| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Hepatic cholesterol metabolism in human obesity Stahlberg, D., M. Rudling, et al. (1997), Hepatology 25(6): 1447-50. Abstract: Hepatic cholesterol metabolism was studied in operative liver biopsies from 17 morbidly obese subjects and compared with that in samples from 15 nonobese controls. The aim was to understand the mechanisms causing the hypersecretion of cholesterol into bile. The content of cholesteryl esters was increased threefold in the liver of obese subjects compared with that of the controls (P <.0001). The activity and the messenger RNA (mRNA) level of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate limiting enzyme for cholesterol synthesis, were higher in the obese subjects compared with the nonobese subjects (75% and 140%, respectively; P <.01). In the obese subjects, the activity and mRNA level of cholesterol 7alpha-hydroxylase, which regulates the catabolism of cholesterol to bile acids, were also increased by 140% (P <.05) and 180% (P =.06), respectively, as compared with the controls. There was a significant correlation between the activities and the mRNA levels of cholesterol 7alpha-hydroxylase among the obese subjects (r = +0.65, P <.01). The activities of acyl-coenzyme A:cholesterol acyltransferase (ACAT), which governs cholesteryl ester formation, in obese and nonobese patients were 12.5 +/- 1.7 and 8.1 +/- 1.2 pmol/min/mg protein, respectively (P <.05), and the low-density lipoprotein (LDL) receptor mRNA levels were 5.3 +/- 0.7 and 4.5 +/- 0.9 molecules of mRNA/microg of RNA, respectively. We conclude that the activities of three key enzymes in hepatic cholesterol metabolism were increased in morbidly obese subjects compared with nonobese controls, as were mRNA levels of HMG CoA reductase and cholesterol 7alpha-hydroxylase. The mRNA level of the LDL receptor in the obese subjects was not significantly changed. The hypersecretion of cholesterol occurring in obesity is neither due to a reduced conversion of cholesterol to bile acids nor to a decreased esterification of hepatic cholesterol but may be due to an increased synthesis of cholesterol. |
| Hepatic cholesterol metabolism in patients with cholesterol gallstones: enhanced intracellular transport of cholesterol Ito, T., S. Kawata, et al. (1996), Gastroenterology 110(5): 1619-27. Abstract: BACKGROUND & AIMS: Alterations of hepatic cholesterol metabolism in patients with cholesterol gallstones are still controversial. This study investigated whether hepatic cholesterol metabolism is altered in Japanese patients with cholesterol gallstones. METHODS: In this systematic study of 24 middle-aged nonobese and nondiabetic Japanese patients who had cholesterol gallstones and were undergoing elective cholecystectomy, an analysis of three regulatory enzymes in the cholesterol metabolism, as well as cytosolic total and free cholesterol levels and sterol carrier protein 2/nonspecific lipid transfer protein (SCP2/nsLTP) levels, was conducted using liver biopsy samples obtained during surgery. RESULTS: The activities of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, cholesterol 7 alpha-hydroxylase, and acyl-CoA/cholesterol acyltransferase were not significantly different between patients and controls. Nevertheless, patients with gallstones showed tendencies for elevated HMG-CoA reductase activity and protein content and decreased cholesterol 7 alpha-hydroxylase activities. As anticipated, serum levels of 7 alpha-hydroxycholesterol and squalene paralleled these findings. The patients with gallstones also had significantly increased cytosolic total and free cholesterol levels (P < 0.001), which correlated strongly with increased cytosolic levels of SCP2/nsLTP (r = 0.80, P < 0.001 and r = 0.81, P < 0.001, respectively). CONCLUSIONS: The results suggest that intracellular cholesterol transport is enhanced in patients with cholesterol gallstones. |
