Molecular Mechanisms Triggered by Bile Acids on Intestinal Ca2+ Absorption.

BACKGROUND: Bile acids (BAs) are among the main components of bile. Lately, they are also considered important signaling molecules, not only by regulating their own synthesis, but also having a role in several metabolic diseases. OBJECTIVE: In this review we focus on the effect of sodium deoxycholate (NaDOC), ursodeoxycholic (UDCA) and litocholic (LCA) acids and their combination upon the intestinal Ca2+ absorption. To make clear the actions of those BAs on this physiological process, an overview of current information about the mechanisms by which the intestinal Ca2+ occurs is described. METHODS: The PubMed database was searched until 2017, using the keywords bile acids, NaDOC, UDCA and LCA and redox state, apoptosis, autophagy and intestinal Ca2+ absorption. RESULTS: The modulation of redox state, apoptosis and autophagy are mechanisms that are involved in the action of BAs on intestinal Ca2+ absorption. Although the mechanisms are still not completely understood, we provide the latest knowledge regarding the effect of BAs on intestinal Ca2+ absorption. CONCLUSION: The response of the intestine to absorb Ca2+ is affected by BAs, but it is different according to the type and dose of BA. When there is a single administration, NaDOC has an inhibitory effect, UDCA is an stimulator whereas LCA does not have any influence. However, the combination of BAs modifies the response. Either UDCA or LCA protects the intestine against the oxidative injury caused by NaDOC by blocking the oxidative/nitrosative stress, apoptosis and autophagy.

Coenzyme Q in pregnant women and rats with intrahepatic cholestasis.

BACKGROUND & AIMS: Intrahepatic cholestasis of pregnancy is a high-risk liver disease given the eventual deleterious consequences that may occur in the foetus. It is accepted that the abnormal accumulation of hydrophobic bile acids in maternal serum are responsible for the disease development. Hydrophobic bile acids induce oxidative stress and apoptosis leading to the damage of the hepatic parenchyma and eventually extrahepatic tissues. As coenzyme Q (CoQ) is considered an early marker of oxidative stress in this study, we sought to assess CoQ levels, bile acid profile and oxidative stress status in intrahepatic cholestasis. METHODS: CoQ, vitamin E and malondialdehyde were measured in plasma and/or tissues by HPLC-UV method whereas serum bile acids by capillary electrophoresis in rats with ethinyl estradiol-induced cholestasis and women with pregnancy cholestasis. RESULTS: CoQ and vitamin E plasma levels were diminished in both rats and women with intrahepatic cholestasis. Furthermore, reduced CoQ was also found in muscle and brain of cholestatic rats but no changes were observed in heart or liver. In addition, a positive correlation between CoQ and ursodeoxycholic/lithocholic acid ratio was found in intrahepatic cholestasis suggesting that increased plasma lithocholic acid may be intimately related to CoQ depletion in blood and tissues. CONCLUSION: Significant CoQ and vitamin E depletion occur in both animals and humans with intrahepatic cholestasis likely as the result of increased hydrophobic bile acids known to produce significant oxidative stress. Present findings further suggest that antioxidant supplementation complementary to traditional treatment may improve cholestasis outcome.

Bile acids content in brain of common duct ligated rats.

INTRODUCTION: Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Bile duct ligated rats constitute an interesting model to study the mechanism of cholestasis, and its action on several organs and tissues, including the brain. AIM: To analyze brain bile acids individually in ligated rats to evaluate if its profile is altered towards a more toxic condition in cholestasis. MATERIAL AND METHODS: Male Wistar rats were used and separated in two groups: bile duct ligated rats and sham operated rats (n = 5 in each group). Bile acid profile was assessed in brain homogenates. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase determinations, bilirubin and ammonia plasma concentration were also measured in both groups. RESULTS: Although the total amount of bile acids in control animal brains showed a higher concentration than in bile duct ligated rats, the bile acid profile in this group was found more toxic composition than in controls. Lithocholic acid was present in brain in higher concentration (87.4 % of total brain bile acids) in ligated rats and absent in controls. Alkaline phosphatase, bilirubin and ammonia were significantly higher in bile duct ligated rats than in control group. CONCLUSION: It was found a toxic brain bile acid profile during hepatic cholestasis which could be one of the explanations of hepatic encephalopathy observed in cholestatic diseases.

