highest level of daily nutrient intake that is unlikely to pose a risk of adverse health effects to almost all individuals in the population. To set this, the committee first sets a no observed adverse effect level (NOAEL) and/or the lowest observed adverse effect level (LOAEL). The UL is then set lower based on a number of uncertainty/safety factors off the NOAEL or LOAEL as shown below. The right vertical axis is used to represent the risk of an adverse event. Notice the NOAEL at the point where no adverse effects have been reported. The LOAEL is somewhere above the NOAEL. The UL is set at a level where it is believed that people will not experience the selected adverse effect.
How are Americans doing in meeting the DRIs? The following figure shows the percentage of Americans that are not meeting the EAR for some of the earlier micronutrients that had DRIs set. Keep in mind that the EAR is lower than the RDA.
As you can see, a large percentage of Americans don't meet the EAR for vitamin E, magnesium, vitamin A, and vitamin C. Also, keep in mind that this also does not include micronutrients that have AI instead of EARs and RDAs. The Chronic Disease Risk Reduction Intake (CDRR) is the newest of the DRI components, being introduced in 2019 with a CDRR being set for sodium. As the name indicates, the CDRR is an intake that there is evidence reduces the risk of chronic disease. In the case of sodium, intake below the CDRR is associated with beneficial effects on cardiovascular disease risk, hypertension risk, systolic blood pressure, and diastolic blood pressure2.
In this chapter, we are going to cover vitamin E, vitamin C, and selenium in detail because being an antioxidant is their primary function. Iron, copper, zinc, and manganese are cofactors for the antioxidant enzymes catalase and superoxide dismutase, as shown below.
Superoxide dismutase converts superoxide into hydrogen peroxide. Catalase converts hydrogen peroxide into water. Iron, copper, and zinc will be covered in more detail in the blood, bones, and teeth chapter (chapter 11). Manganese will be covered in the macronutrient metabolism chapter.
The following example shows normal oxygen losing an electron from its outer orbital and thus, becoming an oxygen free radical. Figure 9.112 Normal oxygen is converted to an oxygen free radical by losing one electron in its outer orbital, leaving one unpaired electron
Oxidized LDL is more atherogenic, meaning it is more likely to contribute to atherosclerosis (hardening of the arteries) than normal LDL. Protein oxidation is believed to be involved in the development of cataracts. Cataracts are a clouding of the lens of the eye. If you would like to see what it looks like, see the link below.
We are ready to move on to antioxidants, which as their name indicates, combat free radicals, reactive oxygen species (ROS), and oxidative stress. As a humorous introduction, the link below is to a cartoon that shows Auntie Oxidant kicking free radicals out of the bloodstream. But it is not quite that simple. You have probably heard the saying "take one for the team." Instead of taking one for the team, antioxidants "give one for the team." The ‘giving’ is the donation of an electron from the antioxidant to a free radical, in order to regenerate a stable compound, as shown below. Figure 9.121 Regeneration of normal oxygen from oxygen free radical by the donation of an electron from an antioxidant
Antioxidants are thought to work in concert with one another, forming what is known as the antioxidant network. A theorized antioxidant network is shown below. Alpha-tocopherol (major form of vitamin E in our body) is oxidized by donating an electron to the reaction oxygen species, thus stabilizing it. This leads to the formation of alpha-tocopherol radical. Ascorbate (vitamin C) is then oxidized, forming dehydroascorbate to regenerate (reduce) alpha-tocopherol. Ascorbate is then regenerated by the selenoenzyme thioredoxin reductase. This demonstrates how antioxidants can function as a network to regenerate one another so they can continue to function as antioxidants.
References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Packer L, Weber SU, Rimbach G. (2001) Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131(2): 369S-373S.
There is a lot of confusion among the public on antioxidants. For the most part, this is for a good reason. Many food companies put antioxidant numbers on the packages that sound good to consumers, who have no idea how to interpret them. Thus, it is increasingly important to have an understanding of what a meaningful antioxidant actually is.
