| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Hemodynamic changes associated with reduction in total cholesterol by treatment with the HMG-CoA reductase inhibitor pravastatin Muramatsu, J., A. Kobayashi, et al. (1997), Atherosclerosis 130(1-2): 179-82. Abstract: Hemodynamic changes associated with the lowering of total cholesterol (TC) by the water-soluble HMG-COA reductase inhibitor pravastatin were investigated in 59 patients with hypercholesterolemia (TC level at least 220 mg/dl) who received pravastatin therapy for 6 months. The patients were divided into two groups according to the reduction in TC: a > or = 15% reduction group and a < 15% reduction group. The changes in hemodynamics were compared before and after pravastatin treatment. No changes in blood pressure, heart rate or aortic damping factor were found in either group. However, significant decreases in pulse wave velocity and total peripheral resistance, and increase in cardiac output were seen in the > or = 15% reduction group. All these hemodynamic parameters remained unchanged in the < 15% reduction group. The 12 patients with a clear pravastatin-induced reduction in TC maintained over a 5-year period showed no changes in blood pressure, heart rate or aortic damping factor, but the reductions in pulse wave velocity and total peripheral resistance, and increase in cardiac output were maintained. These changes in hemodynamics were not dependent on aortic elasticity, and appeared to result from improved peripheral hemodynamics. Lowering of TC levels by pravastatin results in improvement in the peripheral endothelium-dependent vasodilation disorder associated with hypercholesterolemia. |
| Hemostatic variables in homozygous familial hypercholesterolemia. Effect of regular plasma cholesterol removal by low density lipoprotein apheresis Di Minno, G., A. M. Cerbone, et al. (1990), Arteriosclerosis 10(6): 1119-26. Abstract: Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) and the in vitro ability of platelets to aggregate and of monocytes to express procoagulant (tissue factor) activity (PCA) were evaluated in five patients who are homozygous for familial hypercholesterolemia (FH) before and after a single and a regular 5-month cholesterol removal by low density lipoprotein (LDL) apheresis. The biweekly procedure resulted in a 25% to 30% reduction (approximately 150 mg/dl) in total and LDL cholesterol (both were greater than 550 mg/dl at the beginning of the study). The basal levels of t-PA antigen and fibrinolytic activity before and after 10 minutes of venous stasis, basal PAI activity, and PAI-1 antigen were comparable to controls and were not affected by LDL apheresis. Likewise, regardless of the cholesterol removal, the PCA of freshly isolated monocytes and that of monocytes incubated with lipopolysaccharide did not differ from control values. Finally, the pre-apheresis sensitivity of platelets to adenosine diphosphate, arachidonic acid, and collagen was 1.5 to 2 times the normal value. This ratio was unchanged throughout the 5-month procedure. We conclude that fibrinolysis and monocyte PCA are normal in FH patients, whereas platelet aggregation is abnormally high, and none of these parameters is significantly affected by a 25% to 30% reduction in total and LDL cholesterol by LDL apheresis. Furthermore, our data suggest that removal of cholesterol from plasma by LDL apheresis is important for gaining insight into the mechanisms involved in the ischemic complications of arteriosclerosis in FH patients. |
| Hep G2 cells as a resource for metabolic studies: lipoprotein, cholesterol, and bile acids Javitt, N. B. (1990), Faseb J 4(2): 161-8. Abstract: Hep G2, a liver cell line derived from a human hepatoblastoma that is free of known hepatotropic viral agents, has been found to express a wide variety of liver-specific metabolic functions. Among these functions are those related to cholesterol and triglyceride metabolism. Confluent Hep G2 monolayers express normal low-density lipoprotein (LDL) receptors and continue to internalize and metabolize chylomicrons, very low-density lipoproteins (VLDL), LDL, and high-density lipoproteins. In lipoprotein-free medium, apolipoproteins A-I, A-II, B, C, and E accumulate in the medium together with cholesterol, cholesteryl ester, triglyceride, and all the primary bile acids. The regulation of their synthesis and secretion is not fully known and their interrelationships have not been established. Because Hep G2 cells express these and other components of cholesterol and triglyceride metabolism, they are a microcosm for studying the central role of the liver. |