| Hepatic cholesterol synthesis and the secretion of newly synthesized cholesterol in bile Robins, S. J., J. M. Fasulo, et al. (1993), Biochem J 289 (Pt 1): 41-4. Abstract: To determine the effect of increased hepatic cholesterol synthesis on the secretion of newly synthesized cholesterol in bile, rats were fed with cholestyramine, a bile-acid-binding resin that increases the number of hepatocytes that synthesize cholesterol. Cholesterol synthesis was measured 15 min after 3Hwater injection to avoid appreciable exchange between the liver and serum of newly synthesized cholesterol that accumulates in the serum in studies of several hours duration. At 15 min after 3Hwater injection, the specific radioactivity of cholesterol in the liver and hepatic microsomes was greatly increased in resin-fed animals compared with controls. However, with resin, the specific radioactivity of newly synthesized cholesterol that was secreted in bile was the same as for controls. At 15 min after 3Hwater injection the specific radioactivity of serum cholesterol was minimally increased and not different in resin and control groups. In contrast, in studies that were longer than 60 min, newly synthesized cholesterol in serum was appreciably increased in resin-fed animals, and newly synthesized cholesterol in bile was also greatly increased compared with controls. Thus, when appreciable cholesterol exchange is avoided, an increase in hepatic cholesterol synthesis and the number of hepatocytes that synthesized cholesterol does not result in an increase in newly synthesized cholesterol in bile. Our results suggest that newly synthesized cholesterol is secreted in bile from a fixed subpopulation of hepatocytes. From a comparison of the specific radioactivity of newly synthesized cholesterol in whole liver and bile, it can be estimated that this subpopulation of hepatocytes represents about 20% of the total hepatocyte mass. |
| Hepatic cholesterol-acyltransferase activity on cholesterol supplementation in chronically fed alcohol and pair-fed control rats Venkatesan, S. and K. J. Simpson (1990), Biochem Soc Trans 18(6): 1191-2. |
| Hepatic esterification rate of cholesterol and biliary lipids in human obesity Sahlin, S., L. Granstrom, et al. (1994), J Lipid Res 35(3): 484-90. Abstract: Obesity is often associated with an increased hepatic secretion rate of cholesterol and saturated gallbladder bile. In order to evaluate the role of hepatic esterification of cholesterol in this phenomenon, we assayed the activity of acyl CoA:cholesterol acyl transferase (ACAT), which catalyzes the esterification of cholesterol, in liver microsomes obtained from 19 morbidly obese patients without gallstones undergoing vertical banded gastroplasty. Gallbladder bile was obtained and analyzed for lipid composition, cholesterol saturation, nucleation time, and occurrence of cholesterol crystals. Fourteen non-obese gallstone-free subjects undergoing cholecystectomy because of suspected polyp or adenomyoma in the gallbladder served as controls. The hepatic content of esterified cholesterol was increased by about 70% in the obese patients (P < 0.05). Still, the mean levels of the ACAT activity were equal in the obese and non-obese patient groups (11 +/- 1 and 11 +/- 2 pmol/min per mg protein, respectively). When exogenous cholesterol was added to the assay system, the activity was increased markedly in both groups. The ACAT activity was higher in obese patients with steatosis of the liver compared with those displaying normal liver morphology (12 +/- 1 vs 8 +/- 1 pmol/min per mg, P < 0.05). Obese patients did not have significantly more saturated gallbladder bile than the non-obese controls (84 +/- 7 and 77 +/- 8%, respectively). They had a normal nucleation time and their gallbladder bile did not contain any cholesterol crystals. We conclude that obese patients without gallstones usually have a normal esterification rate of cholesterol in the liver. Steatosis of the liver was associated with increased ACAT activity.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Hepatic expression of apolipoprotein E inhibits progression of atherosclerosis without reducing cholesterol levels in LDL receptor-deficient mice Tsukamoto, K., R. K. Tangirala, et al. (2000), Mol Ther 1(2): 189-94. Abstract: Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liver and by tissue macrophages. Plasma apoE (derived primarily from the liver) regulates plasma lipoprotein metabolism, but macrophage-derived apoE was shown to slow the progression of atherosclerosis independent of plasma lipid levels. We utilized liver-directed gene transfer to test the hypothesis that hepatic expression of human apoE would inhibit atherogenesis even in a model in which apoE expression has little effect on plasma lipoproteins. LDL receptor-deficient mice fed a western-type diet for 5 weeks were injected with a second-generation recombinant adenovirus encoding human apoE3 or control virus. Plasma cholesterol levels were not significantly different in the two groups of mice after virus injection. Four weeks after injection, atherosclerosis was examined using three independent assays. Expression of apoE was associated with significantly reduced atherosclerosis compared with control mice in both the aortic arch (decreased by 43%) and the aortic root (decreased by 59%). In summary, hepatic overexpression of apoE inhibited progression of atherosclerosis in LDL receptor-deficient mice without reducing plasma cholesterol levels. This finding indicates that liver-derived plasma apoE can influence early atherogenesis through mechanisms other than modulation of lipoprotein metabolism and that liver-directed gene transfer and overexpression of apoE may be a therapeutic approach to atherosclerosis. |
