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The small intestine is the primary site of digestion. It is divided into three sections: the duodenum, jejunum, and ileum (shown below). After leaving the stomach, the first part of the small intestine that chyme will encounter is the duodenum.

Going even closer, we discover that the surface of the microvilli is covered by the hair-like glycocalyx, which is made up of glycoproteins (proteins with carbohydrates attached to them) and carbohydrates as shown below.

Before we go into the digestive details of the small intestine, it is important that you have a basic understanding of the anatomy and physiology of the following digestion accessory organs: pancreas, liver, and gallbladder. Digestion accessory organs assist in digestion, but are not part of the gastrointestinal tract. How are these organs involved? Upon entering the duodenum, chyme causes the release of two hormones from the small intestine: secretin and cholecystokinin (CCK, previously known as pancreozymin) in response to acid and fat, respectively. These hormones have multiple effects on different tissues. In the pancreas, secretin stimulates the secretion of bicarbonate (HCO3), while CCK stimulates the secretion of digestive enzymes. The bicarbonate and digestive enzymes released together are collectively known as pancreatic juice, which travels to the small intestine, as shown below. Figure 3.411 The hormones secretin and CCK stimulate the pancreas to secrete pancreatic juice1

The pancreas is found behind the stomach and has two different portions. It has an endocrine (hormone-producing) portion that contains alpha and beta cells that secrete the hormones glucagon and insulin, respectively. However, the vast majority of the pancreas is made up of acini, or acinar cells, that are responsible for producing pancreatic juice. The following video does a nice job of showing and explaining the function of the different pancreatic cells. Bicarbonate is a base (high pH) meaning that it can help neutralize acid. You can find sodium bicarbonate (NaHCO3, baking soda) on the ruler below to get an idea of its pH. Figure 3.412 pH of some common items2

The liver is made up of two major types of cells. The primary liver cells are hepatocytes, which carry out most of the liver’s functions. Hepatic is another term for liver. For example, if you are going to refer to liver concentrations of a certain nutrient, these are often reported as hepatic concentrations. The other major cell type is the hepatic stellate (also known as Ito) cells. These are lipid storing cells in the liver. These two cell types are depicted below.

bilirubin and biliverdin. Bile acids are synthesized from cholesterol. The two primary bile acids are chenodeoxycholic acid and cholic acid. In the same way that fatty acids are found in the form of salts, these bile acids can also be found as salts. These salts have an (-ate) ending, as shown below. Figure 3.415 Structures of the 2 primary bile acids

The gallbladder is a small sac-like organ found just off the liver (see figures above). Its primary function is to store and concentrate bile made by the liver. The bile is then transported to the duodenum through the common bile duct.

Bile is important because fat is hydrophobic and the environment in the lumen of the small intestine is watery. In addition, there is an unstirred water layer that fat must cross to reach the enterocytes in order to be absorbed.

Here triglycerides form large triglyceride droplets to keep the interaction with the watery environment to a minimum. This is inefficient for digestion, because enzymes cannot access the interior of the droplet. Bile acts as an emulsifier, or detergent. It, along with phospholipids, forms smaller triglyceride droplets that increase the surface area that is accessible for triglyceride digestion enzymes, as shown below. Figure 3.417 Bile acids and phospholipids facilitate the production of smaller triglyceride droplets. Secretin and CCK also control the production and secretion of bile. Secretin stimulates the flow of bile from the liver to the gallbladder. CCK stimulates the gallbladder to contract, causing bile to be secreted into the duodenum, as shown below.

The small intestine is the primary site of carbohydrate digestion. Pancreatic alpha-amylase is the primary carbohydrate digesting enzyme. Pancreatic alpha-amylase, like salivary amylase, cleaves the alpha 1-4 glycosidic bonds of carbohydrates, reducing them to simpler carbohydrates, such as glucose, maltose, maltotriose, and dextrins (oligosaccharides containing 1 or more alpha 1-6 glycosidic bonds). Pancreatic alpha-amylase is also unable to cleave the branch point alpha 1-6 bonds1.

The pancreatic alpha-amylase products, along with the disaccharides sucrose and lactose, then move to the surface of the enterocyte. Here, there are disaccharidase enzymes (lactase, sucrase, maltase) on the outside of the enterocyte. Enzymes, like these, that are on the outside of cell walls are referred to as ectoenzymes. Individual monosaccharides are formed when lactase cleaves lactose, sucrase cleaves sucrose, and maltase cleaves maltose. There is also another brush border enzyme, alpha-dextrinase. This enzyme cleaves alpha 1-6 glycosidic bonds in dextrins, primarily the branch point bonds in amylopectin. The products from these brush border enzymes are the single monosaccharides glucose, fructose, and galactose that are ready for absorption into the enterocyte1.

The small intestine is the major site of protein digestion by proteases (enzymes that cleave proteins). The pancreas secretes a number of proteases as zymogens into the duodenum where they must be activated before they can cleave peptide bonds1. This activation occurs through an activation cascade. A cascade is a series of reactions in which one step activates the next in a sequence that results in an amplification of the response. An example of a cascade is shown below.