| Heparan sulfate proteoglycans mediate internalization and degradation of beta-VLDL and promote cholesterol accumulation by pigeon macrophages Seo, T. and R. W. St Clair (1997), J Lipid Res 38(4): 765-79. Abstract: Pigeon and rabbit beta-migrating very low density lipoprotein (beta-VLDL) are similar in size and composition, yet rabbit beta-VLDL consistently stimulates greater cholesteryl ester accumulation in pigeon peritoneal macrophages than does pigeon beta-VLDL. The purpose of this study was to determine the mechanism of this difference. Pigeon beta-VLDL bound to both a high and low affinity site while rabbit beta-VLDL bound primarily to a low affinity site. The high affinity site had the characteristics of the LDL receptor. Most rabbit beta-VLDL and some pigeon beta-VLDL bound to the low affinity site that was not down-regulated by cholesterol loading. beta-VLDL binding to the low affinity site and subsequent internalization and degradation were mediated by cell surface heparan sulfate proteoglycans (HSPG). Evidence for this includes inhibition of binding and uptake by chlorate, which prevents sulfation of proteoglycans, and by treatment with heparinase but not chondroitinase ABC. beta-VLDL uptake was stimulated by lipoprotein lipase (LpL) and apolipoprotein E (apoE), both known to bind HSPGs. Uptake and degradation of beta-VLDL were not mediated by the LDL receptor or the alpha(2)MR/LRP. Thus, binding of beta-VLDL to low affinity, high capacity HSPG binding sites on pigeon macrophages appears to directly promote internalization and degradation and is largely responsible for the greater ability of rabbit beta-VLDL to stimulate cholesterol accumulation. |
| Heparin inhibits rat peritoneal macrophages to reesterify cholesterol Yoshinari, M., M. Yamamoto, et al. (1995), Ann N Y Acad Sci 748: 634-6. |
| Heparin inhibits the accumulation of re-esterified cholesterol in macrophages loaded with acetylated low-density lipoprotein Yoshinari, M., M. Yamamoto, et al. (1995), Biochim Biophys Acta 1259(2): 155-60. Abstract: Heparin enhances the endocytosis of low density lipoprotein (LDL) in macrophages via a formation of complex with LDL. The direct effect of heparin on the metabolism of cholesterol in macrophages has not been elucidated. We therefore evaluated the effects of heparin on the accumulation and reesterification of cholesterol in cultured macrophages. We used acetylated LDL (acetyl-LDL), which lacks an affinity for heparin. Rat peritoneal macrophages induced with thioglycollate were incubated with 100 micrograms of acetyl-LDL for 14 h. Heparin significantly inhibited the accumulation of total and esterified cholesterol but did not affect the binding of 125I-labeled acetyl-LDL to macrophages or its cellular degradation. Heparin at concentration above 5 micrograms/ml inhibited the incorporation of 3Holeate into cholesteryl oleate in macrophages. Heparin significantly inhibited the acyl CoA:cholesterol acyl transferase (ACAT) activity of macrophages by 68%. Data suggest that heparin inhibits the accumulation and reesterification of cholesterol in macrophages loaded with acetyl-LDL. Heparin-like proteoglycans may thus protect the macrophages against the excessive accumulation of esterified cholesterol. |
| Heparin-immobilized polyhydroxyethylmethacrylate microbeads for cholesterol removal: a preliminary report Denizli, A. and E. Piskin (1995), J Chromatogr B Biomed Appl 670(1): 157-61. Abstract: Heparin-attached polyhydroxyethylmethacrylate (PHEMA) microbeads were investigated for specific removal of cholesterol from human and rabbit plasma. PHEMA microbeads were prepared by a suspension polymerization technique and activated by cyanogen bromide (CNBr) in an alkaline medium (pH 11.5). Heparin was then immobilized by covalent binding onto these microbeads. Cholesterol adsorption onto PHEMA microbeads containing two different amounts of immobilized heparin, i.e., 57.3 and 122.7 mg/g, from both hypercholesterolaemic human and rabbit plasma was investigated. The non-specific cholesterol adsorptions on the plain PHEMA microbeads were 0.47 mg/g and 0.30 mg/g from human and rabbit plasmas, respectively. About 35% and 32% of the cholesterol was removed from human and rabbit plasmas, respectively, when the heparin-immobilized PHEMA microbeads were used. |
