Portal blood concentraiions of conjugated cholic and chenodeoxycholic acids relationship to bile salt synthesis in liver cells (original) (raw)
Related papers
Journal of Clinical Investigation, 1978
was examined. The fractional inhibition of cholesterol synthesis found after administration of an amount of cholesterol sufficient to raise the hepatic cholesterol ester content by 1 mg/g equalled only -0.36 when bile acid synthesis was increased by biliary diversion but was -0.92 when bile acid synthesis was suppressed by bile acid feeding. It is concluded that (a) bile acids are not direct effectors of the rate of hepatic cholesterol synthesis, (b) most of the inhibitory activity seen with bile acid feeding is mediated through increased cholesterol absorption, and (c) bile acids do have an intrahepatic effect in that they regulate hepatic cholesterol synthesis indirectly by altering the flow of cellular cholesterol to bile acids. J. Clin. Invest.
Hepatology, 2003
The e&cts of newly synthesized cholesterol availability on bile acid synthesis are largely unknown, particularly in humans. The present study was aimed to study the changes induced on bile acid synthesis by simvastatin, a competitive inhibitor of hydroxymethyl glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme of cholesterol synthesis, during pharmacologic interruption of the enterohepatic circulation. S i x patients with primary hypercholesterolemia were studied in basal conditions, after treatment with the bile acid binding resin cholestyramine alone (8-16 g/d for 6-8 weeks) and subsequently in combination with simvastatin (40 mg/d for 6-8 weeks). Cholesterol 7a-hydroxylation rate, a measure of total bile acid synthesis, was assayed in vim by tritium release analysis. Serum lathosterol levels were assayed by gas chromatographymass spectrometry as a measure of cholesterol synthesis. Serum total and low-density lipoprotein-cholesterol were reduced significantly after cholestyramine (by 26% and 30%, respectively) and during combined treatment (by 47% and 55%). 7a-Hydroxylation rates increased nearly 4-fold with cholestyramine alone; addition of simvastatin induced a significant decrease of hydroxylation rates (cholestyramine alone, 1,591 2 183 mg/d; plus simvastatin, 1,098 f 232 mg/dj mean 2 SEM; P < .05). Hydroxylation rates significantly correlated with serum lathosterou cholesterol ratio (T = 0.79, P < .05). In conclusion, in conditions of chronic stimulation bile acid synthesis may be affected by changes in newly synthesized cholesterol availability. The finding might relate to the degree of substrate saturation of microsomal cholesterol 7a-hydroxylase; alternatively, newly synthesized cholesterol might induce a stimulatory effkct on cholesterol 7a-hydroxylase transcription. (HEPATOLOGY 2003;38:939-946.) B ile acid production is a major mechanism whereby cholesterol is eliminated from the organism and, therefore, represents a crucial event in the maintenance of cholesterol homeostasis.1-3 Two metabolic path-Abbreviations: HMG-CoA, hydroxymethyl glutaryl-CoA; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1995
The effects of hyodeoxycholic (HDCA) and cu-hyocholic acids (a-HCA), on cholesterol, bile acid and lipoprotein metabolism, were studied in hamsters. The animals were fed a low cholesterol control diet supplemented with 0.1% HDCA or (Y-HCA for 3 weeks. In both treated groups, the LDL-cholesterol concentration was significantly lowered and was associated with a global hypocholesterolemic effect. Moreover, hepatic cholesterol ester storage was reduced and HMGCoA reductase activity was respectively enhanced 13.5-times and 7.7-times in HDCA and (Y-HCA groups compared to controls. In contrast, cholesterol 7cy-hydroxylase activity and LDL-receptor activity and mass were not modified. In bile, the cholesterol saturation index was increased 5-fold (HDCA group) and 2-fold (a-HCA group) as a consequence of an enlarged proportion of biliary cholesterol. The two 6-hydroxylated bile acids induced an enhanced fecal excretion of neutral sterols (HDCA group: 11.6-times, cr-HCA group: 3.2-times versus controls) which was consistent with a 59% decrease in intestinal cholesterol absorption in the HDCA group. The major effects due to bile acid treatments were a decrease in LDL-cholesterol concentration, a strong stimulation of hepatic cholesterol biosynthesis and an excessive loss of cholesterol in feces. These perturbations might be the result of the enrichment of bile with hydrophilic bile acids, leading to a limited return of endogenous cholesterol from the intestine to the liver.
Altered bile acid metabolism in primary biliary cirrhosis
Digestive Diseases and Sciences, 1981
Selected aspects of bile acid metabolism were assessed in six women with primary biliary cirrhosis and varying degrees of cholestasis. Urinary bile acid excretion was markedly increased and correlated highly with serum levels. In three patients in whom urinary bile acids were separated by chromatography, the majority of urinary bile acids were monosulfated (34%, 42%, 32%) or polysulfated and~or glucuronidated (30%, 20%, 38%). The monosulfates of chenodeoxycholic acid were conjugated at either the 3 position (67%, 68%, 73%) or the 7 position (33%, 32%, 27%); similarly, the monosulfates of cholic cicid were conjugated at the 3 position (65%, 58%, 68%) or the 7position (35%, 42%, 32%). The position of sulfation was not markedly influenced by the mode of amidation with glycine or taurine. Chenodeoxycholic exchangeable pool size, turnover rate, and synthesis were measured by isotope dilution and found to be well within normal limits, despite the cholestasis. The fraction of chenodeoxycholic acid synthesis excreted in urine ranged from 9 to 48%; 4-38% of chenodeoxycholic acid synthesis was sulfated. These data indicate that the major abnormalities in bile acid metabolism in patients with cholestasis secondary to primary biliary cirrhosis are formdtion of sulfated bile acids in greatly increased amounts, elevation of blood levels of primary bile acids, and a shift to renal excretion aS a major mechanism for bile acid elimination. Chenodeoxycholic acid Synthesis continues at its usual rate despite cholestasis. Whether these changes, including the formation of 7-monosulfated bile acids, occur in other forms of cholestasis and whether either" the persistance of unchanged chenodeoxycholic acid synthesis or the formation of such novel conjugates has any pathophysiological significance remain to be investigated.