Hepatitis bile acid metabolism

An early observation about endogenous functions of PXR and CAR has been their implication in hepatic bile acid metabolism [48,49]. Most of the more recent findings on this topic are summarized in a number of reviews [9,50-52]. Briefly, CAR and PXR have been shown to play overlapping but not identical roles in hepatic bile acid detoxification [53,54]. Recent work has also drawn attention to the importance of PXR in cholesterol detoxification in the liver, kidney and intestine [55-59]. Both CAR and PXR are involved in bilirubin metabolism and clearance [60] activation of these pathways is of potential therapeutic interest in jaundice and chronic arthritis [61]. 

Romero, A. L., West, K. L., Zern, T., and Eemandez, M. L. (2002). The seeds from Plantago ovata lower plasma lipids by altering hepatic and bile acid metabolism in guinea pigs. /. Nutr. 132, 1194-1198. 

In liver cirrhosis, there are several changes reduction in LCAT (with cholesterol ester fall ), HDL and LDL as well as in VLDL, with a corresponding change in their distribution pattern occurrence of hypertriglycerid-aemia and atypical lipoproteins reduction in phospholipid synthesis (28), possibly with greatly impaired structure and function of the biomembranes. Hepatic extraction of bile acids is reduced with the result that they reach the peripheral circulation - even in the early stages of cirrhosis - and give rise to increased serum values. Bile acids have cholestatic and cytotoxic effects. When bile acid metabolism is markedly compromised, enteral absorption of fat-soluble vitamins is impeded, so that A, D, E and K hypovitaminoses may be observed. 

The regulation of bile acid metabolism is a major function of the liver. Alterations in bile acid metabolism are usually a reflection of liver dysfunction. Cholesterol homeostasis is in large part maintained by the conversion of cholesterol to bile acids and subsequent regulation of bile add metabolism. Bile acids themselves provide surface-active detergent molecules that facilitate both hepatic excretion of cholesterol and solubilization of lipids for intestinal absorption. Bile acid homeostasis requires normal terminal ileum function to absorb bile adds for recirculation (enterohepatic circulation). Alterations in hepatic bile acid synthesis, intracellular metabolism, excretion, intestinal absorption, or plasma extraction are reflected in derangements in bile add metabolism. 

Kinetics of Bile Acid Metabolism. Using an isotope dilution technique, the bile acid pool in normal adults has been found to average from 2 to 4g. Steady state is reached when hepatic synthesis and fecal loss are in balance. In health, the magnitude of each process is 0.3 to 0.8g/day. There are usually 4 to 10 enterohepatic cycles per day. Because of this recycling mechanism, the jejunal concentration of bile acids is maintained at -5 to lOmmol/L during the postprandial state, much higher than the critical micellar concentration of 2mmol/L. Between meals, with decreased entry of bile acids into the intestine, the intraluminal concentration... 

Disturbances of Bile Acid Metabolism in Hepatocellular Disease. Fasting plasma bile acid concentrations are elevated in hepatocellular diseases, such as hepatitis and cirrhosis. The mechanisms responsible are regurgitation of bile acids from cholestatic hepatocytes and portosystemic shunting. These defects allow the plasma concentrations to rise proportionately much higher than normal following meals, suggestmg that the postprandial rise in plasma bile acids may be a sensitive test for the detection of liver disease. 

The significance of other hormones in bile acid metabolism is not known. Most of the obese and triglyceridemic patients presented in Table II had latent diabetes and, as obese patients in general, apparently a marked hyper-insulinemia. Since hyperinsulinemia markedly stimulates hepatic lipogenesis in man (166), it is logical to infer that insulin causes in these patients an augmented cholesterol production and an indirectly increased bile acid synthesis. The metabolism of bile acids in insulin-dependent diabetes and in hyperlipidemia of ketotic diabetes is not known. 

Andersson KE, Axling U, Xu J, et al. Diverse effects of oats on cholesterol metabolism in C57BL/6 mice correlate with expression of hepatic bile acid-producing enzymes. Eur J Nutr. 2013 52 1755-1769. 

A closer analysis of bile acid metabolism with the isotope dilution technique has shown that the low bile acid production in hypercholesterolemia is mainly due to low cholic acid synthesis. This may be related to low hepatic cholesterol synthesis because the cholic acid and cholesterol synthesis rates appear to be interrelated. Cholestyramine actually increases cholic acid synthesis especially in hypercholesterolemic subjects with a low basal cholic acid and cholesterol production. Table 2 shows that the relative amount of cheno is actually quite high in hypercholesterolemic subjects and is lowered by cholestyramine in most subgroups. 

In human infectious hepatitis severe derangement of the liver structure occurs. Light microscopical studies as well as electron microscopy have revealed a wide spectrum of more or less pronounced alterations, including degeneration of the parenchymal cells and alterations of practically all cytoplasmic components of the hepatocytes (Schaffner and Popper, 1967). Hence, disturbances in the liver cell functions including alterations in the cholesterol and bile acid metabolism in this disease seem probable. How -cver, only few studies have been presented concerning bile acid metabolism. 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Hypolipidemic activity. Seed hull, administered to mice at a dose of 2.5% of diet for 18 weeks, was inactive " . The husk, administered orally to male Hartley guinea pigs at doses of 7.5 or 10 g/100 g of Plantago ovata for 4 weeks, exerted a hypolipidemic effect by affecting bile acid absorption and altering hepatic cholesterol metabolism Insulin release inhibition. Seed administered orally to 18 patients with noninsulin-dependent diabetes at a dose of 13.6 g/day lowered insulin levels by 17% . 

Important alterations in hepatic drug excretion and metabolism also occur. Estrogens in the amounts seen during pregnancy or used in oral contraceptive agents delay the clearance of sulfobromophthalein and reduce the flow of bile. The proportion of cholic acid in bile acids is increased while the proportion of chenodeoxycholic acid is decreased. These changes may be responsible for the observed increase in cholelithiasis associated with the use of these agents. 

Among the different roles previously described, the liver exerts an excretory function, being involved in the formation of bile, which drains into the small intestine. Bile salts in the bile play an important role as emulsifying agents for the reabsorption of lipids and fatty acids from the intestine. Hepatic and obstructive biliary diseases lead to abnormal metabolism of bile acids (BAs). 

The metabolism of HDL probably involves interaction with both hepatic and peripheral cells, as well as with other lipoproteins. HDL may remove cholesterol from tissues, the "scavenger hypothesis (11,12). The cholesterol may then be esterifed by the action of lecithin cholesterol acyl transferase. HDL may provide cholesterol to the liver for bile acid synthesis (13) and some HDL may be catabolized by the liver in the process. HDL has not been found to interfere with the binding of LDL in cultured human fibroblasts (6). However, in cultured human arterial cells, porcine or rat hepatocytes, and rat adrenal gland, there appears to be some competition of HDL with LDL binding sites, suggesting the presence of a "lipoprotein-binding" site (14). 

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