Biochemical epidemiology of gallbladder cancer.

To evaluate the a priori hypotheses that an increased level of glyco and tauro lithocholic acid, perhaps because of a decreased capacity for hepatic sulfation, contributed to the biochemical epidemiology of gallbladder cancer, a case-control study was undertaken at four hospitals in La Paz, Bolivia, and at one hospital in Mexico City, Mexico. Eighty-four cases with newly diagnosed histologically confirmed gallbladder cancer were compared with 264 controls with cholelithiasis or choledocholithiasis in the absence of cancer and with 126 controls with normal biliary tracts. All study subjects were undergoing abdominal surgery. Interview data were collected for all study subjects, as well as blood, bile, and gallstone specimens when feasible. Sera were analyzed for carcinoembryonic antigen, cholesterol concentration, and total bile acids. Bile specimens were analyzed for carcinoembryonic antigen; and for concentration of bile salts; cholesterol; phospholipids; and the glycine and taurine conjugates of cholic, ursodeoxycholic, chenodeoxycholic, deoxycholic, and lithocholates; sulfoglycolithocholate; and sulfotaurolithocholate. Gallstone specimens were analyzed for the percentage of cholesterol content, the percentage of calcium bilirubinate content, and the percentage of calcium carbonate content. Serum bile acids were increased in cases versus the two control groups (median 11.7 nmol/mL vs. 9.3 nmol/mL for stone controls and 8.2 nmol/L for nonstone controls, P < or = .02 for each pairwise comparison). Biliary bile acids were markedly decreased in the cases (median 3.98 micromol/mL vs. 33.09 micromol/mL, and 154.0 micromol/L, respectively, P < or = .0001 for each comparison), even after excluding those with a serum bilirubin higher than 2.0 mg/dL. Bile cholesterol was lower for the cases as well (median 1.70 micromol/mL vs. 4.90 micromol/mL, and 16.81 micromol/ mL, respectively, P < or = .02), as was the concentration of bile phospholipids (median 2.97 micromol/mL vs. 6.26 micromol/mL, and 52.69 micromol/mL, P = .1 and .0004, respectively). Contrary to our a priori hypothesis, there was no difference between the cases and either control group in their bile concentrations of lithocholate, the proportion of bile acids which were sulfated, or the concentration of nonsulfated lithocholate. However, the cases had a higher concentration of ursodeoxycholate (UDC) (P < .004 for both control groups), especially glycoursodeoxycholate (P < .001 for both control groups). A previously published suggestion that gallstone size differed between cases and controls was not confirmed. In conclusion, cases with gallbladder cancer differed from controls with stones and from controls with normal biliary tracts in their serum and bile biochemistries. These findings may be a reflection of the disease process, or may provide useful clues to its pathogenesis.

Morphologic changes in livers of hamsters treated with high doses of ursodeoxycholic acid: correlation with bile acids in bile.

The effects of high doses of ursodeoxycholic acid on bile acid composition and the liver morphology was examined in 60 male Syrian golden hamsters. The animals were allocated to five groups: I, control; II and IV received 0.5 g and 1 g of ursodeoxycholic acid per 100 g of standard diet respectively over 30 days and III and V received 0.5 g and 1 g of ursodeoxycholic acid per 100 g of standard diet respectively over 60 days. Bile acids were determined by high performance liquid chromatography. In all treated groups there was a significant increase in chenodeoxycholic and lithocholic acid in the bile. The mean glyco/tauro ratio was significantly higher than in the control group, reaching values > 1 for individual bile acids, except for lithocholic acid values which remained < 1. Under light microscopy, the livers of the hamsters showed damage which was dose/time related, namely portal inflammatory infiltrate, bile duct proliferation, cholestasis, fat infiltration and necrosis. Electron microscopy revealed pronounced changes starting with microvilli edema and extending to canalicular membrane destruction and necrosis. The changes observed in the relation glyco/tauro lithocholic acids, may be due to defence mechanisms to avoid hepatotoxicity. The hepatotoxicity resulting from ursodeoxycholic acid administration is presumed to be due primarily to lithocholic acid or some lithocholic acid metabolite.