In this example, A activates B, B activates C, D, and E, C activates F and G, D activates H and I, and E activates K and L. Cascades also help to serve as control points for certain process. In the protease cascade, the activation of B is really important because it starts the cascade. The protease/colipase activation scheme starts with the enzyme enteropeptidase (secreted from the intestinal brush border) that converts trypsinogen to trypsin. Trypsin can activate all the proteases (including itself) and colipase (involved in fat digestion)1 as shown in the 2 figures below.

At the brush border, much like disaccharidases, there are peptidases that cleave some peptides down to amino acids. Not all peptides are cleaved to individual amino acid, because small peptides can be taken up into the enterocyte, thus, the peptides do not need to be completely broken down to individual amino acids. Thus the end products of protein digestion are primarily dipeptides and tripeptides, along with individual amino acids1.

The small intestine is the major site for lipid digestion. There are specific enzymes for the digestion of triglycerides, phospholipids, and cleavage of esters from cholesterol. We will look at each in this section.

The pancreas secretes pancreatic lipase into the duodenum as part of pancreatic juice. This major triglyceride digestion enzyme preferentially cleaves the sn-1 and sn-3 fatty acids from triglycerides. This cleavage results in the formation of a 2-monoglyceride and two free fatty acids as shown below. Figure 3.441 Pancreatic lipase cleaves the sn-1 and sn-3 fatty acids of triglycerides

If nothing else happened at this point, the 2-monoglycerides and fatty acids produced by pancreatic lipase would form micelles. The hydrophilic heads would be outward and the fatty acids would be buried on the interior. These micelles are not sufficiently water-soluble to cross the unstirred water layer to get to the brush border of enterocytes. Thus, mixed micelles are formed containing cholesterol, bile acids, and lysolecithin in addition to the 2-monoglycerides and fatty acids, as illustrated below1.

Mixed micelles are more water-soluble, allowing them to cross the unstirred water layer to the brush border of enterocytes for absorption. Figure 3.449 Mixed micelles can cross the unstirred water layer for absorption into the enterocytes

We have reached a fork in the road. We could follow the uptake of the digested compounds into the enterocyte or we could finish following what has escaped digestion and is going to continue into the large intestine. Obviously from the title of this section we are going to do the latter. As we learned previously, fiber is a crude term for physical material (since there is some water as well) has survived digestion and reached the large intestine.

The large intestine is responsible for absorbing the remaining water and electrolytes (sodium, potassium, and chloride). It also forms and excretes feces. The large intestine contains large amounts of microorganisms like those shown in the figure below.

the flora, microflora, biota, or microbiota. Technically, microbiota is the preferred term because flora means "pertaining to plants". There are 10 times more microorganisms in the gastrointestinal tract than cells in the whole human body4. As can be seen in the figure below, the density of microorganisms increases as you move down the digestive tract. Figure 3.65 Relative amount of bacteria in selected locations of the GI tract. cfu/ml = colony forming unit, a measure of the number of live microorganisms in 1 mL of digestive sample5,6 As described in the fiber sections, there are two different fates for fiber once it reaches the large intestine. The fermentable, viscous fiber is fermented by bacteria. An example of fermentation is the utilization of the oligosaccharides raffinose and stachyose by microorganisms that results in the production of gas, which can lead to flatulence. Also, some bile acids are fermented by microorganisms to form secondary bile acids that can be reabsorbed. These secondary bile acids represent approximately 20% of the total bile acids in our body. Fermentable fibers can be used to form short-chain fatty acids that can then be absorbed and used by the body. The nonfermentable, nonviscous fiber is not really altered and will be a component of feces, that is then excreted through the rectum and anus. This process involves both an internal and external sphincter that are shown in figure 3.63 above.

References & Links https://commons.wikimedia.org/wiki/File:Gray1075.png http://en.wikipedia.org/wiki/Image:Illu_intestine.jpg http://commons.wikimedia.org/wiki/Image:Cholera_bacteria_SEM.jpg Guarner F, Malagelada J. (2003) Gut flora in health and disease. The Lancet 361(9356): 512. DiBaise J, Zhang H, Crowell M, Krajmalnik-Brown R, Decker , et al. (2008) Gut microbiota and its possible

There is increased attention given to the potential of a person's microbiota to impact health. This is because there are beneficial and non-beneficial bacteria inhabiting our gastrointestinal tracts. Thus, theoretically, if you can increase the beneficial or decrease the non- beneficial bacteria, there may be improved health outcomes. In response to this, probiotics and prebiotics have been identified/developed. A probiotic is a live microorganism that is consumed, and colonizes in the body as shown in the figures below.