What do these mean? Let's consider the example of lycopene and vitamin E (alpha-tocopherol), which are both fat-soluble antioxidants. In vitro antioxidant assays have found that lycopene is 10-fold more effective in quenching singlet oxygen than alpha-tocopherol1. However, when you look at the concentrations found in the body, there is far more alpha-tocopherol than lycopene. For example: LDL on average contains 11.6 molecules of alpha tocopherol and 0.9 molecules of lycopene. Thus, if we divide alpha tocopherol by lycopene 11.6/0.9 we find that there is on average 12.9 times more alpha-tocopherol than lycopene1.
Prostate - 162-fold higher alpha-tocopherol than lycopene concentrations Skin - 17 to 269-fold higher alpha-tocopherol than lycopene concentrations Plasma - 53-fold higher alpha tocopherol than lycopene concentrations1 Thus, despite the fact that lycopene is a better antioxidant in vitro, since the concentration of alpha-tocopherol is so much higher in tissues (locations of need), it is likely the more meaningful antioxidant. In addition, if lycopene and alpha-tocopherol have similar antioxidant functions (fat-soluble antioxidants), lycopene’s potential antioxidant action is redundant to alpha-tocopherol’s antioxidant function and thus, also less likely to be a meaningful antioxidant. Indeed, further examination of the literature has not suggested that lycopene can act as an antioxidant in vivo, even though it is a good one in vitro1. The oxygen radical absorbance capacity (ORAC) assay is one of these in vitro antioxidant assays. These values have been used to market the antioxidant potential of food products companies/businesses. The link below is to a database of food ORAC values. USDA removed its database of ORAC values (similar to the one above) “due to mounting evidence that the values indicating antioxidant capacity have no relevance to the effects of specific bioactive compounds, including polyphenols on human health2.” However, going back to the two characteristics of meaningful antioxidants, there really is no evidence that shows that a high ORAC score leads to any benefit in vivo. This is because the measure also does not take into account important factors such as bioavailability. Bioavailability is the amount of a compound that is absorbed or reaches circulation. Many of these purported super antioxidants have not been shown to be absorbed or maintained in the body in a way that would suggest that they would be meaningful antioxidants. Five years after it was removed, industry and suppliers think it has been a good thing that it is no longer used as indicated in the following article.
Chapter 1 described a clinical trial that found that high-dose beta-carotene supplementation increased lung cancer risk in smokers. This is an example of findings that support that high doses of antioxidants may be “too much of a good thing”, causing more harm than benefit. The parabolic, or U-shaped, figure below displays how the level of nutrient concentration or intake (x-axis) relates to an antioxidant measure (y-axis). The lowest level of antioxidant intake or tissue concentration results in nutrient deficiency if the antioxidant is essential (vitamins and minerals). Intake levels above deficient, but less than optimal, are referred to as low suboptimal. Suboptimal means the levels are not optimal. Thus, low suboptimal and high suboptimal sandwich optimal. The high suboptimal level is between optimal and where the nutrient becomes toxic. Figure 9.141 How the levels of nutrient concentration or intake alters oxidative stress in the body. Going up the y-axis and to the right on the x-axis is higher (or increasing). Adapted from reference 1
Researchers found that when they plotted prostate DNA damage (antioxidant measure) against toenail selenium status (nutrient concentration or intake) that it resulted in a U-shaped curve like the one shown above1. Thus, it is good to have antioxidants in your diet, but too much can be counterproductive. References & Links 1. Waters DJ, Shen S, Glickman LT, Cooley DM, Bostwick DG, et al. (2005) Prostate cancer risk and DNA damage: Translational significance of selenium supplementation in a canine model. Carcinogenesis 26(7): 1256-1262.
There are 8 different forms of vitamin E: 4 tocopherols and 4 tocotrienols. The difference between tocopherols and tocotrienols is that the former have a saturated tail, while the latter have an unsaturated tail. Within tocopherols and tocotrienols, the difference between the different forms is the position of the methyl groups on the ring. The 4 different forms within the tocopherol and tocotrienols are designated by the Greek letters: alpha, beta, gamma, and delta. The difference in these structures is shown in the figures below.
