Bile acids hepatic uptake

FATP5 KO mice have been characterized in two studies focusing on the role of FATP5 in hepatic lipid and bile metabolism. LCFA uptake in primary hepato-cytes isolated from FATP5 KO mice was reduced by 50% and hepatic lipid content in the KO mice was significantly reduced despite an increased fatty acid de novo biosynthesis. Detailed analysis of the hepatic lipidome of FATP5 KO mice revealed significant... 

Recently, molecular biology studies have been carried out on hepatic uptake transporters. With regard to the Na+-dependent hepatic uptake of bile acids, Na+-taurocholate cotransporting polypeptide (Ntcp/NTCP) has been cloned from both rodents and humans [14-17]. Ntcp/NTCP accepts bile salts, such as taurocholate and glycocholate, as well as some anionic compounds such as dehydroepian-drosterone sulfate and bromosulfophthalein [16, 18]. However, the presence of unidentified Na+-dependent transporters for anionic drugs (e.g., bumetanide) has also been suggested [19, 20]. 

Figure 4.13 Uptake of bile acids in the jejunum. Bile adds (BA) and cholesterol (C) are secreted from the liver, via the bile, into the duodenum. Cholesterol is transported back into the blood, from the enterocyte, within chylomicrons. The latter enter the lymphatic system (i.e. the lacteals). Bile acids are absorbed from the jejunum into the hepatic portal vein for re-uptake into the liver.

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

Fig. 12. The relation between hepatocyte shape ( ), 3H-thymidine uptake ( ) expressed as ratio to hepatocytes cultured on polystyrene dishes coated with 1 pg/ml PVLA solution and hepatic function, bile acid secretion (A), expressed as ratio to bile add secretion of hepatocytes cultured on dishes coated with 1 pg/ml of PVLA solution (Reproduced from New Functionality Materials, Vol. B [Ref. 181] through the courtesy of Elsevier Sdence Publisher B.V.)...

Cholestyramine or colestipol (resins). These are compounds that bind bile acids the drop in hepatic reabsorption of bile acids releases a feedback inhibition, resulting in a greater amount of cholesterol being converted to bile acids to maintain a steady level in the circulation. Additionally, synthesis of LDL receptors increases to allow for the increased cholesterol uptake for bile acid synthesis the overall effect is a reduction in plasma cholesterol. 

In general, drugs act to reduce the concentration of cholesterol within hepatocytes, causing a compensatory increase in low-density lipoprotein-receptors (LDL-R) on their surface, and increased uptake of cholesterol-rich LDL particles from the bloodstream (see Fig. 25.1). Statins decrease the synthesis of cholesterol and the secretion of VLDL and increase the activity of hepatic LDL-receptors. Bile-acidbinding resins deplete the bile acid and thus the cholesterol pool. Fibrates decrease the secretion of VLDL and increase the activity of lipoprotein lipase, thereby increasing the removal of tri-... 

Several mechanisms have been proposed to explain the cholestasis that occurs during parenteral nutrition, but there is little direct evidence to support any of them. Nutrient deficiencies that may be critical for hepatic uptake, biotransformation, and secretion of bile may be involved. Deficiency of taurine, which is important for bile acid conjugation, may cause cholestasis in premature infants. Certain amino acids may act as toxins. Reduced... 

Increased plasma bile acid concentrations in the fasting state suggest impaired hepatic uptake or secretion, or portosystemic shunting. Thus, such measurements may be used as a sensitive endogenous clearance test. However, a diagnosis suggested by an increase in plasma bile acid concentrations should be confirmed by standard liver function tests. In a similar manner, abnormal standard liver function tests can be confirmed as indicative of hepatic dysfunction by concomitant measurement of plasma bile acids. Plasma bile acid measurements may also be used serially to monitor patients with suspected or proven hepatic disease. However, they add little to standard tests of hver function and are now rarely used in clinical medicine. 

Ho RH, Tirana RG, Leake BF et al (2006) Drug and bile acid transporters in rosuvas-tatin hepatic uptake function, expression and pharmacogenetics. Gastroenterol 130 1793-1806... 