A prebiotic is a nondigestible food component that selectively stimulates the growth of beneficial intestinal bacteria. Typically the food component is fermented by the bacteria. An example of a prebiotic is inulin, which is shown in the figure below. Figure 3.612 Inulin, an indigestible food component that is a commonly used prebiotic

The claims that companies made about their produce probiotic products have come under scrutiny. Dannon settled with the US Federal Trade Commission to drop claims that its probiotic products will help prevent colds or alleviate digestive problems, as seen in the top link below. General Mills also settled a lawsuit that accused them of falsely advertising the digestive benefits of Yo-Plus a product it no longer sells, as seen in the second link. Some examples of prebiotics include inulin, other fructose-containing oligosaccharides and polysaccharides, and resistant starch. Inulin is an oligosaccharide that contains mainly fructoses that are joined by beta-bonds, which allows them to survive digestion. The structure of inulin is shown below. Figure 3.614 Structure of inulin1

References & Links http://en.wikipedia.org/wiki/File:Inulin_strukturformel.png Douglas L, Sanders M. (2008) Probiotics and prebiotics in dietetics practice. American Dietetic Association.Journal of the American Dietetic Association 108(3): 510.

The term absorption can have a number of different meanings. Not everything that is taken up into the enterocyte from the lumen will be absorbed, so the term uptake refers to compounds being transported into the enterocyte. Absorption means that a compound is transported from the enterocyte into circulation. Under most circumstances, compounds that are taken up will then be absorbed. After this chapter, hopefully this distinction between these terms will be clear. After later micronutrient chapters, hopefully you will understand the reason for emphasizing this distinction.

Crypts of Lieberkuhn & Enterocyte Maturation Absorptive Lineup & Cell Membranes Types of Cell Uptake/Transport Carbohydrate Uptake, Absorption, Transport & Liver Uptake Protein Uptake, Absorption, Transport & Liver Uptake Lipid Uptake, Absorption & Transport Glycemic Response, Insulin & Glucagon

There are some additional anatomical and physiological features of the small intestine that are important to understand before defining uptake and absorption. Crypts of Lieberkuhn are pits between villi as pointed out by the green arrow in the figure below.

The crypts of Lieberkuhn (often referred to simply as crypts) are similar to the gastric pits in the stomach. The crypts contain stem cells that can differentiate to produce a number of different cell types, including enterocytes2. From these stem cells in the crypt, immature enterocyte cells are formed that mature as they rise, or migrate, up the villi. Thus, the tips at the top of the villi are where the mature, fully functioning enterocytes are located, as represented by the purple cells in the figure below3. Figure 4.12 Crypts are represented by green arrows, fully mature enterocytes are represented

This maturation and migration is a continuous process. The life cycle of an enterocyte is 72 hours once it enters the villus from the crypt2. Once enterocytes have reached the top of the villus, they are sloughed off and are either digested (lipid and protein contents taken up by other enterocytes), or excreted in feces as depicted in the figure below.

Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.

Having completed digestion in the small intestine, a number of compounds are ready for uptake into the enterocyte. The figure below shows the macronutrient uptake lineup, or what is ready to be taken up into the enterocyte.

From lipids, we have the lysolecithin (from phospholipid), 2-monoglyceride (from triglycerides), fatty acids, and cholesterol. From protein, there are small peptides (di- and tripeptides) and amino acids. From carbohydrates, only the monosaccharides glucose, galactose, and fructose will be taken up. The other macronutrient, water, has not been discussed so far because it does not undergo digestion. However, these compounds must now cross the plasma (cell) membrane, which is a phospholipid bilayer. In the cell membrane, the hydrophilic heads of the phospholipids point into the lumen as well as towards the interior of the cell, while the tails are on the interior of the plasma membrane as shown below.

The plasma membrane contains proteins, cholesterol, and carbohydrates in addition to the phospholipids. Membrane proteins, such as carriers, channels, pumps and transporters, are important for moving some compounds through the cell membrane. The figure and two videos below do a nice job of illustrating the components of the cell membrane.

There are a number of different forms of uptake/transport utilized by your body. These can be classified as passive or active. The difference between the two is whether energy is required and whether (from a solute perspective) they move with or against a concentration gradient. Passive transport does not require energy to move with a concentration gradient. Active transport requires energy to move against the concentration gradient.

Phosphorylation is the formation of a phosphate bond. Dephosphorylation is removal of a phosphate bond. Overall phosphorylation is a process that requires energy. The net effect of dephosphorylation is the release of energy. Thus, energy is required to add phosphates to ATP, energy is released through removing phosphates from ATP. The concentration gradient is a way to describe the difference between the concentration of the solute outside of a cell versus the concentration inside of a cell. A solute is dissolved in a solvent in a solution; the more solute the higher the concentration. Moving with the gradient is typically moving of solute from a region of higher concentration to an area of lower concentration (in order to reach equal solute concentrations on both sides of the membrane). The exception is osmosis, which moves solvent instead of solute to have the same effect of equalizing concentrations on both sides of the membrane. Moving against the gradient is moving solute from an area of lower concentration to an area of higher concentration.

