Hepatic 3-hydroxy-3-methylglutaryl-CoA Research Articles

Berberine attenuates inflammation and oxidative stress and modulates lymphocyte E-NTPDase in acute hyperlipidemia.

Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductasein P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6,IL-1β, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR towardLPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation.

Eugenol Reduces LDL Cholesterol and Hepatic Steatosis in Hypercholesterolemic Rats by Modulating TRPV1 Receptor

Eugenol, a component of essential oils of medicinal and food plants, has a hypolipidemic effect in experimental animals although its mechanism of action is still unclear. This study aims to explore the mechanism of the hypolipidemic effect of eugenol in rats fed a high cholesterol and fat diet (HCFD). Eugenol significantly reduced total cholesterol (TC), low-density lipoproteins (LDL), atherogenic index (AI) but not high-density lipoproteins (HDL) or triglycerides (TG). Eugenol also decreased steatosis and hepatic inflammation in liver sections, decreased hepatomegaly, and the hepatic marker enzymes alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity and increased the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) activity in hypercholesterolemic rats. Eugenol did not inhibit hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase but caused down-regulation of transient receptor potential vanilloid (TRPV1) channels in the liver. Docking simulation using fast, rigid exhaustive docking (FRED) software indicated a tail-up/head-down interaction of eugenol with TRPV1 channel. Data indicate that eugenol does not inhibit HMG-CoA reductase but rather induces its action by interaction with TRPV1 channels.

Consortia of bioactives in supercritical carbon dioxide extracts of mustard and small cardamom seeds lower serum cholesterol levels in rats: new leads for hypocholesterolaemic supplements from spices.

Melatonin-rich and 1,8-cineole-rich extracts have been successfully obtained from yellow mustard (YM) and small cardamom (SC) seeds, respectively, employing green technology of supercritical CO2 (SC-CO2) extraction. Chemical profiling confirmed the presence of melatonin and 1,8-cineole and co-extractants in the respective extracts. Electron paramagnetic resonance spectroscopy attested strong antioxidant activities of the extracts foregoing pan-assay interference compounds involved in spectroscopic analysis. These extracts also exhibited synergistic efficacies greater than unity confirming antioxidant synergy among the co-extracted bioactives therein. To ascertain hypocholesterolaemic efficacies, these extracts were co-administered orally with Triton X (at the pre-optimised dose of 175 mg/kg body weight (BW)) to Wistar albino rats at doses of 550, 175 and 55 mg/kg BW. Serum total cholesterol levels in the rats were monitored on days 3, 7, 15 and 21. On day 21, total cholesterol level reduced appreciably by 49·44 % in rats treated with YM seed extract and by 48·95 % in rats treated with SC seed extract, comparable with atorvastatin-administered rats (51·09 %). Either extract demonstrated inhibitory effects on hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity. A molecular docking exercise identified specific compounds in the extracts which possessed binding affinities comparable with therapeutically used HMG-CoA reductase inhibitors. In silico and in vivo studies concertedly concluded that the consortium of bioactive components in the extracts cannot be considered as invalid metabolic panaceas and therefore these 'green' extracts could be safely subjected to clinical studies as preventive biotherapeutics for hypercholesterolaemia. These extracts could be consumed per se as hypocholesterolaemic supplements or could be ingredients of new spice-based therapeutic foods.

Cholesterol-lowering activity of sesamin is associated with down-regulation on genes of sterol transporters involved in cholesterol absorption.

Sesame seed is rich in sesamin. The present study was to (i) investigate the plasma cholesterol-lowering activity of dietary sesamin and (ii) examine the interaction of dietary sesamin with the gene expression of sterol transporters, enzymes, receptors, and proteins involved in cholesterol metabolism. Thirty hamsters were divided into three groups fed the control diet (CON) or one of two experimental diets containing 0.2% (SL) and 0.5% (SH) sesamin, respectively, for 6 weeks. Plasma total cholesterol (TC) levels in hamsters given the CON, SL, and SH diets were 6.62 ± 0.40, 5.32 ± 0.40, and 5.00 ± 0.44 mmol/L, respectively, indicating dietary sesamin could reduce plasma TC in a dose-dependent manner. Similarly, the excretion of total fecal neutral sterols was dose-dependently increased with the amounts of sesamin in diets (CON, 2.65 ± 0.57; SL, 4.30 ± 0.65; and SH, 5.84 ± 1.27 μmol/day). Addition of sesamin into diets was associated with down-regulation of mRNA of intestinal Niemann-Pick C1 like 1 protein (NPC1L1), acyl-CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP-binding cassette transporters subfamily G members 5 and 8 (ABCG5 and ABCG8). Results also showed that dietary sesamin could up-regulate hepatic cholesterol-7α-hydroxylase (CYP7A1), whereas it down-regulated hepatic 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase and liver X receptor alpha (LXRα). It was concluded that the cholesterol-lowering activity of sesamin was mediated by promoting the fecal excretion of sterols and modulating the genes involved in cholesterol absorption and metabolism.

