The mechanisms of and the interrelationship between bile acid and chylomicron-mediated regulation of hepatic cholesterol synthesis in the liver of the rat (original) (raw)
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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.
Regulation of biliary cholesterol secretion in the rat. Role of hepatic cholesterol esterification
Journal of Clinical Investigation, 1984
Although the significance of the enterohepatic circulation of bile salts in the solubilization and biliary excretion of cholesterol is well established, little is known about the intrahepatic determinants of biliary cholesterol output. Studies were undertaken to elucidate some of these determinants in the rat. Feeding 1% diosgenin for 1 wk increased biliary cholesterol output and saturation by 400%. Bile flow, biliary bile salt, phospholipid and protein outputs remained in the normal range. When ethynyl estradiol (EE) was injected into these animals, biliary cholesterol output decreased to almost normal levels under circumstances of minor changes in the rates of biliary bile salt and phospholipid outputs. Similarly, when chylomicron cholesterol was intravenously injected into diosgenin-fed animals, biliary cholesterol output significantly decreased as a function of the dose of chylomicron cholesterol administered.
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.
Effect of cholesterol feeding and biliary obstruction on hepatic cholesterol biosynthesis in the rat
Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1973
I. It has been suggested that the amount of cholesterol reaching the liver from the intestine determines the suppression of cholesterol biosynthesis which occurs with cholesterol feeding and the rise in synthesis which occurs with bile duct ligation. We hypothesized that microsomal cholesteryl ester might be the inhibitor. 2. Cholesterol feeding suppressed cholesterol biosynthesis in rat liver slices; although there was little change in hepatic free cholesterol levels, hepatic and microsomal cholesteryl ester levels rose markedly. Following the cessation of cholesterol feeding synthesis returned to normalwith a corresponding fall in microsomal cholesteryl ester levels. These observations would agree with our hypothesis. 3. Biliary obstruction increased hepatic cholesterol biosynthesis to levels greater than those found at the peak of normal diurnal variation, but microsomal cholesteryl ester levels did not fall. 4. Cholesterol feeding prior to obstruction inhibited the rise in cholesterol biosynthesis as did the administration of DL-ethionine or cycloheximide. These results suggest that the microsomal cholesteryl ester level may be an inhibitor of cholesterol biosynthesis but other factors including protein synthesis are involved in the elevation of synthesis following bile duct ligation.
2000
results show that bile acids strongly interfere with the The existence of a relationship between bile acid and assembly or secretion of VLDL particles by human hepatriacylglycerol metabolism in humans has been estabtocytes, suggesting a physiological function of the enlished, but the underlying mechanism and its physiologiterohepatic circulation of bile acids in the regulation of cal relevance have remained unclear. We have studied postprandial serum lipid levels. (HEPATOLOGY 1996; the effects of bile acids on the secretion of very-low-den-23:218-228.) sity lipoprotein (VLDL)-associated triacylglycerol, using [ 3 H]glycerol labeling technique, and apolipoprotein B (apoB) in human hepatocytes in primary culture. Hu-Hepatocytes secrete substantial amounts of lipids at man hepatocytes secrete nascent VLDL with an average their apical (canalicular) pole into bile and at the basodiameter of about 40 nm. Lipid composition of the partilateral (sinusoidal) side into the blood, the latter cles resembles that reported for plasma VLDL, with the mainly in the form of very-low-density lipoprotein exception of a markedly lower cholesterylester content. (VLDL). The apical route, i.e., the flux of free choles-In 24-hour cultured human hepatocytes, physiological terol (CH) and phospholipids (PL) into the bile, is (i.e., portal) concentrations of taurocholic acid (10 to 200 thought to occur mainly through vesicle formation at mmol/L) suppressed [ 3 H]triacylglycerol secretion dose
Metabolism-clinical and Experimental, 1999