Simple diffusion is the movement of solutes from an area of higher concentration (with the concentration gradient) to an area of lower concentration without the help of a protein, as shown below. Figure 4.311 Simple diffusion

Osmosis is similar to simple diffusion, but water moves instead of solutes. In osmosis water molecules move from an area of lower solute concentration to an area of higher solute concentration of solute as shown below. The effect of this movement is to dilute the area of higher solute concentration to equalize the solute concentrations on both sides of the membrane.

greater concentration of salt outside (extracellular) the red blood cells than within them (intracellular). Water will then move out of the red blood cells to the area of higher salt concentration, resulting in the shriveled red blood cells depicted. Isotonic means that there is no difference between concentrations. There is an equal exchange of water between intracellular and extracellular fluids. Thus, the cells are normal, functioning red blood cells. A hypotonic solution contains a lower extracellular concentration of salt than the red blood cell intracellular fluid. As a result, water enters the red blood cells, possibly causing them to burst.

The last form of passive absorption is similar to simple diffusion in that it follows the concentration gradient (higher concentration to lower concentration). However, it requires a carrier protein to transport the solute across the membrane. The following figure and video do a nice job of illustrating facilitated diffusion. Figure 4.314 Facilitated diffusion examples2 References & Links http://en.wikipedia.org/wiki/File:Osmotic_pressure_on_blood_cells_diagram.svg 2.https://en.wikipedia.org/wiki/Facilitated_diffusion#/media/File:Scheme_facilitated_diffusion_in_cell_membrane -en.svg

Active carrier transport is similar to facilitated diffusion in that it utilizes a protein (carrier or transport). However, energy is also used to move compounds against their concentration gradient. The following figure and video do a nice job of illustrating active carrier transport.

Endocytosis is the engulfing of particles, or fluids, to be taken up into the cell in vesicles formed from the cell membrane. If a particle is endocytosed, this process is referred to as phagocytosis. If a fluid is endocytosed, this process is referred to as pinocytosis as shown below.

Monosaccharides are taken up into the enterocyte. Glucose and galactose are taken up by the sodium-glucose cotransporter 1 (SGLT1, active carrier transport). The cotransporter part of the name of this transporter means that it also transports sodium along with glucose or galactose. Fructose is taken up by facilitated diffusion through glucose transporter (GLUT) 5. There are 12 glucose transporters that are named GLUT 1-12, and all use facilitated diffusion to transport monosaccharides. The different GLUTs have different functions and are expressed at high levels in different tissues. Thus, the intestine might be high in GLUT5, but not in GLUT12. Moving back to monosaccharides, inside the enterocyte, all three are then transported out of the enterocyte into the capillary (absorbed) through GLUT2 as shown below1.

Inside of each villus there are capillaries and lacteals as shown below. Capillaries are the smallest blood vessels in the body, lacteals are also small vessels but are part of the lymphatic system, as will be described further in a later subsection.

The capillaries in the small intestine join to the portal vein, which transports monosaccharides directly to the liver. The figure below shows the portal vein and all the smaller vessels from the stomach, small intestine, and large intestine that feed into it.

At the liver, galactose and fructose are completely taken up through GLUT 2 and GLUT5, respectively, while only 30-40% of glucose is taken up through GLUT2. After the monosaccharides are taken up, they are phosphorylated by their respective kinase enzymes forming galactose-1-phosphate, fructose-1-phosphate, and glucose-6-phosphate as shown below.

Kinase enzymes normally phosphorylate substrates. Phosphorylation of the monosaccharides is important for maintaining the gradient (by keeping unphosphorylated monosaccharide levels within hepatocytes low) needed for facilitated diffusion through the GLUT transporters and for keeping monosaccharides in cells (so they do not move back out if the gradient changes)3. In order, for the monosaccharide to leave the phosphate will need to be cleaved or removed. References & Links Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. http://en.wikipedia.org/wiki/File:Intestinal_villus_simplified.svg https://commons.wikimedia.org/wiki/File:Gray591.png

If only 30-40% of glucose is being taken up by the liver, then what happens to the rest? How the body handles the rise in blood glucose after a meal is referred to as the glycemic response. The pancreas senses the blood glucose levels and responds appropriately. After a meal, the pancreatic beta-cells sense that glucose concentrations are high and secrete the hormone insulin, as shown below1.

Blood glucose and insulin concentrations rise following carbohydrate consumption, and they drop after tissues have taken up the glucose from the blood (described below). Higher than normal blood sugar concentrations are referred to as hyperglycemia, while lower than normal blood sugar concentrations are known as hypoglycemia. Insulin travels through the bloodstream to the muscle and adipose cells. There, insulin binds to the insulin receptor. This causes GLUT4 transporters that are in vesicles inside the cell to move to the cell surface as shown below.

The movement of GLUT4 to the cell surface allows glucose to enter the muscle and adipose cells. The glucose is phosphorylated to glucose-6-phosphate by hexokinase (different enzyme but same function as glucokinase in liver) to maintain gradient.