| Hepatic HMG-CoA reductase expression and resistance to dietary cholesterol Ness, G. C. and K. R. Gertz (2004), Exp Biol Med (Maywood) 229(5): 412-6. Abstract: The premise that the intrinsic level of expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase determines the relative sensitivity to the serum cholesterol raising action of dietary cholesterol was examined in 9 strains of rat. For further comparison purposes, hamsters were also examined. The basal expression of hepatic HMG-CoA reductase, extent of feedback regulation by cholesterol, and changes in serum cholesterol levels and the hepatic low-density lipoprotein (LDL) receptor in response to cholesterol challenge were determined in these animals. The Sprague-Dawley, Wistar-Furth, Spontaneously Hypertensive, Lewis, and Wistar-Kyoto rats were all very resistant to dietary cholesterol and exhibited hepatic HMG-CoA reductase activities above 150 pmol / min(-1) / mg(-1). The Buffalo, Brown Norway, and Copenhagen 2331 rats had hepatic HMG-CoA reductase activities below 90 pmol / min(-1) / mg(-1) and had increases in serum cholesterol levels ranging from 12 to 33 mg/dl when given a 4-day, 1% cholesterol challenge. The extent of feedback regulation was reduced to only 3-fold in the Fisher 344 and Brown Norway rats that exhibited significant increases in serum cholesterol levels when given a cholesterol challenge. The Golden Syrian hamsters exhibited the largest increase (197 mg/dl) in serum cholesterol levels in response to dietary cholesterol and the lowest basal expression of hepatic HMG-CoA reductase (3.3 pmol / min(-1) / mg(-1)). Hepatic LDL receptor levels were not significantly decreased by dietary cholesterol in any of the animals. The data from these inbred rats and the hamsters strongly support the conclusion that the animals expressing the highest levels of hepatic HMG-CoA reductase are the most resistant to the serum cholesterol raising action of dietary cholesterol. |
| Hepatic lipase C-480T polymorphism modifies the effect of HDL cholesterol on the risk of acute myocardial infarction in men: a prospective population based study Fan, Y. M., J. T. Salonen, et al. (2004), J Med Genet 41(3): e28. |
| Hepatic lipase deficiency increases plasma cholesterol but reduces susceptibility to atherosclerosis in apolipoprotein E-deficient mice Mezdour, H., R. Jones, et al. (1997), J Biol Chem 272(21): 13570-5. Abstract: The effect of hepatic lipase (HL) deficiency on the susceptibility to atherosclerosis was tested using mice with combined deficiencies in HL and apoE. Mice lacking both HL and apoE (hhee) have a plasma total cholesterol of 917 +/- 252 mg/dl (n = 24), which is 184% that of mice lacking only apoE (HHee; 497 +/- 161 mg/dl, n = 20, p < 0. 001). The increase in cholesterol was mainly in beta-migrating very low density lipoproteins, although high density lipoprotein cholesterol (HDLc) was also increased (53 +/- 37 versus 20 +/- 13 mg/dl, p < 0.01). Despite the increase in plasma cholesterol, we found that HL deficiency significantly decreased aortic plaque sizes in female mice fed normal chow (31 x 10(3) +/- 22 x 10(3) microm2 in hhee versus 115 x 10(3) +/- 69 x 10(3) microm2 in HHee, p < 0.001). Reduction of plaque sizes was also observed in female heterozygous apoE-deficient mice fed an atherogenic diet (2 x 10(3) +/- 2.5 x 10(3) microm2 in hhEe versus 56 x 10(3) +/- 49 x 10(3) microm2 in HHEe, p < 0.01). Changes in aortic lesion size were not apparent in the small number of male mice studied. In HHee females, both HDLc and the capacity of high density lipoprotein (HDL) particles to promote cholesterol efflux from cultured cells were 26% of the wild type. The absence of HL in hhee females partially restored HDLc levels to 57% and cholesterol efflux to 55% of the wild type. Circulating pre-beta1-migrating HDL were present in all mutants, suggesting that there are alternative pathways in the formation of these pre-beta-HDL not involving apoE, HL, or cholesteryl ester transfer protein. The improved capacity to promote cholesterol efflux, together with increased HDL, may explain why these animals can overcome the increase in atherogenic lipoproteins. |