| Hepatic acyl-coenzyme A:cholesterol acyltransferase activity is decreased in patients with cholesterol gallstones Smith, J. L., I. R. Hardie, et al. (1990), J Lipid Res 31(11): 1993-2000. Abstract: Altered hepatic cholesterol metabolism has been implicated in the etiology of cholesterol gallstones. This hypothesis has been examined by determining acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity in liver biopsies from 31 cholesterol gallstone patients and 12 control subjects. Hepatic ACAT activity in gallstone patients was decreased to one-third that in controls (P less than 0.001). No differences in hepatic homogenate or microsomal free and total cholesterol concentrations were observed between the two groups. However, marked increases in free (107%) and total (98%) cholesterol concentrations were found in the cytosolic fraction of liver biopsies from gallstone patients. The total phospholipid concentration of the liver homogenate fraction was unchanged in both groups; however, the microsomal total phospholipid concentration was reduced by 17% (P less than 0.01) in gallstone samples compared with controls. This difference did not result in a significantly increased microsomal cholesterol/phospholipid ratio for the gallstone group (0.180 +/- 0.030) compared with the control group (0.169 +/- 0.042). These results show that hepatic ACAT activity is significantly decreased in cholesterol gallstone patients. These changes in ACAT activity in livers of patients with cholesterol gallstones are consistent with the known increase in the amount of free cholesterol secreted in the bile of these patients. Thus, the changes in ACAT activity may contribute to the pathogenesis of cholesterol gallstones. |
| Hepatic acylcoenzyme A:cholesterol acyltransferase activity is low in hamsters fed apples in addition to a standard diet Sable-Amplis, R. and R. Sicart (1993), Ann Nutr Metab 37(1): 1-7. Abstract: The effect of consumption of apples as a supplement to a standard diet on hepatic acylcoenzyme A: cholesterol acyltransferase (ACAT) activity was investigated in adult golden hamsters (Mesocricetus auratus). The experimental diet was given for 2 months. IN response to the high-fruit intake, the level of cholesteryl esters was reduced in the liver, and hepatic ACAT activity, determined in vitro under various conditions of incubation, was lowered by about 30%. Moreover, plasma cholesterol was redistributed among the lipoproteins, with a decrease in the cholesterol transported in the ApoB-rich lipoproteins. |
| Hepatic and extrahepatic sterol 27-hydroxylase: roles in cholesterol and bile acid metabolism and associated diseases Souidi, M., S. Dubrac, et al. (2003), Gastroenterol Clin Biol 27(1): 100-11. |
| Hepatic bile versus gallbladder bile: a comparison of protein and lipid concentration and composition in cholesterol gallstone patients Keulemans, Y. C., K. S. Mok, et al. (1998), Hepatology 28(1): 11-6. Abstract: Many studies have demonstrated that gallbladder bile (but not hepatic bile) of animals or patients with cholesterol gallstones contains higher protein concentrations than does gallbladder bile of control patients without stones or with pigment stones. The underlying defect has not been elucidated. To establish whether there is net production or net absorption/degradation of protein by gallbladder epithelium for different classes of protein, paired samples of hepatic and gallbladder bile were obtained from fourteen patients with cholesterol gallstones during elective cholecystectomy. In these paired samples, lipid and protein composition were determined. To obtain the concentration ratio (CR) of protein and lipid, its concentration in the gallbladder was divided by the concentration determined in the paired hepatic bile sample. The CR of bile salts was used as a parameter for water absorption in the gallbladder. Of the biliary proteins that were determined only mucin, albumin, immunoglobulin (Ig) G, and aminopeptidase N appeared to increase in the gallbladder from another cause than water absorption. A strong correlation was found between mucin, albumin, and IgG. Haptoglobin, alpha1-acid glycoprotein, IgM, and IgA appeared to be absorbed by gallbladder epithelium in the majority of patients. In cholesterol gallstone patients, total protein concentration in gallbladder bile of cholesterol gallstone patients is increased when compared with hepatic bile. The increase in protein concentration cannot be explained for all bile samples solely by water absorption. In this study we show that the defect is largely caused by a selective increase in albumin, mucin, and IgG. All other proteins which were investigated are taken up by the gallbladder. |
