A number of gastrointestinal hormones can only be secreted by their cells of origin as a consequence of the active digestion and absorption of nutrients in the stomach and duodenum. The stomach has been recognized to be the major control center to coordinate digestion. Table 1 summarizes 11 types and sources of secretory cells of the stomach and intestine. The ingestion of nutrients into the duodenum is postulated to be the initiating signal for gastroenteropancreatic hormone release. Ingestion is accomplished by drinking or eating food through the mouth and delivering it via the esophagus and stomach to the gastrointestinal tract. Carbohydrate ingestion leads to the secretion of GIP and enteroglucagon, while fat ingestion stimulates CCK, GIP, neurotensin, and possibly motilin release.

Table1. Endocrine-related Cell Types and Their Hormones That Are Present in the Gastrointestinal System

Because these hormonal responses occur within 15 min of ingestion, it seems probable that cellular absorption of the dietary components cannot have played a significant role in stimulating the prompt but selective release of the GI hormones. It is now known that gastric hormones or releasing factors function as control signals for hormone release from the duodenal, jejunal and ileal cells, as well as from the pancreas. A gastrin-releasing protein has been isolated from the fundic portion of the stomach.

Pepsin is the most important protease in initiating the breakdown of proteins in the stomach. Pepsin can break down any protein in the diet. Pepsinogen (Mol. Wt 40,554) is an inactive enzyme (zymogen) in the stomach and has an additional 44 amino acid residues more than the catalytically active daughter pepsin. The vagus nerve and gastrin hormone facilitate the release of both HCl and pepsinogen from the stomach lining when food is present. The zymogen pepsinogen is activated solely by the presence of hydrochloric acid at a pH of ~2.5. The presence of the acid permits the pepsinogen to partially unfold and use its autocatalytic properties to cleave off its own 44 amino acid N-terminal peptide, thereby creating active pepsin (Mol.Wt. 34,614). Pepsin then processes the incoming proteins in the stomach and cleaves at any peptide bonds on the amino-terminal side of one of the aromatic amino acid residues (Phe, Trp, and Tyr), creating large peptides.

The challenge is that while the stomach is extraordinarily well organized, it does not have the responsibility of converting all the food components into free amino acids, and peptides of various sizes, etc. That responsibility falls principally to the proteases available in the duodenum, jejunum, and ileum with the assistance of the pancreas. Accordingly, the pH ~2.5 environment work-product of the stomach’s fundus, corpus, and antrum (large peptides, carbohydrates, and fat) are sent through the pyloric sphincter to the duodenum. This promptly signals the release of the GI hormone, secretin, into the blood for the delivery of the secretin messenger to the pancreas. This activates the production of the pancreatic secretion containing two different protease, zymogen granules that contain either catalytically inactive trypsinogen or chymotrysinogen. Also at the same time the pro carboxypeptidases A and B are also packaged as zymogen granules. Collectively, they are all delivered to the duodenum via the pancreatic duct. Secretin also stimulates the transport of biocarbonate from the pancreas via the pancreatic duct to its release in the duodenum. The presence of the bicarbonate has the desired consequence of neutralizing the gastric HCl to ~pH of 7.

When the stomach sends partially ingested food nutrients to the duodenum, they become candidates for further breakdown by proteases present in the duodenum, jejunum, and ileum. The ultimate goal is to have small peptides that can be readily absorbed by the duodenal intestinal lining. Enterokinase, also known as enteropeptidase, is secreted from the intestinal glands of the duodenum; see Figure 1, panel B. The enterokinase enzyme converts the inactive zymogen form of trypsinogen (received from the pancreas) into a catalytically active trypsin.

Fig1. Organization of the small intestinal duodenum from the macro level down to just one intestinal villus. (A) Macro details of the cross section of the duodenum. The outer width of the duodenum is ~2 cm and the inner width of the lumen is ~1 cm. The predominant cell type is the abundant villus; the villi face the interior of the duodenum, jejunum, and ileum and are responsible for nutrient absorption. (B) Close-up of the intestinal columnar villi that line the inner surface of the duodenum. The lumen of the small intestine is composed of a multitude of these finger-like projections, which are termed villi. See the black circle in panel A illustrating the source of the highly magnified image of the intestinal columnar villi. (C) Cross-sectional highly magnified view of one villus. Typically the villi range from 0.5–1.5 mm in length.

The duodenum secretes enterokinase promptly after the passage through the pyloric sphincter and arrival in the duodenum of digested proteins and other food components. Newly secreted enterokinase consists of a disulfide-linked 82–140 kDa heavy chain which holds the enterokinase in the intestinal brush border and a 35–62 kDa light chain that contains the catalytic sub unit that will convert principally trypsinogen (also a zymogen) into a catalytically active trypsin protease. Enterokinase is a serine protease enzyme that preferentially cleaves after a lysine if the following amino acid sequence (Asp-Asp-Asp-Asp-Lys) is present in the candidate zymogen. Trypsinogen is virtually the only protein which has this necessary signal sequence. Trypsin is the principal protease present in the intestine.

Figure 2 summarizes the activation process for six zymogens (chymotrypsinogen, proelastase, procarboxy peptidase, prophospholipase, procolipase, and kallikreinogen); see the left and right green boxes. Colipases are enzymes that break down fats to fatty acids and glycerol. Kallikreins are enzymes that cleave peptide bonds in proteins. Each of these zymogen enzymes are activated in the duodenum by trypsin to produce six active enzymes that also collectively contribute to further maximizing the breakdown process of all the ingested food particles.

Fig2. Activation of both the duodenal pre-protease enzymes (enterokinase and trypsinogen) and the stomach’s pepsinogen are required to convert an inactive enzyme (zymogen) into a catalytically active useful enzyme. The pair of top yellow boxes describes the autoactivation in the stomach of pepsinogen into active pepsin. Pepsinogen that is secreted into the stomach’s corpus and antrum where it is quite acidic (pH 2–3) becomes autoactivated. The second pair of yellow boxes shows the amplification by enterokinase of trypsinogen > > trypsin. Trypsinogen becomes activated by the duodenal peptidase, enterokinase (also known as enteropeptidase), by cleavage of trypsinogen’s lysine residue 15. This fully activates the trypsin (right box). The bottom pair of yellow boxes describes the active trypsin activating each of the six pro enzymes (see left green box) into an active enzyme (right green box). The mechanism of pepsinogen’s self-activation is described under section II.E, “Coordination of Gastroenteropancreatic Hormone Release.”

The physiological importance of enterokinase (also known as enteropeptidase) is emphasized in the second pink arrow of Figure 2. As emphasized in section I.C, “Problems of Food Processing and Digestion,” it is essential that the gastrointestinal digestion system be very efficient in processing the food intake to provide maximal amounts of amino acids and carbohydrates which can all be reutilized for ultimate transfer to the circulatory system for delivery to the liver and muscle to participate in gluconeogenesis and/or glycolysis.

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مواضيع ذات صلة

Pancreatic, Biliary, and Intestinal Secretions

Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex

Leptin Functions as a Satiety Factor

Glucagon and Glucagon-like Peptides— Biosynthesis and Secretion

Adult Growth Hormone Deficiency

Hypopituitary crisis

Thyroid Replacement in TSH Deficiency

Glucagon’s Structure

Insulin and Its Glucose Transporter

Insulin Receptor

Insulin Structure

Biological Actions of T3