| Hepatic lipase function and the accumulation of beta-very-low-density lipoproteins in the plasma of cholesterol-fed rabbits Chang, S. and J. Borensztajn (1993), Biochem J 293 (Pt 3): 745-50. Abstract: The accumulation of cholesterol-rich beta-very-low-density lipoproteins (beta-VLDL) in the plasma of rabbits fed on a high-fat high-cholesterol diet is due to a defect in the clearance of these lipoprotein remnants from circulation by the liver. In view of the evidence that hepatic lipase participates in the process of rapid removal of remnants from circulation, and considering that rabbits are naturally deficient in hepatic lipase, we examined whether this defect in the clearance of beta-VLDL could be reversed by exogenous hepatic lipase. We report that treatment in vitro of 3Hcholesterol-labelled beta-VLDL, or rat chylomicrons, with hepatic lipase resulted in the formation of particles that were rapidly cleared from circulation by the liver when injected intravenously into hypercholesterolaemic rabbits. These results are consistent with the notion that, in addition to the well-established requirement for lipoprotein lipase activity, the generation of remnants capable of being efficiently taken up by the liver also requires the action of hepatic lipase. Lipoprotein lipase acts on triacylglycerol-rich lipoproteins to transform them into particles (remnants) which bind to the surface of liver cells, where they become accessible to hepatic lipase. Hepatocyte endocytosis of these remnants occurs only after further modification by hepatic lipase. According to this scheme, the results presented suggest that the accumulation of beta-VLDL in the circulation of rabbits fed on a high-fat high-cholesterol diet is the result of the saturation of the available hepatic lipase by abnormally high levels of lipoprotein-lipase-generated chylomicron remnants. |
| Hepatic lipase mutations,elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: the Copenhagen City Heart Study Andersen, R. V., H. H. Wittrup, et al. (2003), J Am Coll Cardiol 41(11): 1972-82. Abstract: OBJECTIVES: We investigated associations between single nucleotide polymorphisms (SNPs) in the hepatic lipase promoter, levels of high-density lipoprotein (HDL), and risk of ischemic heart disease (IHD). Our primary hypothesis was that these SNPs associate with IHD after adjustment for HDL levels. BACKGROUND: Hepatic lipase influences HDL metabolism, and may thus affect reverse cholesterol transport and consequently risk of IHD. METHODS: We genotyped 9,121 white subjects aged 20 to 93 years from the Copenhagen City Heart Study, 456 of whom had incident IHD, as well as 921 Danish patients with IHD for the -216, -480, and -729 SNPs in the hepatic lipase promoter. RESULTS: Frequencies of wild-type, triple heterozygotes, and triple mutation homozygotes in the general population were 61%, 33%, and 5%, respectively. Compared with wild-type, HDL cholesterol levels were 4% (0.06 mmol/l) and 10% (0.15 mmol/l) higher in heterozygotes and mutation homozygotes; the equivalent values for apolipoprotein A1 were 3% and 7% higher. In prospective and case-control studies, mutation homozygotes versus wild-type had relative risk (RR) and odds ratio (OR) for IHD of 1.5 (95% confidence interval CI: 1.0 to 2.2) and 1.4 (CI: 1.1 to 1.9) when adjusted for age, gender, and HDL cholesterol. In individuals with the epsilon43 apolipoprotein E genotype, RR and OR for IHD in mutation homozygotes versus wild-type was 2.9 (CI: 1.5 to 5.6) and 2.0 (CI: 1.2 to 3.2). CONCLUSIONS: Hepatic lipase promoter SNPs are associated with increased HDL cholesterol and, paradoxically, an increased risk of IHD after adjustment for HDL cholesterol, and particularly in individuals with apolipoprotein E epsilon43 genotype. Implications are that increased HDL levels may in certain situations be not protective, but rather associated with increased IHD risk. |