Glucagon binds to the glucagon receptor in the liver, which causes the breakdown of glycogen to glucose as illustrated below. Figure 4.56 Glucagon binding to its receptor leads to the breakdown of glycogen to glucose.

References & Links Webb , Akbar , Zhao , Steiner . (2001) Expression profiling of pancreatic beta-cells: Glucose regulation of secretory and metabolic pathway genes. Diabetes 50 Suppl 1: S135. http://en.wikipedia.org/wiki/File:Suckale08_fig3_glucose_insulin_day.jpg

Type 1 diabetes was previously known as juvenile-onset, or insulin-dependent diabetes and is estimated to account for 5-10% of diabetes cases1. Type 1 diabetics receive insulin through injections or pumps to manage their blood sugar. In type 2 diabetes, the body produces enough insulin, but the person's body is resistant to it. In type 2 diabetics the binding of insulin to its receptor does not cause enough GLUT4 to move to the surface of the muscle and adipose cells, thus not enough glucose is taken up.

Type 2 diabetes accounts for 90-95% of diabetes cases and was once known as non-insulin-dependent diabetes or adult-onset diabetes1. However, with the increasing rates of obesity, many younger people are being diagnosed with type 2, making the latter definition no longer appropriate. Some people with type 2 diabetes can control their condition with a diet and exercise regimen. This regimen improves their insulin sensitivity, or their response to the body’s own insulin. Others with type 2 diabetes must receive insulin. These individuals are producing enough insulin, but are so resistant to it that more is needed for glucose to be taken up by their muscle and adipose cells.

Research has indicated that hyperglycemia is associated with chronic diseases and obesity. As a result, measures of the glycemic response to food consumption have been developed so that people can choose foods with a smaller glycemic response. The first measure developed for this purpose was the glycemic index. The glycemic index is the relative change in blood glucose after consumption of 50 g of carbohydrate in a test food compared to 50 g of carbohydrates of a reference food (white bread or glucose). Thus, a high glycemic index food will produce a greater rise in blood glucose concentrations compared to a low glycemic index food, as shown below.

As a general guideline, a glycemic index that is 70 or greater is high, 56-69 is medium, and 55 and below is low. A stop light graphical presentation has been designed to emphasize the consumption of low glycemic index foods while cautioning against the consumption of too many high glycemic index foods2.

The main problem with the glycemic index is that it does not take into account serving sizes. Let's take popcorn (glycemic index 89-127) as an example. A serving size of popcorn is 20 g, 11 g of which is carbohydrate3. This is equal to approximately 2.5 cups of popcorn4. Thus, a person would have to consume over 11 cups of popcorn to consume 50 g of carbohydrate needed for the glycemic index measurement. Another example is watermelon, which has a glycemic index of 103, with a 120 g serving containing only 6 g of carbohydrates3. To consume 50 g of carbohydrates needed for glycemic index measurement, a person would need to consume over 1000 g (1 kg) of watermelon. Assuming this is all watermelon flesh (no rind), this would be over 6.5 cups of watermelon4. The website glycemicindex.com (link provided below) contains a database where you can search to see the food's glycemic index and glycemic load (covered in the next section). The database contains details on how the measurement was done and more information on the product itself. The top link below will take you to this website. The second link is to another database that contains the same information that might be easier for some people to use. However, please note that in the second link the glycemic loads are calculated using 100 g serving sizes for all foods. This might not be the actual serving size for all foods, which is what is typically used, so it is important to keep this in mind.

Thus, in most instances, the glycemic load is a more meaningful measure of the glycemic response of different foods. Considering the two examples from the glycemic index section, their glycemic loads would be:

You can also use the top two links below to find the glycemic load of foods. However, please note that in the second link the glycemic loads are calculated using 100g serving sizes for all foods. This might not be the actual serving size for all foods, which is what is typically used, so it is important to keep this in mind. The third link is to the NutritionData estimated glycemic load tool that is pretty good at estimating the glycemic loads of foods, even if actual glycemic indexes have not been measured.

Over 60% of all amino acids are taken up into the enterocyte as di- and tripeptides through the PepT1 transporter. Individual amino acids are taken up through a variety of amino acid transporters. Once inside the enterocyte, peptidases cleave the peptides to individual amino acids. These cleaved amino acids, along with those that were taken up as individual amino acids, are moved into the capillary by another variety of amino acid transporters (some are the same as on the brush border, some are different).

Amino acids are taken up into the hepatocyte through a variety of amino acid transporters. The amino acids can then be used to either make proteins or are broken down to produce glucose, as will be described in chapter 6.

Once mixed micelles reach the brush border of the enterocyte, two different lipid uptake mechanisms are believed to occur, but lipid uptake is not completely understood. One mechanism is that individual components of micelles may diffuse across the enterocyte. Otherwise, it is believed that some components may be taken up through unresolved transporters. For example, cholesterol transporters have been identified, but their overall mechanism of absorption is not well understood. The individual compounds are taken up as shown below.

