Absorption of iron is regulated by total body iron require- ments and by the bioavailability of iron. Under physiologic conditions, dietary iron is acquired through transport pro- cesses in the proximal small intestine. Although the stomach, ileum, and colon have some capacity for iron absorption, this process is most prevalent in the duodenum and jeju- num. Normally, because body iron is conserved, absorption of iron by the gut is low compared with the amount ingested.
Heme (derived from meat) is an important dietary source of iron. After it is absorbed intact by enterocytes, it loses iron from its porphyrin ring. Heme is absorbed by endocytosis and digested by lysosomal enzymes to release free iron. In all other chemical forms, iron is absorbed only to the extent to which it can be released from food in ion- izable form. The insoluble complexes of iron with food become more soluble at a low pH. Gastric acid is import- ant in solubilizing iron, and patients with deficient acid secretion absorb less iron. Organic acids such as ascorbic or citric reduce Fe3+ to Fe2+, which is absorbed more effi- ciently. A brush border reductase, duodenal cytochrome b (DCYTB), plays an important role in reducing ferric to ferrous iron. Nonheme iron represents the largest fraction of dietary iron. The cellular mechanism of iron transport has not been completely described. However, a working hypothesis can be synthesized from what is known about the influx of iron across the brush border, its intracellular processing, and its efflux across the basolateral membrane of enterocytes into the circulation (Fig. 12.7).
Once reduced, ferrous iron is transported across the apical surface by divalent metal transporter 1 (DMT1).
An inward flux of H+, dependent on the outward flux of Na+ established by the Na+,K+-ATPase, provides the driv- ing force for the carrier. Within the cell, the fate of the iron depends on the body supply. If body stores are filled,
Ca2 ATPase
Calbindin Protein synthesis 1, 25 (OH)2-D3
25-OH-D3 Vitamin D3 Liver
Kidney Parathyroid
hormone
Ca2
Ca2 Ca2
Ca2
Ca2 TRPV
Fig. 12.6 Calcium (Ca2+) absorption by an enterocyte within a larger scheme of Ca2+ homeostasis. Vitamin D3, 1,25-(OH)2-D3, stimulates Ca2+ transport by interacting with nuclear receptors to control the synthesis of a Ca2+ channel (TRPV6), a calci- um-binding protein (calbindin), and the Ca adenosine triphos- phatase (ATPase). During periods of high intake, Ca2+ is also absorbed paracellularly.
128 CHAPTER 12 Fluid and Electrolyte Absorption
most iron will be stored within ferritin and lost when the enterocyte is sloughed into the lumen. If iron stores are low, most will cross the basolateral membrane via the iron export protein ferroprotein 1 (FPN1). During the export process, iron is oxidized for binding to transferrin (TF) in the interstitial fluid and plasma. Oxidation is carried out by the iron oxidase hephaestin (HEPH), which is expressed in the basolateral membrane.
The uptake pathway for heme is not understood in detail, but the HCP1 receptor is probably involved. Heme
can be broken down in lysosomes and the iron released for export, or it can exit the cell intact and be bound to hemo- pexin for distribution to the body.
The body requirement for iron influences intestinal uptake. Absorption is thought to be regulated at a mini- mum of two sites. First, during iron deficiency, transcrip- tion factors are activated that enter the enterocyte nucleus and increase the synthesis the enzyme DCYTB and the iron transporter, DMT1. Second, the amount of the stor- age protein, ferritin, is also regulated. The formation of Heme
Fe2 Fe3
Heme
Lysosome
Ferritin
Heme Heme
Fe3 TF Hemopexin
Fe2
Fe3
Na
K Na
Na
H H
Fe2
Fe2 HCP1
HEPH FPN1
DCYTB
DMT1
Fig. 12.7 Inorganic iron (Fe3+) is reduced to the ferrous form (Fe2+) by the reductase, DCYTB, in the apical membrane and is transported into the cell by the divalent metal transporter, DMT1. Some iron is bound to ferritin and stored within the cell. Cytoplasmic iron is pumped out of the cell via ferroprotein 1 (FPN1), oxidized by hephaestin (HEPH), and bound to transferrin (TF) in the interstitial space. H+, Hydrogen ion; K+, potassium;
Na+, sodium.
129 CHAPTER 12 Fluid and Electrolyte Absorption
ferritin is least when the body iron levels are low. Thus iron transfer out of the duodenal cells to the blood is increased.
The reverse holds when iron stores are replete. Intestinal
absorption of iron decreases as enzyme and transporter synthesis is decreased, and exit from the enterocytes decreases as the formation of ferritin is increased.
S U M M A R Y
• Approximately 9 L of water enters the GI tract per day.
Of this amount, 2 L is ingested and 7 L is secreted into the lumen. The small intestine absorbs approximately 8.5 L and the colon 0.4 L, thus leaving only 100 mL to be excreted in the stool.
• The absorption of water occurs by diffusion down an osmotic gradient created by the absorption of Na+, Cl−, other electrolytes, and nutrients such as sugars and amino acids.
• Four mechanisms account for the absorption of Na+: passive diffusion, countertransport with H+, cotransport with organic solutes (sugars and amino acids), and cotransport with Cl−. The presence of these mechanisms varies along the length of the bowel.
• Throughout the bowel, Cl− is absorbed passively down its electrical gradient. In addition to being absorbed with Na+, Cl− is absorbed in the distal ileum and colon in exchange for HCO3−, which is secreted into the lumen and accounts for the alkalinity of stool water.