| Hepatic lipase promoter C-514T polymorphism influences serial changes in HDL cholesterol levels since childhood: the Bogalusa Heart Study Chen, W., S. R. Srinivasan, et al. (2003), Atherosclerosis 169(1): 175-82. Abstract: Hepatic lipase (HL) is an important determinant of high-density lipoprotein (HDL) concentrations. A common C-to-T substitution at position -514 of the promoter region of the HL gene has been shown to be associated with HL activity and HDL cholesterol (HDL-C) levels. The current study examines the influence of this polymorphism on both levels and serial changes of HDL-C from childhood to adulthood in a community-based sample of 707 white and 291 black unrelated individuals aged 4-38 years using a repeated measures analysis. The frequency of the -514T allele was lower in whites than in blacks (0.228 vs. 0.545, P<0.001). After adjusting for age and BMI, the genotype effect on longitudinal profiles of HDL-C levels was significant (P=0.003) in white males with values in the order of T/T>T/C>C/C. Although a similar trend was seen, the genotype effect was not significant in white females and blacks. Further, the slopes of the age trajectories of HDL-C were similar in three genotype groups in blacks and whites. A sex-genotype interaction effect (P=0.043) on longitudinal profiles of HDL-C levels was found in whites, but not in blacks. White males showed a stronger genotype effect (3.6 mg/dl, P=0.003) than white females (0.5 mg/dl, P=0.601). Thus, the -514T variant of the HL gene is consistently associated with higher levels of HDL-C longitudinally since childhood, but not with rate of change over time. These results suggest that the HL gene may play an important role in the regulation of HDL-C levels from childhood to adulthood, especially in white males. |
| Hepatic lipase promotes the uptake of HDL esterified cholesterol by the perfused rat liver: a study using reconstituted HDL particles of defined phospholipid composition Marques-Vidal, P., C. Azema, et al. (1994), J Lipid Res 35(3): 373-84. Abstract: The role of hepatic triacylglycerol lipase (H-TGL) in promoting the liver uptake of high density lipoprotein (HDL) free and esterified cholesterol was studied in a recirculating rat liver perfusion, a situation where the enzyme is physiologically expressed and is active at the vascular bed. For this purpose, reconstituted HDL of defined phospholipid composition were prepared, containing either 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, a substrate for H-TGL, or 1-O-hexadecyl-2-oleoyl-sn-glycero-3-phosphocholine, a non-hydrolyzable analog. Reconstituted HDL were then used in the perfused rat liver system. The main results are the following. 1) Reconstituted HDL were obtained by sonication of lipids and apolipoproteins and isolated by ultracentrifugation in the 1.07-1.21 g/ml density interval. Reconstituted HDL containing either diacylphosphatidylcholine or alkyl-acyl-phosphatidylcholine were similar in terms of chemical composition, apparent size, and apolipoprotein A-I immunoreactivity, and were comparable to native HDL3. 2) Reconstituted HDL were labeled with free 14Ccholesterol and 3Hcholesteryl ether, a non-hydrolyzable tracer of esterified cholesterol, and were perfused through the rat liver. Liver uptake of 3Hcholesteryl ether was 2.5-fold higher from reconstituted HDL containing diacylphospholipid than from HDL reconstituted with alkyl-acyl-phospholipids. Liver uptake of free 14Ccholesterol was identical in both cases. 3) H-TGL-depleted rat livers were obtained by a 12-min preperfusion in the presence of heparin, displacing 90% of the enzymatic activity. The residual activity in the perfusate was inhibited by a specific antibody directed against rat H-TGL. Liver uptake of 3Hcholesteryl ether from reconstituted HDL containing diacylphospholipid was reduced by 35% in hepatic lipase-depleted livers compared to controls. On the other hand, hepatic lipase depletion had no effect on the liver uptake of esterified cholesterol from HDL reconstituted with alkyl-acyl-phospholipids. The above findings support a role for the phospholipase A1 activity of H-TGL in stimulating the delivery of HDL esterified cholesterol to liver cells. |
| Hepatic lipase secretion in human hepatoblastoma cell line Hep G2 is not related to cellular cholesterol homeostasis Berg, A. L., C. H. Floren, et al. (1995), Horm Metab Res 27(12): 523-6. Abstract: The human hepatoblastoma cell line Hep G2 releases the enzyme hepatic lipase during incubation with heparin. In this study, hepatic lipase activity was released by low concentrations of heparin, and the release was linear with time for up to about 10 hours. Preincubations of cells with LDL or compactin induced marked but differential changes in hepatic lipase secretion, cellular cholesterol content and low density lipoprotein receptor activity, suggesting that the secretion of hepatic lipase is regulated independently of cholesterol homeostasis. |