Once inside the enterocyte, there are different fates for fatty acids, depending on their length. Short- and medium-chain fatty acids move through the enterocyte and enter circulation through the capillaries; they are transported by the protein albumin. They will be carried to the liver by the portal vein, like monosaccharides and amino acids. Long-chain fatty acids, 2-monoglyceride, lysolecithin, and cholesterol will be re-esterified forming triglycerides, phosphatidylcholine, and cholesterol esters, respectively. These re-esterified lipids are then packaged into chylomicrons, which are lipoproteins, that are described in further detail in the next section. These chylomicrons are too large to fit through the pores in the capillaries, but they can fit through the larger fenestrations (openings) in the lacteal.

The lymphatic system is a system similar to the circulatory system in that it contains vessels that transport fluid. However, instead of blood, the lymphatic system contains a clear fluid known as lymph. There are a number of lymph nodes (small glands) within the lymphatic system that play a key role in the body's immune system. The figure below shows the lymphatic system.

The lymphatic system enters general circulation through the thoracic duct that enters the left subclavian vein as shown below. General in this case means that it is not directed to the liver like other components that have been absorbed.

The animation below is an overview of lipid digestion, uptake, and initial transport. The video gives a general overview of macronutrient digestion, uptake, and absorption now that you have learned about all 3 macronutrients.

Lipoproteins, as the name suggests, are complexes of lipids and protein. The proteins within a lipoprotein are called apolipoproteins (aka apoproteins). There are a number of different apolipoproteins that are abbreviated apo-, then an identifying letter (i.e. Apo A) as shown in the chylomicron below.

There are a number of lipoproteins in the body. They differ by the apolipoproteins they contain, size (diameter), density, and composition. The table below shows the difference in density and diameter of different lipoproteins. Notice that as diameter decreases, density increases.

Protein is more dense than triglyceride (why muscle weighs more than fat), thus the higher protein/lower triglyceride composition, the higher the density of the lipoprotein. Many of the lipoproteins are named based on their densities (i.e. very low-density lipoproteins). As described in the last subsection, the lipoproteins released from the small intestine are chylomicrons. The video below does a nice job of showing, describing, and illustrating how chylomicrons are constructed and function. The endothelial cells that line blood vessels, especially in the muscle and adipose tissue, contain the enzyme lipoprotein lipase (LPL). LPL cleaves the fatty acids from lipoprotein triglycerides so that the fatty acids can be taken up into tissues. The figure below illustrates how endothelial cells are in contact with the blood that flows through the lumen of blood vessels.

LPL cleaves fatty acids from the triglycerides in the chylomicron, decreasing the amount of triglyceride in the lipoprotein. This lipoprotein with less triglycerides becomes what is known as a chylomicron remnant, as shown below.

This process of clearing chylomicrons from the blood takes 2-10 hours after a meal2. This is why people must fast 12 hours before having their blood lipids (triglycerides, HDL, LDL etc.) measured. This fast allows all the chylomicrons and chylomicron remnants to be cleared before blood is taken. However, whether patients should be asked to fast has been questioned as described in the link below. After the chylomicron remnant is endocytosed, it is broken down to its individual components (triglycerides, cholesterol, protein etc.). In the liver, VLDL are produced, similar to how chylomicrons are produced in the small intestine. The individual components are packaged into VLDL and secreted into circulation as shown below.

Like it does to chylomicrons, LPL cleaves fatty acids from triglycerides in VLDL, forming the smaller IDL (aka VLDL remnant). Further action of LPL on IDL results in the formation of LDL. The C in Figures 4.715 and 4.716 represents cholesterol, which is not increasing; rather, since triglyceride is being removed, it constitutes a greater percentage of particle mass of lipoproteins. As a result, LDL is composed mostly of cholesterol, as depicted in the figure below.

LDL contains a specific apolipoprotein (Apo B100) that binds to LDL receptors on the surface of target tissues. The LDL are then endocytosed into the target tissue and broken down to cholesterol and amino acids. HDL are made up of mostly protein and are derived from the liver and intestine. HDL participates in reverse cholesterol transport, which is the transport of cholesterol back to the liver. HDL picks up cholesterol from tissues/blood vessels and returns it to the liver itself or transfers it to other lipoproteins returning to the liver.

You are probably familiar with HDL and LDL being referred to as "good cholesterol" and "bad cholesterol," respectively. This is an oversimplification to help the public interpret their blood lipid values, because cholesterol is cholesterol; it's not good or bad. LDL and HDL are lipoproteins, and as a result you can't consume good or bad cholesterol, you consume cholesterol. A more appropriate descriptor for these lipoproteins would be HDL "good cholesterol transporter" and LDL "bad cholesterol transporter." What's so bad about LDL? LDL enters the endothelium where it is oxidized. This LDL and/or oxidized LDL is engulfed by white blood cells (macrophages), leading to the formation of what are known as foam cells. The foam cells eventually accumulate so much LDL that they die and accumulate, forming a fatty streak. From there the fatty streak, which is the beginning stages of a lesion, can continue to grow until it blocks the artery. This can result in a myocardial infarction (heart attack) or a stroke. HDL is good in that it scavenges cholesterol from other lipoproteins or cells and returns it to the liver. The figure below shows the formation of the fatty streak and how this can progress to a point where it greatly alters blood flow.