Catabolism of chylomicron remnants may be viewed as the second step in the processing of chylomicrons. After the loss of apo C-II and other C and A apoproteins, LPL no longer acts upon the remnants, and they leave the capillary surface. Chylomicron remnants are rapidly removed by uptake into liver parenchymal cells via receptor-mediated endocytosis. Apo E is important in this uptake process. The chylomicron receptors in liver are distinct from the B-E receptor that mediates uptake of LDL. The hepatic receptor for chylomicrons binds with apo E, but not apo B-48. Another receptor, known as the LDL receptor-related protein (LRP), may also function in chylomicron uptake. Chylomicron remnants are transported into the lysosomal compartment where acid lipases and proteases complete their degradation. In the liver, fatty acids so released are oxidized or are reconverted to triacylglycerol, which is stored or secreted as VLDL. The cholesterol may be used in membrane synthesis, stored as cholesteryl ester, or excreted in the bile unchanged or as bile acids. 

Synthesis of the bile acid (75) conjugated to either the 3 -end of an ODN or via a linker to the of dU are described. When used in vivo in rats, there was an increase in uptake to the liver, and this may be a method of targeting applications, such as antisense, to hepatic cells. The steroid 7-deoxycholic acid has also been incorporated into DNA via the of dU. When used in TFOs, there was an increase in the triplex stability compared to unmodified controls. 

Bile salts can also displace BSP from plasma albumin and hepatic intracellular protein (A14), which may contribute to the reduced uptake of the dye. BSP can reduce the transport maximal rate for bile acids... 

EPHXs are important multifunctional enzymes from both the deactivation and activation of reactive species. Furthermore, they convert any potentially reactive epoxide formed by the P450s system into a diol metabolite, which is usually less reactive, more water soluble, and more easily cleared by GSTs. There are two major types of EPHX enzymes the microsomal (mEPHX), which uses epoxides of polycyclic aromatics or drugs as substrates (type 1) and which controls hepatic uptake of bile acids (type 2) [67], and the soluble EPHX (sEPHX), which forms diols from many endogenous and exogenous epoxides, including fatty acids and leukotrienes [68],... 

Since plasma lipoprotein cholesterol must be the major substrate for bile acid biosynthesis under conditions when the rate of hepatic synthesis of cholesterol is low, regulation of the uptake of lipoprotein cholesterol by the hepatocytes should be of importance not only for the rate of cholesterol synthesis but also for the activity of cholesterol 7a-hydroxylase. It should be mentioned that bile acids are included among the different factors known to be able to modulate the receptor-mediated uptake of cholesterol by the apo-B, E or LDL receptor. The apo-B, E receptor can thus be induced to high levels by treatment with a bile acid sequestrant ]259]. Angelin et al. have shown that preparation of a bile fistula in adult dogs markedly induced the expression of the apo-B, E receptor and that the binding of this receptor could be almost totally abolished by reinfusion of taurocholate [260]. 

Plasma bile acids (total bile acids, TBAs) have been recommended as an alternative measurement to plasma bilirubin because TBAs can indicate biliary functionality in terms of the response to food intake. TBA values are dependent upon a number of factors, including stomach emptying gall bladder contraction, where it exists intestinal motility intestinal absorption hepatic uptake and hepatic excretion. The enterohepatic circulation amplifies deficiencies in the hepatic transport system this results in reduced secretion of bile acids into the bile. Studies with dogs have shown that timed postprandial measurements have greater diagnostic value than fasting or random samples (Center et al. 1991 Jensen and Poulsen 1992), but the collection of timed postprandial samples is more difficult. 

Ann Jeina was treated with a statin (pravastatin) and cholestyramine, a bile acid sequestrant. With the introduction of the cholesterol absorption blocker ezetimibe, the use of cholestyramine with its high level of gastrointestinal side effects may decline. Ezetimibe reduces the percentage of absorption of free cholesterol present in the lumen of the gut and hence the amount of cholesterol available to the enteroc5de to package into chylomicrons. This, in turn, reduces the amount of cholesterol returning to the liver in chylomicron remnants. The net result is a reduction in the cholesterol pool in hepatocytes. The latter induces the synthesis of an increased number of LDL receptors by the hver cells. As a consequence, the capacity of the liver to increase hepatic uptake of LDL from the circulation leads to a decrease in serum LDL levels. 

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