| Hepatic lipogenesis and cholesterol synthesis in hyperthyroid patients Cachefo, A., P. Boucher, et al. (2001), J Clin Endocrinol Metab 86(11): 5353-7. Abstract: To determine the effect of hyperthyroidism on hepatic lipogenesis and cholesterol synthesis we measured these metabolic pathways (deuterated water method) in euthyroid and hyperthyroid subjects investigated in the postabsorptive state. Hyperthyroid patients had increased concentrations of glucose (P < 0.05), insulin (P < 0.05), nonesterified fatty acids (P < 0.01), and triglycerides (P < 0.05) and decreased levels of plasma cholesterol (P < 0.01). The contribution of hepatic lipogenesis to plasma triglycerides was largely increased in hyperthyroid subjects (23.0 +/- 1.8% vs. 7.5 +/- 0.2%; P < 0.001), whereas the fractional synthetic rate of cholesterol was moderately higher (5.0 +/- 0.8% vs. 3.3 +/- 0.2%; P < 0.05). mRNA levels of beta-hydroxy-beta-methyl glutaryl-coenzyme A reductase, measured in circulating mononuclear cells, were increased (P < 0.05), whereas those of low density lipoprotein (LDL) receptor and LDL receptor-related protein were unchanged. Sterol responsive element binding protein-1c mRNAs were undetectable in mononuclear cells from both groups of subjects. The large stimulation of hepatic lipogenesis in hyperthyroid patients is probably explained by both a direct action of thyroid hormones and the increase in insulin. It could contribute to their moderate rise in triglycerides levels. The decreased plasma cholesterol level is observed despite an enhanced synthetic rate and is thus related to an increased clearance rate. The lack of increased expression of LDL receptor and LDL receptor-related protein suggests that other receptors are implicated. |
| Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol Espirito Santo, S. M., N. M. Pires, et al. (2004), Blood 103(10): 3777-82. Abstract: The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre(+)LRP(flox/flox)LDLR(-/-)APOE(-/-)). On an LDLR(-/-)APOE(-/-) background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 +/- 5.2 vs 23.4 +/- 6.3 mM, P =.025; triglycerides: 1.1 +/- 0.5 vs 2.2 +/- 0.8 mM, P =.002, for MX1Cre(+)LRP(flox/flox)-LDLR(-/-)APOE(-/-) and control LRP(flox/flox)-LDLR(-/-)APOE(-/-) mice, respectively). Lower plasma cholesterol in MX1Cre(+)LRP(flox/flox)-LDLR(-/-)APOE(-/-) mice coincided with increased plasma lipoprotein lipase (71.2 +/- 7.5 vs 19.1 +/- 2.4 ng/ml, P =.002), coagulation factor VIII (4.4 +/- 1.1 vs 1.9 +/- 0.5 U/mL, P =.001), von Willebrand factor (2.8 +/- 0.6 vs 1.4 +/- 0.3 U/mL, P =.001), and tissue-type plasminogen activator (1.7 +/- 0.7 vs 0.9 +/- 0.5 ng/ml, P =.008) compared with controls. Strikingly, MX1Cre(+)LRP(flox/flox)LDLR(-/-)APOE(-/-) mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408.5 +/- 115.1 vs 219.1 +/- 86.0 10(3)microm(2), P =.003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands. |
| Hepatic metabolism of cholesterol Garcia Mediavilla, V., J. E. Bayon Darkistade, et al. (1996), Nutr Hosp 11(1): 37-42. Abstract: Cholesterol is an essential component of all tissues, as it is a part of the structure of cell membranes, and it is an immediate precursor of a series of essential substances such as vitamins, steroid hormones, and bile acids. Under physiologic conditions, the intake and output of cholesterol in the organism is coordinated and balanced with the aim of guaranteeing the availability of adequate amounts of cholesterol to satisfy the needs of the different tissues (fig. 1). Under pathological conditions there is an imbalance between these mechanism, which leads to an increase in the circulating levels of cholesterol, leading to pathological processes such as hyperlipemias, atherosclerosis and bile stones. The liver plays a central role in the regulation of the homeostasis of cholesterol. The molecule enters the liver in the form of chylomicrons and low density lipoproteins (LDL), through lipoprotein receptors, and this is also the most important organ for the de novo biosynthesis of cholesterol from acetyl coenzyme A, by means of a cascade enzyme reaction in which the enzyme 3-hydroxy-3 methyl glutaryl CoA reductase (HMG-CoA) is the key of the entire process. Cholesterol is found in the liver in the form of cholesterol esters or as free cholesterol. The two most effective ways of eliminating body cholesterol are found in the liver, with the degradation of the compound to bile acids and the biliary secretion of cholesterol. The conversion to bile acids takes place through a series of enzymatic steps in which the formation of 7-alpha-hydroxycholesterol by the enzyme cholesterol 7-alpha-hydroxylase is the key of the process. The biliary secretion of cholesterol is 600 mg/day. Both the abundance and the universality of cholesterol in living things as its clinical implications emphasize the importance and interest of this compound. |