| Hepatic cholesterol 7 alpha-hydroxylase activity and serum 7 alpha-hydroxy-cholesterol level during liver regeneration after partial hepatectomy in rats Nakano, K., K. Chijiiwa, et al. (1995), Eur Surg Res 27(6): 389-95. Abstract: Hepatic cholesterol 7 alpha-hydroxylase is a rate-limiting enzyme for bile acid synthesis, and we have previously shown that the serum 7 alpha-hydroxycholesterol level reflects the enzyme activity in patients with an intact liver. The purpose of this study was to evaluate the alterations in hepatic cholesterol 7 alpha-hydroxylase activity and the serum 7 alpha-hydroxycholesterol level after hepatectomy and the correlations between these parameters and liver mass. Hepatic cholesterol 7 alpha-hydroxylase activity, the serum 7 alpha-hydroxycholesterol level and the remaining liver weight were determined after 70% hepatectomy in rats. Cholesterol 7 alpha-hydroxylase activity was decreased on days 1 and 2 (from 28.3 +/- 3.7 to 8.5 +/- 2.8 and 13.3 +/- 3.6 pmol/min/mg protein, respectively), returned to the preoperative level on day 3 (24.7 +/- 2.6 pmol/min/mg protein) and further elevated thereafter (71.4 +/- 10.9 on day 7 and 51.3 +/- 6.6 pmol/min/mg protein on day 14). The serum level of 7 alpha-hydroxycholesterol changed simultaneously with the enzyme activity, and a significant correlation between the two parameters was observed (r = 0.915, p < 0.0001). The correlations between the liver weight and hepatic cholesterol 7 alpha-hydroxylase activity and serum 7 alpha-hydroxycholesterol level were significant (p < 0.01), but the significances disappeared for the period of days 3-14 (r = 0.424, p = 0.08; r = 0.299, p = 0.228, respectively). In conclusion, hepatic cholesterol 7 alpha-hydroxylase activity is suppressed by hepatectomy and then activated as the liver regenerates. The serum 7 alpha-hydroxycholesterol level is a good parameter of this enzyme activity after partial hepatectomy. |
| Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice Mardones, P., V. Quinones, et al. (2001), J Lipid Res 42(2): 170-80. Abstract: The scavenger receptor class B type I (SR-BI), which is expressed in the liver and intestine, plays a critical role in cholesterol metabolism in rodents. While hepatic SR-BI expression controls high density lipoprotein (HDL) cholesterol metabolism, intestinal SR-BI has been proposed to facilitate cholesterol absorption. To evaluate further the relevance of SR-BI in the enterohepatic circulation of cholesterol and bile salts, we studied biliary lipid secretion, hepatic sterol content and synthesis, bile acid metabolism, fecal neutral sterol excretion, and intestinal cholesterol absorption in SR-BI knockout mice. SR-BI deficiency selectively impaired biliary cholesterol secretion, without concomitant changes in either biliary bile acid or phospholipid secretion. Hepatic total and unesterified cholesterol contents were slightly increased in SR-BI-deficient mice, while sterol synthesis was not significantly changed. Bile acid pool size and composition, as well as fecal bile acid excretion, were not altered in SR-BI knockout mice. Intestinal cholesterol absorption was somewhat increased and fecal sterol excretion was slightly decreased in SR-BI knockout mice relative to controls. These findings establish the critical role of hepatic SR-BI expression in selectively controlling the utilization of HDL cholesterol for biliary secretion. In contrast, SR-BI expression is not essential for intestinal cholesterol absorption. |
| Hepatic cholesterol and bile acid synthesis in Japanese patients with cholesterol gallstones Honda, A., T. Yoshida, et al. (1993), Gastroenterol Jpn 28(3): 406-14. Abstract: In Japan the composition of gallstones is changing rapidly from the once-predominant brown-pigment stones to cholesterol ones. The present work was undertaken to clarify the mechanism of cholesterol supersaturated bile production in Japanese patients with cholesterol gallstones. In 26 non-obese and normolipidemic patients (11 with cholesterol gallstones, 8 with black- or brown-pigment gallstones, 7 without gallstones) a liver biopsy and hepatic bile were surgically obtained under standardized conditions. The cholesterol saturation of hepatic bile was significantly higher in cholesterol gallstone patients than in gallstone-free controls (195 +/- 10 vs. 146 +/- 8%, respectively; P < 0.01). The microsomal activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis, cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme for bile acid synthesis, and 7 alpha-hydroxy-4-cholesten-3-one 12 alpha-hydroxylase (12 alpha-hydroxylase), the rate-limiting enzyme for cholic acid synthesis, were assayed simultaneously in the same subjects. There were positive correlations between HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities (Rs = 0.62, P < 0.005), and between cholesterol 7 alpha-hydroxylase and 12 alpha-hydroxylase activities (Rs = 0.44, P < 0.05) in all subjects, irrespective of the existence of gallstones. The activities of the three rate-limiting enzymes did not differ significantly among the three groups (cholesterol stone, pigment stone and stone-free). In conclusion, the cholesterol supersaturation of hepatic bile in nonobese and normolipidemic Japanese patients with cholesterol gallstones does not result from an increased hepatic cholesterol synthesis or a decreased bile acid synthesis. |