The video below does an excellent job of illustrating this process. However there are two caveats to point out. First, it incorrectly refers to cholesterol (LDL-C etc.), and second, it is clearly made by a drug company, so keep these factors in mind. The link below is the American Heart Association’s simple animation of how atherosclerosis develops. Despite what you learned above about HDL, a recent study questions its importance in preventing cardiovascular disease. It found that people who have genetic variations that lead to higher HDL levels were not at decreased risk of developing cardiovascular disease. You can read

References & Links http://en.wikipedia.org/wiki/File:Chylomicron.svg Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Anatomy_artery.png 7. Erdman JW Jr., MacDonald IA, Zeisel SH, editors. (2012) Present knowledge in nutrition - 10th ed. Ames, IA: Wiley-Blackwell. http://en.wikipedia.org/wiki/File:Endo_dysfunction_Athero.PNG Links Ask Well: Should you fast before a cholesterol test - Lipoprotein Animation - Cholesterol and CAD - Doubt Cast on the ‘Good’ in ‘Good Cholesterol’ - Study Questions Fat and Heart Disease Link -

The first video says that goblet cells secrete mucus in the stomach. This is not correct; they secrete mucus in the intestine. It should be neck cells in the stomach. The second link shows what two ulcers actually look like in the stomach. 10% of Americans will develop an ulcer in their lifetime. Despite common beliefs, these ulcers are not caused by stress or spicy foods. Most ulcers are believed to be caused by the acid-resistant bacteria, Helicobacter pylori. 30-40% of Americans are infected with this bacteria. Helicobacter pylori causes a thinning of the mucus that protects the stomach and duodenum from gastric acid. It is not clear how Helicobacter pylori is transmitted, though it may be through contaminated food or water. It might also be spread through contact with vomit, feces, or saliva of an infected person1.

It is estimated that up to 1 million Americans are hospitalized annually as a result of gallstones, making it the most common of all digestive diseases1. Gallstones are formed when bile hardens in the gallbladder. 80% of gallstones are a result of cholesterol precipitation, while 20% are a result of bile pigment precipitation2. The cause of gallstones is unknown2. The way in which gallstones are formed is shown in the following video.

Many people do not experience symptoms from gallstones. They are usually discovered during examination for another health condition. However, some people experience an "attack" or pain that results from blockage of the bile ducts. The gallbladder is not essential, so the primary treatment is cholecystectomy, the removal of the gallbladder. Bile then flows directly from the liver into the small intestine.

Up to 20% of Americans may have irritable bowel syndrome (IBS). A syndrome is a group of symptoms, not a disease. In IBS, the colon does not function correctly. The symptoms of IBS are cramping, bloating, gas, diarrhea, and/or constipation. The cause of IBS is unknown. Diet changes, stress reduction, and medicine may help manage the condition1. To learn more about IBS, see the reference below.

Inflammatory bowel disease refers to a number of inflammatory conditions in the intestine. The two most common are Crohn's Disease and ulcerative colitis. These two conditions differ mainly in the areas of the intestine that are affected. Crohn's disease can occur anywhere throughout the GI tract, but most commonly occurs in the last part of the ileum. Crohn's disease may also involve all layers of the intestine1. Ulcerative colitis are ulcers in the lining of the colon and/or rectum2. It is estimated that up to 1 million people have IBD in the United States. Half of these individuals have Crohn's disease, and the other half have ulcerative colitis3.

The exact causes of these two diseases is not known. One hypothesized cause is an overactive immune system (autoimmune response, the immune system attacks tissues/cells rather than pathogens) that results in the chronic inflammation and collateral damage to the cells of the intestine, resulting in formation of lesions.

1 out of every 133 people in the United States has celiac disease1. People with celiac disease cannot consume the protein gluten because it causes their body to generate an autoimmune response (immune cells attack the body's own cells) that causes damage to the villi in the intestine, as shown below.

This damage to the villi impairs the absorption of macronutrients and micronutrients from food. There are a variety of symptoms for celiac disease that vary depending on age and from person to person.

Gluten-free diets have been increasing in popularity even for people who don’t have celiac disease. The thinking among those consuming these diets is that they might be non-celiac, gluten-sensitive, meaning that they experience adverse effects from consuming it. However, as the study describes, it seems more likely that it is fructan, a fructooligosaccharide, that causes these issues as found in the research described in the abstract below. These are apart of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs). Low FODMAP diets are increasing in use for similar reasons as gluten-free diets were used, but there is better evidence justification for their use.

Approximately 10% of people under 40, and 50% of people over 60 years old have a condition known as diverticulosis1. In this condition, diverticula (plural, diverticulum singular), or outpouches, are formed at weak points in the large intestine, primarily in the lowest section of the sigmoid colon, as nicely shown in the figure below and in the video in the web link below.