• Crypt cells contain channels for Cl− secretion in their apical membranes that respond to increases in cAMP. Various toxins, such as cholera toxin, and GI peptides, such as VIP, trigger secretion via this mechanism, which depends on the Na+,K+-ATPase of the basolateral membrane.
• The small intestine actively absorbs Ca2+ by a process dependent on vitamin D, which stimulates the synthesis of a channel protein in the apical membrane, a cytoplas- mic binding protein, and Ca ATPase in the basolateral membrane.
• Most iron is absorbed as inorganic iron. Ferric iron is reduced by the enzyme DCYTB in the brush border to ferrous iron, which is transported into the cell by the divalent metal transporter, DMT1. If body stores are filled, most is bound to ferritin and lost when the cell is shed. During depletion, the iron exits the cell via the FPN1 transporter, is oxidized by HEPH, and is bound to TF and carried in the blood. Heme is also absorbed and can exit the cell intact or be broken down in lyso- somes to release ferrous iron.
K E Y W O R D S A N D C O N C E P T S
Transcellular pathways Paracellular pathways
Tight junctions/zonulae occludens Electrogenic potential
Osmotic diarrhea Secretory diarrhea Vitamin D Ferritin
S E L F - S T U D Y P R O B L E M S
1. Naturally occurring peptides, like secretin and VIP, stimulate secretion by intestinal crypt cells. How does the mechanism of their action differ from that of chol- era toxin, which stimulates the same cells to secrete?
2. What transport processes in the gut account for the fact that prolonged diarrhea results in hypokalemic metabolic acidosis?
SUGGESTED READINGS
Binder HJ, Sandle GI. Electrolyte transport in the mammalian colon. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 3rd ed. New York: Raven Press; 1994.
Chang EB, Rao MC. Intestinal water and electrolyte transport:
mechanisms of physiological and adaptive responses. In:
Johnson LR, ed. Physiology of the Gastrointestinal Tract. 3rd
Collins JF, Anderson GJ. Molecular mechanisms of intesti- nal iron transport. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 5th ed. Vol. 2. San Diego: Elsevier;
2012.
Dharmsathaphorn K. Intestinal water and electrolyte transport.
In: Kelly WN, ed. Textbook of Internal Medicine. Philadelphia:
Lippincott; 1989.
130 CHAPTER 12 Fluid and Electrolyte Absorption
Kiela PR, Collins JF, Ghishan FK. Molecular mechanisms of intestinal transport of calcium, phosphate, and magnesium.
In: Johnson LR, ed. Physiology of the Gastrointestinal Tract.
5th ed. Vol. 2. San Diego: Elsevier; 2012.
Kiela PR, Ghishan FK. Na+/H+ exchange in mammalian digestive tract. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 5th ed. Vol. 2. San Diego: Elsevier; 2012.
Montrose MH. Small intestine, absorption and secretion. In:
Johnson LR, ed. Encyclopedia of Gastroenterology. vol. 3. San Diego: Academic Press; 2004:399–404.
Thiagarajah JR, Verkman AS. Water transport in the gas- trointestinal tract. In: Johnson LR, ed. Physiology of the Gastrointestinal Tract. 5th ed. Vol. 2. San Diego: Elsevier;
2012.
O B J E C T I V E S
• Understand the importance of food intake to clinical medicine.
• Discuss the role of the nervous system in the regulation of food intake.
• Explain the role of the endocrine system in the regula- tion of metabolism and food intake.
• Discuss the role of the gastrointestinal (GI) system in the regulation food intake.
• Understand how input from the nervous, endocrine, and GI systems is integrated to regulate food intake and metabolism.
• Discuss the various treatments for obesity.
Regulation of Food Intake
13
The human species evolved during a time when the source of the next meal was highly uncertain. As a result, the gas- trointestinal (GI) tract evolved to optimize the processing of ingested material when it became available. Receptive relaxation allows the stomach to accommodate large vol- umes with minimal increases in gastric pressure. Digestive enzymes are secreted in great excess. The secretion of pan- creatic lipase, for example, must be reduced by at least 80% before steatorrhea occurs. There is significant overlap in the specificity of transport proteins or carriers for the absorption of most amino acids. Indeed, even the absorp- tive surface of the small intestine can be reduced 60% to 70%, as long as sufficient ileum remains to reabsorb bile acids and to absorb vitamin B12, before increased amounts of nutrients appear in the stool.
The result is that virtually all ingested carbohydrate, protein, and fat are broken down and absorbed. It is impossible to saturate the digestive and absorptive capaci- ties of the GI tract. This situation was advantageous when acquiring a meal was uncertain and also required an expen- diture of calories in the form of exercise, but now that the nearest meal is available by opening the refrigerator door or, worse, pulling into the parking lot of the nearest convenience store or fast food restaurant, the result is an epidemic of obesity with its sequelae of diabetes, cardiovas- cular disease, and some forms of cancer.
At present, more than two-thirds of Americans are overweight, and one-third can be classified as obese. The prevalence of obesity in children has increased markedly.
Obesity has now displaced cigarette smoking as the num- ber one health problem in the nation. In the United States approximately 300,000 deaths per year are directly attributed to obesity. In rare cases obesity can be caused by a gene mutation, but in an overwhelming majority of instances obesity is the result of a long-term imbal- ance between intake and expenditure of calories. These two quantities must remain equivalent to maintain body weight. Although a certain amount of weight control can be effected by increasing caloric expenditure in the form of exercise, the fact of the matter is that most of us overeat.