For reasons that will be covered in a later subsection, the primary form of vitamin E found in the body is alpha-tocopherol. The major, and possibly only, function of vitamin E is as an antioxidant. When it serves as an antioxidant it forms an alpha-tocopherol radical, as shown below. Figure 9.23 Alpha-tocopherol radical1 Alpha-tocopherol is believed to be the first part of an antioxidant network (shown below) where it is oxidized to donate an electron to stabilize reactive oxygen species. Alpha-tocopherol radical can then be reduced by the donation of an electron from ascorbate.
To help protect the antioxidant function of alpha-tocopherol (by preventing the formation of alpha-tocopherol radical) in foods and during digestion, some manufacturers have added compounds to this site of alpha-tocopherol through ester bonds. These are referred to as alpha-tocopherol derivatives or alpha-tocopherol esters. The most common forms are alpha-tocopherol acetate, alpha-tocopherol succinate, and alpha-tocopherol phosphate (Ester-E®). The figures below show the structure of alpha-tocopherol acetate, and the structure of succinic acid. Figure 9.25 Alpha-tocopherol acetate
Alpha-tocopherol derivatives, such as acetate in alpha-tocopherol acetate, are cleaved prior to absorption in the small intestine by esterases, meaning that alpha-tocopherol is absorbed, not the alpha-tocopherol derivative.
References & Links https://en.wikipedia.org/wiki/Radical_(chemistry)#/media/File:VitE.gif Packer L, Weber SU, Rimbach G. (2001) Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr 131(2): 369S-373S http://en.wikipedia.org/wiki/File:Bernsteins%C3%A4ure2.svg
In addition to being found naturally in foods, alpha-tocopherol can also be synthesized. It is important to know whether alpha-tocopherol is natural or synthetic because the stereochemistry (spatial arrangement) differs between these forms. In some cases stereochemistry is used to three dimensionally depict whether a molecule is coming out towards your or alternatively away from you. Alpha-tocopherol contains 3 chiral centers (non-superimposable mirror images) designated as R or S. The 3 chiral centers in alpha-tocopherol are located at the 2, 4’, and 8’ positions. You can see the full numbering of tocopherols in the link below. In short, the rings are normal numbers and the tail are prime numbers.
In natural alpha-tocopherol, all 3 chiral centers are in the R configuration. Thus, it is designated RRR-alpha-tocopherol. The R’s represent the 2, 4’, and 8’ positions of alpha-tocopherol, respectively, as shown below1.
You might be saying to yourself, “who cares about natural versus synthetic alpha-tocopherol.” But the small change in stereochemistry makes a big difference in how alpha-tocopherol is maintained in the body. All forms of vitamin E (tocopherols, tocotrienols) are absorbed equally. Fat-soluble vitamins are handled like lipids and thus are incorporated into chylomicrons that have triglycerides removed by lipoprotein lipase. The chylomicron remnants containing the different forms of vitamin E are then taken up by the liver. The figure below shows the absorption, metabolism, and excretion of vitamin E. Figure 9.221 The absorption, metabolism, and excretion of vitamin E The liver contains a protein called alpha-tocopherol transfer protein (alpha-TTP), which is responsible for maintaining higher levels of alpha-tocopherol in the body. Alpha-TTP preferentially binds to 2R alpha-tocopherol and helps facilitate its incorporation into VLDL. 2R means any form of alpha-tocopherol in which the 2 position is in the R conformation. The following table summarizes the forms of alpha-tocopherol that bind well to alpha-TTP, and those that don't bind well to alpha-TTP.
Other forms of vitamin E (gamma-tocopherol, tocotrienols) also don't bind well to alpha-TTP and thus, are found in lower levels than alpha-tocopherol in the body. The following graph shows plasma (liquid component of blood) vitamin E levels from a study in which subjects were given 150 mg each of RRR-alpha-tocopherol, all-rac-alpha-tocopherol, or gamma-tocopherol1.