| Hepatic cholesterol and bile acid synthesis, low-density lipoprotein receptor function, and plasma and fecal sterol levels in mice: effects of apolipoprotein E deficiency and probucol or phytosterol treatment Moghadasian, M. H., L. B. Nguyen, et al. (2001), Metabolism 50(6): 708-14. Abstract: We compared hepatic cholesterol metabolism in apolipoprotein (apo) E-knockout (KO) mice with their wild-type counterparts. We also investigated the effects of treatment with phytosterols or probucol on the activity of hepatic 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase (cholesterol synthesis), cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase (bile acid synthesis), and low-density lipoprotein (LDL) receptor function in this animal model of atherogenesis. These findings were then related to treatment-induced changes in plasma, hepatic, and fecal sterol concentrations. Mouse liver membranes have binding sites similar to LDL receptors; the receptor-mediated binding represents 80% of total binding and is LDL concentration-dependent. These binding sites have higher affinity for apo E-containing particles than apo B only-containing particles. Deletion of apo E gene was associated with several-fold increases in plasma cholesterol levels, 1.5-fold increase in hepatic cholesterol concentrations, 50% decrease in HMG-CoA reductase activity, 30% increase in cholesterol 7 alpha-hydroxylase and 25% decrease in LDL receptor function. Treatment of apo E-KO mice with either probucol or phytosterols significantly reduced plasma cholesterol levels. Phytosterols significantly increased the activity of hepatic HMG-CoA reductase, and probucol significantly increased cholesterol 7 alpha-hydroxylase activity. Neither treatment significantly altered hepatic LDL receptor function. Phytosterols, but not probucol, significantly increased fecal sterol excretion and decreased hepatic cholesterol concentrations. Plasma cholesterol lowering effects of phytosterols and probucol are due to different mechanisms: stimulation of cholesterol catabolism via increased bile acid synthesis by probucol and decreased cholesterol absorption by phytosterols. In the absence of apo E, hepatic LDL receptors could not be upregulated and did not contribute to the cholesterol lowering effects of either agent. |
| Hepatic cholesterol and fatty acid synthesis in pregnant and fetal rats: effect of maternal dietary fat and cholestyramine Haave, N. C. and S. M. Innis (1991), J Nutr 121(10): 1529-35. Abstract: Previous studies from this laboratory have demonstrated that 20% rather than 5% (wt/wt) safflower oil or addition of 5% (wt/wt) cholestyramine to the diet of pregnant rats leads to an increase in the activity of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of cholesterol synthesis, in the fetal liver. Total cholesterol, however, was not altered in fetal plasma or liver. The effect of these diets on cholesterol and fatty acid synthesis in vivo was therefore studied in fetal and maternal liver. In fetuses of rats fed a reference nonpurified diet, rates of hepatic cholesterol and fatty acid synthesis decreased from gestation d 20 to 21. In contrast, total and active 3-hydroxy-3-methyl-glutaryl CoA reductase activity increased. Adding cholestyramine to the diet or modifying the quantity of safflower oil fed had no effect on fetal hepatic lipogenesis. Maternal hepatic cholesterol synthesis was greater in rats fed cholestyramine, whereas fatty acid synthesis was lower in the dams fed the diet containing 20% compared with 5% safflower oil. The results suggest near-term fetal liver 3-hydroxy-3-methylglutaryl CoA reductase activities do not reflect fetal cholesterol synthesis in vivo. |
| Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice Alberti, S., G. Schuster, et al. (2001), J Clin Invest 107(5): 565-73. Abstract: The nuclear oxysterol-receptor paralogues LXRalpha and LXRbeta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRalpha has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRbeta in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared their responses to dietary cholesterol. Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXRbeta(-/-) and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXRbeta(-/-) mice compared with LXRbeta(+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRbeta(-/-) mice - in contrast to LXRalpha(-/-) mice - maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXRbeta has no complete overlapping function compared with LXRalpha in the liver. |