| Hepatic metabolism of cholesterol in Crohn's disease. Effect of partial resection of ileum Akerlund, J. E., E. Reihner, et al. (1991), Gastroenterology 100(4): 1046-53. Abstract: To study cholesterol metabolism in Crohn's disease and especially the effect of ileum resection, liver biopsy specimens were obtained from patients undergoing partial ileal resection because of Crohn's disease (n = 17) and patients with Crohn's colitis undergoing colectomy (n = 3). Gallstone-free patients (n = 16) undergoing cholecystectomy because of adenomyomas or polyps of the gallbladder served as controls. The mean levels of cholesterol 7 alpha-hydroxylase activity and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, rate-determining enzymes in bile acid, and cholesterol synthesis, respectively, were twofold to threefold higher in the ileum-resected patients than in the controls. Significant positive correlations were obtained between length of resected ileum and cholesterol 7 alpha-hydroxylase activity. Provided patients who had received total parenteral nutrition preoperatively were excluded from analysis, a significant correlation was also observed between length of resected ileum and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Significant positive correlations were also obtained between length of resected ileum and serum levels of 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) and lathosterol (a marker for cholesterol synthesis). The plasma levels of total and low-density lipoprotein cholesterol were negatively correlated to the length of resected ileum. The expression of hepatic low-density lipoprotein-receptor binding activity was determined in five of the patients and in three of the controls. A significant positive correlation was observed between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein-receptor binding activity. The results show that malabsorption of bile acids leads to parallel stimulation of cholesterol synthesis, cholesterol degradation, and low-density lipoprotein-receptor expression in human liver. The resulting effect in the present patients was a significant reduction in low-density lipoprotein cholesterol. |
| Hepatic microsomal triglyceride transfer protein messenger RNA concentrations are increased by dietary cholesterol in hamsters Bennett, A. J., J. S. Bruce, et al. (1996), FEBS Lett 394(3): 247-50. Abstract: In hamsters fed high fat diets enriched in trimyristin, tripalmitin or tristearin, increased dietary cholesterol content was associated with increased plasma concentrations of very low density lipoprotein (VLDL) cholesterol and triacylglycerol (p < 0.0001 and p = 0.0017, respectively). Hepatic microsomal triglyceride transfer protein (MTP) mRNA concentration also increased (p < 0.0001), independent of the nature of dietary fat, and was significantly correlated with the plasma VLDL lipid concentrations (p = 0.0002 and p = 0.0106 for cholesterol and triacylglycerol, respectively) and hepatic cholesterol concentrations. Increased expression of the MTP gene may be part of a coordinated response to hepatic cholesterol accumulation leading to increased VLDL lipid secretion. |
| Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile Ji, Y., N. Wang, et al. (1999), J Biol Chem 274(47): 33398-402. Abstract: The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptor-mediated. Based on our finding that scavenger receptor BI (SR-BI) promotes free cholesterol (FC) exchange between high density lipoprotein (HDL) and cells, we tested whether SR-BI would effect FC movement in vivo using (14)CFC- and (3)Hcholesteryl ester (CE)-labeled HDL in mice with increased (SR-BI transgenic (Tg)) or decreased (SR-BI attenuated (att)) hepatic SR-BI expression. The initial clearance of HDL FC was increased in SR-BI Tg mice by 72% and decreased in SR-BI att mice by 53%, but was unchanged in apoA-I knockout mice compared with wild-type mice. Transfer of FC to non-HDL and esterification of FC were minor and could not explain differences. The hepatic uptake of FC was increased in SR-BI Tg mice by 34% and decreased in SR-BI att mice by 22%. CE clearance and uptake gave similar results, but with much slower rates. The uptake of HDL FC and CE by SR-BI Tg primary hepatocytes was increased by 2.2- and 2.6-fold (1-h incubation), respectively, compared with control hepatocytes. In SR-BI Tg mice, the initial biliary secretion of (14)CFC was markedly increased, whereas increased (3)HFC appeared after a slight delay. Thus, in the mouse, a major portion of the clearance of HDL FC from plasma is mediated by SR-BI. |