Intestinal bile-acid binding protein

Intestinal bile-acid-binding protein (IBABP) is a small 14-15-kDa protein found in the cytoplasm of cells in the ileum that binds bile acids as they enter the cell. By using photolabile bile-acid derivative and immunoprecipitation, expression was primarily found in the soluble protein fraction of ileal enter-ocytes, although cholangiocytes do show a low level of expression. One molecule of IBABP binds two bile-acid molecules as shown in Figure 2.4. 

IBABP intestinal bile-acid-binding protein... 

In the intestine the ileal bile acid transporter (IBAT) imports bile acids from the lumen into intestinal epithelial cells (step 2]). IBAT is a Na -linked symporter (see Figure 7-21) that uses the energy released by the movement of Na down its concentration gradient to power the uptake of about 95 percent of the bile acids. Those bile acids Imported on the apical side of intestinal epithelial cells move intracellularly with the aid of intestinal bile acid-binding protein (I-BABP) to the basolateral side. There, they are exported into the blood by poorly characterized transport proteins (step 3]) and eventually returned to liver cells by another Na -linked... 

Katongole, J.B.D. and March, B.E. (1980) Fat utilization in relation to intestinal fatty acid binding protein and bile salts in chicks of different ages and different genetic sources. Poultry Science 59,819-827. 

Another nuclear receptor, called FXR, is activated by the binding of bile acids. Expressed in hepatocytes and intestinal epithelial cells, FXR plays a key role in regulating the en-terohepatlc circulation of bile acids. Bile acid-activated FXR stimulates the expression of Intracellular bile acid-binding protein (I-BABP) and of transport proteins (e.g., ABCBll, NTCP) that mediate cellular export and Import of bile acids (see Figure 18-11). In contrast, active FXR represses the expression of cholesterol 7a-hydroxylase, thereby decreasing the synthesis of bile acids from cholesterol in the liver—another example of end-product Inhibition of a metabolic pathway. Both FXR and LXR function as heterodimers with the nuclear receptor RXR. 

Figure 8.9. Physiology and molecular biology of intestinal bile acid transport. Bile acids are actively absorbed in enterocytes through a sodium-dependent cotransporter, ASBT. The sodium gradient is maintained by the sodium-potassium ATPase, located at the basolateral membrane. In the ( osol, bile acids are shuttled through the cell by the aid of various proteins, most importantly the ileal hille acid binding protein, iBABP. An anion exchanger transports bile acids across the basolateral membrane into the portal circulation.

Bile acid-binding resin therapy Oral administration of a bile acid-binding resin, or sequestrant (D), increases the loss of bile acids from the body by preventing their absorption by intestinal epithelial cells through the IBAT transport protein and reduces bile acids delivered to the blood (0) and then to the liver (0) by the transporter NTCR Step The lower levels of cytoplasmic bile acids reduce the amount of bile acid bound to the nuclear hormone receptor EXP (0) and its suppression (0) of the expression of cholesterol 7a-hydroxylase. The consequent increased levels of expression and activity of cholesterol 7a-hydroxylase (B) reduce the levels of intracellular cholesterol (0). As with the statin treatment, the reduced cellular cholesterol levels (EHB) increase LDLR activity, lower plasma LDL levels, and protect against atherosclerosis. [Part (a) adapted from M. S. Brown and J. L. Goldstein, 1986, Sdence 232 34.]... 

Vitamin A is readily absorbed from the intestine as retinyl esters. Peak serum levels are reached 4 h after ingestion of a therapeutic dose. The vitamin is distributed to the general circulation via the lymph and thoracic ducts. Ninety percent of vitamin A is stored in the liver, from which it is mobilized as the free alcohol, retinol. Ninety-five percent is carried bound to plasma proteins, the retinol-binding protein. Vitamin A undergoes hepatic metabolism as a first-order process. Vitamin A is excreted via the feces and urine. Beta carotene is converted to retinol in the wall of the small intestine. Retinol can be converted into retinoic acid and excreted into the bile and feces. The elimination half-life is 9 h. 

Preformed vitamin A, most often in the form of retinyi ester, or carotenoids are subject to emulsification and mised micelle formation by the action of bile salts before being transported into the intestinal cell. Here the retinyi esters are moved across the mucosal membrane and hydrolyzed to retinol within the cell to then be reesterified by cellular retinol-binding protein II and packaged into chylomicra, which then enter the mesenteric lymphatic system and pass mto the systemic circulation. A small amount of the ingested retinoid is also converted into retinoic acid in the intestinal cell. The efficiency of absorption of preformed vitamin A is high at between 70% and 90%. ... 

A number of different members of the nuclear-receptor superfamily regulate lipid metabolism. Specific small molecules are typical activators. Such molecules can be either synthesized inside the target cell, diffuse into the cell, or be transported into the cell. One example is FXR, which is activated by binding of bile acids. FXR is expressed in hepato-cytes and intestinal epithelial cells. Is the source of bile acid that activates FXR cell synthesized, cell imported, or a combination of the two Rather than giving specific names of proteins whose synthesis is regulated by FXR, predict classes of proteins whose synthesis should be regulated by a bile acid-activated nuclear receptor. 

Kramer, W., Girbig, F., Gutjahr, U., Kowalewski, S., Jouvenal, K., Muller, G.. Tiipier, D., and Wess, G. (1993). Intestinal bile absorption Na-(--dependent bile acid transport activity in rabbit small intestine correlates with the coexpressicm of an integral 93-kDa and a peripheral 14-kDa bile aeid-binding membrane protein along the duodenum-ileum axis. J. BioL Chem. 268,18035. 

After ingestion, microcystins are released from cyano-bacterial cells and are absorbed into the portal circulation from the small intestine via bile acid transporters in the intestinal wall. Microcystins are then accumulated in hepatocytes via similar bile acid transporters on hepato-cyte membranes (Hooser et al., 1991). Microcystins irreversibly inhibit serine/threonine protein phosphatases 1 and 2A (Yoshizawa et al., 1990). Microcystin-LR may also bind to AP synthase, leading to hepatocyte apoptosis (Mikhailov et al., 2003). 

Copper is an essential trace element. It is required in the diet because it is the metal cofactor for a variety of enzymes (see Table 50—5). Copper accepts and donates electrons and is involved in reactions involving dismu-tation, hydroxylation, and oxygenation. However, excess copper can cause problems because it can oxidize proteins and hpids, bind to nucleic acids, and enhance the production of free radicals. It is thus important to have mechanisms that will maintain the amount of copper in the body within normal hmits. The body of the normal adult contains about 100 mg of copper, located mostly in bone, liver, kidney, and muscle. The daily intake of copper is about 2—A mg, with about 50% being absorbed in the stomach and upper small intestine and the remainder excreted in the feces. Copper is carried to the liver bound to albumin, taken up by liver cells, and part of it is excreted in the bile. Copper also leaves the liver attached to ceruloplasmin, which is synthesized in that organ. 

---