| Hepatic cholesterol metabolism in cholesterol gallstone disease Reihner, E., B. Angelin, et al. (1991), J Lipid Res 32(3): 469-75. Abstract: Hepatic cholesterol metabolism was examined in 27 Swedish patients with cholesterol gallstone disease and in 13 patients free of gallstones operated for roentgenographically suspect polyps in the gallbladder. All 40 patients underwent cholecystectomy, and a liver biopsy and gallbladder bile were obtained at surgery. The cholesterol saturation of gallbladder bile was significantly higher in patients with gallstones compared to the gallstone-free controls (131 +/- 13 vs. 75 +/- 5%, P less than 0.001). Microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, governing cholesterol synthesis, did not differ between gallstone and gallstone-free patients (104 +/- 11 vs. and 109 +/- 22 pmol/min per mg protein, respectively). The activity of cholesterol 7 alpha-hydroxylase, catalyzing the catabolism of cholesterol to bile acids, was not significantly decreased in gallstone patients (6.2 +/- 1.1 vs. 8.0 +/- 2.0 pmol/min per mg protein). The capacity to esterify cholesterol, judged by the activity of acyl coenzyme A:cholesterol acyltransferase (ACAT), was similar in gallstone and gallstone-free patients (5.4 +/- 0.4 vs. 6.7 +/- 1.1 pmol/min per mg protein). In the presence of exogenous cholesterol, ACAT activity increased by more than fourfold in both groups. No correlation was found between the saturation of gallbladder bile and any of the mentioned enzyme activities in gallstone patients. It is concluded that distinct abnormalities in cholesterol metabolizing enzymes are not of major importance for development of gallstones in Swedish patients with cholesterol gallstone disease. The results support the contention that the etiology of cholesterol gallstones is multifactorial. |
| Hepatic cholesterol metabolism in estrogen-treated men Angelin, B., H. Olivecrona, et al. (1992), Gastroenterology 103(5): 1657-63. Abstract: Operative liver biopsies were obtained from two male patients who developed gallstone disease during estrogen treatment of metastatic prostatic carcinoma. The heparin-sensitive binding of 125I-low-density lipoprotein (LDL) to liver homogenates (reflecting the expression of the LDL receptor) was determined, together with the activities of the rate-limiting enzymes in cholesterol synthesis 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, bile acid production (cholesterol 7 alpha-hydroxylase), and cholesterol esterification (acyl CoA:cholesterol acyl transferase). The results were related to data available in 18 patients (5 male, 13 female) who underwent cholecystectomy because of gallstone disease. The hepatic 125I-LDL-binding activity was increased threefold compared with five controls, and the activity of HMG-CoA reductase was increased twofold. There was no major difference in the activities of cholesterol 7 alpha-hydroxylase or acyl CoA:cholesterol acyl transferase. The concentration of free and total cholesterol in liver microsomes was approximately 30% lower in the estrogen-treated men than in 11 controls. The results indicate that estrogen at pharmacological doses stimulates hepatic LDL-receptor expression and HMG-CoA reductase activity in men. The increased LDL-receptor expression could in part explain the enhanced plasma clearance of injected 125I-LDL and hence the reduction in plasma LDL cholesterol previously shown to occur in estrogen-treated men. |
| Hepatic cholesterol metabolism in experimental nephrotic syndrome al-Shurbaji, A., E. Humble, et al. (1998), Lipids 33(2): 165-9. Abstract: Hypercholesterolemia is a consistent feature of the nephrotic syndrome. However, the mechanisms underlying this perturbation are unclear. In the present work, we have investigated different factors that influence hepatic cholesterol metabolism using the nephrotic rat as a model. The induction of nephrosis resulted in a severe and sustained hypercholesterolemia. However, no effect on the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase, could be detected. Further, plasma lathosterol/cholesterol ratio, a measure of cholesterol synthesis, was not altered. Also, plasma levels of mevalonate, both a substrate for cholesterogenesis beyond the rate-limiting step and a marker for cholesterol synthesis, did not differ between control rats and those with established hypercholesterolemia. There was no detectable change in the expression of low density lipoprotein (LDL) receptor between the two experimental groups. We conclude that the early increase in cholesterol synthesis reported after the induction of nephrosis is not necessary for the maintenance of hypercholesterolemia. Established hypercholesterolemia of the nephrotic syndrome seems to represent a steady state in which neither enhanced hepatic cholesterol synthesis nor retarded LDL cholesterol clearance is of major importance. |