The regulation of the classic and alternative bile acid synthetic pathways by key hepatic enzyme activities (microsomal cholesterol 7oL-hydroxylase and mitochondrial sterol 27-hydroxylase, respectively) was examined in bile acid depletion and replacement and cholesterol-feeding experiments with rats, guinea pigs, and rabbits. The bile acid pool was depleted by creating a bile fistula (BF) and collecting bile for 2 to 5 days, and it was replaced by intraduodenal infusion of the major biliary bile acids (taurocholic acid [TCA], glycochenodeoxycholic acid [GCDCA], and glycocholic acid [GCA] in the rat, guinea pig, and rabbit, respectively) at rates equivalent to the measured hepatic flux of the bile acids. To study the effects of cholesterol, the animals were fed for 7 days on a basal diet with and without 2% cholesterol. Cholesterol 7~-hydroxylase and sterol 27-hydroxylase activities, measured by isotope incorporation assays, were related to bile acid output and composition and hepatic cholesterol concentrations. Intraduodenal infusion of bile acids increased the output of the tested bile acids, but did not significantly change hepatic cholesterol concentrations and had no effect on sterol 27-hydroxylase activity. Neither bile acid depletion nor replacement affected sterol 27-hydroxylase activity when three different substrates (cholesterol, 51~-cholestane-3~,7~-diol, and 51~-cholestane-3~,7~,12~-triol) were tested. In contrast, feeding 2% cholesterol increased hepatic cholesterol concentrations in rats, guinea pigs, and rabbits threefold, twofold, and eightfold, respectively, and increased hepatic mitochondrial stero127-hydroxylase activity (conversion of cholesterol to 27-hydroxycholesterol) in all three animal models. The stimulation and feedback inhibition of cholesterol 7~-hydroxylase activity by bile acid depletion and replacement were observed in all three animal models, whereas the effect of cholesterol feeding was species-dependent (cholesterol 7~-hydroxylase activity increased in the rat, did not change in the guinea pig, and was inhibited in the rabbit). Thus, in contrast to sterol 27-hydroxylase, which was upregulated by cholesterol but not affected by bile acid depletion and replacement in all three animal models, cholesterol 7~-hydroxylase activity was controlled consistently and inversely by the hepatic flux of bile acids, but was species-dependent in its response to a 1-week feeding with 2% cholesterol.
Journal of lipid research, 1983
After incubation in the presence of tritiated water, incorporation of tritium into cholesterol and into different bile acids was several-fold higher using hepatocytes of cholestyramine-fed rats than that found using hepatocytes of control rats. Labeling of the trihydroxylated cholic and beta-muricholic acids was markedly greater than that of dihydroxycholanoic acid. The total amount of label in all bile acids was 30% or less of that in free cholesterol, in both types of hepatocytes. In combination with the data on bile acids mass production we could calculate the average number (N(a)) of tritium atoms incorporated per molecule of newly-formed bile acid. The experimental values of N(a) for cholic and beta-muricholic acid were compared with values of N(n) or N(o), theoretically predicted if these bile acids were derived entirely from newly made or pre-existent cholesterol, respectively. It was deduced for hepatocytes of cholestyramine-fed rats that the bile acids produced in the first...
Kinetics of biliary secretion of chylomicron remnant cholesterol (esters) in the rat
European Journal of Biochemistry, 1993
Chylomicrons labelled with [3H]cholesterol/[3H]cholesterol esters in a ratio of 25.5 : 74.5, were rapidly removed from rat serum in vivo, and taken up predominantly by the parenchymal liver cells (88.2% of the hepatic uptake at 15 min after injection). Lactoferrin reduced the liver uptake of chylomicron remnants by 72%, at 20 min after injection. It appeared that the free cholesterol which is present in the chylomicrons is not readily exchanged within the used time period with other cholesterol pools in the animal. Between 10-60 min after injection of 3H-labelled chylomicrons, cholesterol esters are hydrolysed in the liver. Appearance of radioactivity in bile was rapid and at 3,24 and 72 h after injection, 13.4 %, 44.0 % and 70.0 %, respectively, of the injected dose appeared in bile, mainly as bile acids (> 90 %). Lactoferrin reduced the biliary secretion of radioactivity, especially during the first hour after injection. The total amount of radioactivity recovered was 58.0 % of the injected dose at 72 h after injection. After injection of P-migrating very low-density lipoprotein labelled with [3H]cholesteroY[3H]cholesterol esters in a ratio of 23.5 : 76.5, the maximum amount of radioactivity secreted in bile was much lower than with chylomicrons (2.6 % cf. 5.2% at 1 h after injection), although the kinetics of the initial liver association and cholesterol ester hydrolysis were even more rapid. B i l i q accumulation of radioactivity was also lower with 50.5 % of the injected dose recovered at 72 h after injection. It can be concluded from these studies that the processing of chylomicron remnant cholesterol components in the liver and the subsequent secretion in the bile mainly as bile acids is very efficient. The efficient liver uptake of chylomicron remnants by the liver remnant receptor is thereby essential to achieve this high percentage of removal, thus protecting against extrahepatic cholesterol (ester) deposition.