It is believed that diverticula are formed as a result of a low-fiber diet because people may strain more during bowel movements. Most people with diverticulosis do not know that they have the condition. However, if the pouches become inflamed, then the condition is known as diverticulitis. The most common symptom of this condition is abdominal pain. A liquid diet may be needed until the inflammation is decreased, then fiber is gradually increased1.

Hemorrhoids are swollen or inflamed veins of the anus or lower rectum. An internal hemorrhoid occurs within the anus, while an external hemorrhoid occurs in the skin surrounding the anus. Symptoms of hemorrhoids include bleeding, pain during bowel movements, and/or itching1. It is estimated that “about 75% of people will have hemorrhoids at some point in their lives”2.

The anus and lower rectum experience high pressure during bowel movements. Thus, hemorrhoids are believed to be caused by straining during bowel movements. To prevent this condition from occurring, it is recommended that people consume a high-fiber diet, drink plenty of water, and exercise to produce regular, large, soft stools. In addition, people should "go" at first urge and not wait until it is more than an urge2.

Now that we have digested, taken up, absorbed, and transported the macronutrients, the next step is to learn how these macronutrients are metabolized. Alcohol is also included at the end of this chapter, even though it is not a macronutrient.

Metabolism consists of all the chemical processes that occur in living cells. These processes/reactions can generally be classified as either anabolic or catabolic. Anabolic means to build, catabolic means to breakdown. If you have trouble remembering the difference between the two, remember that anabolic steroids are what are used to build enormous muscle mass.

An anabolic reaction/pathway requires energy to build something. A catabolic reaction/pathway generates energy by breaking down something. This is shown in the example below of glucose and glycogen. The same is true for other macronutrients.

the body needs at that time. Thus, some energy needs to be stored and the macronutrients will be used for synthesis, such as amino acids being used for protein synthesis. However, after a fast, or a prolonged period without energy intake, the body is in negative energy balance and is considered catabolic. In this condition, macronutrients will be mobilized from their stores to be used to generate energy. For example, if prolonged enough, protein can be broken down, then the released amino acids can be broken down to be used as an energy source. A number of the metabolic reactions oxidize or reduce compounds. A compound that is oxidized loses at least one electron, while a compound that is reduced gains at least 1 electron. To remember the difference, a mnemonic device such as OIL (oxidation is lost), RIG (reduction is gained) is helpful. Oxidation-reduction reactions are illustrated in the figure below. Figure 6.13 The purple compound is being oxidized, the orange compound is being reduced1 Another way to remember oxidation versus reduction is LEO goes GER (like a lion) Lose Electrons = Oxidize Gain Electrons = Reduce Iron is a good example we can use to illustrate oxidation-reduction reactions. Iron commonly exists in two oxidation states (Fe3+ or Fe2+). It is constantly oxidized/reduced back and forth between the two states. The oxidation/reduction of iron is shown below.

However, some oxidation reduction reactions are not as easy to recognize. There are some simple rules to help you recognize less obvious oxidation/reduction reactions that are based upon the gain or loss of oxygen or hydrogen. These are as follows:

A number of enzymes require cofactors to function. Some also require what other textbooks and resources refer to as coenzymes. But to keep things simple, we are going to include these coenzymes in our definition of cofactors. Thus, cofactors can be either organic or inorganic molecules that are required by enzymes to function. Many organic cofactors are vitamins or molecules derived from vitamins. Most inorganic cofactors are minerals. The reason why some vitamins and minerals are essential nutrients is because of their required role as cofactors for some enzymes. Cofactors can be oxidized or reduced for the enzymes to catalyze the reactions. Two common cofactors that are derived from the B vitamins, niacin and riboflavin, are nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD), respectively. The structure of NAD and FAD are shown below.

An example of a mineral that serves as a cofactor is Fe2+ for proline and lysyl hydroxylases. We will discuss later in detail why vitamin C (ascorbic acid) is needed to reduce iron to Fe2+ so that it can serve as a cofactor for proline and lysyl hydroxylases.

References & Links http://en.wikipedia.org/wiki/File:NAD%2B_phys.svg http://en.wikipedia.org/wiki/File:Flavin_adenine_dinucleotide.png http://en.wikipedia.org/wiki/File:NAD_oxidation_reduction.svg http://en.wikipedia.org/wiki/File:FAD_FADH2_equlibrium.png

There are many metabolic pathways/cycles/processes/reactions that are involved in the synthesis or degradation of carbohydrates and compounds formed from them. Please note that most of these pathways are not specific to carbohydrates only. Gluconeogenesis will be covered in the protein section, because amino acids are a common substrate used for synthesizing glucose.

Galactose and fructose metabolism is a logical place to begin looking at carbohydrate metabolism, before shifting focus to the preferred monosaccharide glucose. The figure below reminds you that in the liver, galactose and fructose have been phosphorylated.