Algal Sterols are as Effective as β-Sitosterol in Reducing Plasma Cholesterol Concentration

The present study examined the cholesterol-lowering activity of sterol extract (SE) derived from alga Schizochytrium sp. and its interaction with gene expression of transporters, receptors, and enzymes involved in cholesterol absorption and metabolism. GC-MS analyses found that SE was a mixture of various sterols including lathosterol, ergosterol, stigmasterol, 24-ethylcholesta-5,7,22-trienol, stigmasta-7,24(24(1))-dien-3β-ol, and cholesterol. Results showed that SE at doses of 0.06 and 0.30 g/kg diet were able to decrease plasma cholesterol concentration by 19.5 and 34%, respectively, compared with the control, in hamsters maintained on a 0.1% high-cholesterol diet. SE at a dose of 0.30 g/kg diet was as effective as β-sitosterol in reducing plasma total cholesterol (TC). SE-induced reduction in plasma TC was accompanied by down-regulation of intestinal acyl-CoA:cholesterol acyltransferase 2 (ACAT2) and hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and up-regulation of hepatic low-density lipoprotein (LDL) receptor. Addition of SE to the diet increased the excretion of total fecal sterols. It was concluded that SE possessed the same cholesterol-lowering activity as β-sitosterol and the underlying mechanisms were mediated by increasing sterol excretion and decreasing cholesterol absorption and synthesis.

Microalga Decreases Plasma Cholesterol by Down-regulation of Intestinal NPC1L1, Hepatic LDL Receptor, and HMG-CoA Reductase

The present study examined the cholesterol-lowering activity of algal powder (AP), algal lipids (AL), and algal residue (AR) and their interaction with genes of transporters, receptors, and enzymes involved in cholesterol absorption and metabolism. In this experiment, 48 hamsters were fed either control diet or one of the three experimental diets containing 2% AP, 1.0% AL, or 1.0% AR for 6 weeks. Plasma total cholesterol (TC) and non-high-density-lipoprotein-cholesterol (non-HDL-C) were significantly decreased in the AP and AL groups but not in the AR group compared with those in the control hamsters. It was found that the cholesterol-lowering activity of AP and AL was associated with down-regulation of hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, low-density lipoprotein receptor (LDLR), and intestinal Niemann-Pick C1-like 1 (NPC1L1) transporter. It was concluded that the alga possessed the cholesterol-lowering activity and its lipids were the active ingredients. The mechanisms underlying the cholesterol-lowering activity of algae were mediated most likely by increasing the sterol excretion and decreasing the cholesterol absorption and synthesis.

Study on the hypochlolesterolemic and antioxidative effects of tyramine derivatives from the root bark ofLycium cheneseMiller

The aim of the present study was to investigate the hypocholesterolemic effect and potential of tyramine derivatives from Lycii Cortex Radicis (LCR), the root bark of lycium (Lycium chenese Miller) in reducing lipid peroxidation. The activities of enzymes, hepatic 3-hydroxy 3-methylglutaryl (HMG) CoA reductase and acyl-CoA:cholesterol acyltransferase (ACAT) and LDL oxidation were measured in vitro and animal experiments were also performed by feeding LCR extracts to rats. The test compounds employed for in vitro study were trans-N-p-coumaroyltyramine (CT) and trans-N-feruloyltyramine (FT), LCR components, N-(p-coumaroyl)serotonin (CS) and N-feruloylserotonin (FS) from safflower seeds, ferulic acid (FA) and 10-gingerol. It was observed that FT and FS at the concentration of 1.2 mg/mL inhibited liver microsomal HMG CoA reductase activity by ~40%, but no inhibition of activity was seen in the cases of CT, CS, FA and 10-gingerol. Whereas, ACAT activity was inhibited ~50% by FT and CT, 34-43% by FS and CS and ~80% by 10-gingerol at the concentration of 1 mg/mL. A significant delay in LDL oxidation was induced by CT, FT, and 10-gingerol. For the animal experiment, five groups of Sprague-Dawley male rats were fed high fat diets containing no test material (HF-control), 1 and 2% of LCR ethanol extract (LCR1 and LCR2), and 1% of extracts from safflower seed (Saf) and ginger (Gin). The results indicated that total cholesterol level was significantly lower in Saf, LCR2 and Gin groups, and HDL cholesterol level was lower only in Gin group when compared with HF-control group; while there was no difference in the serum triglyceride levels among the five experimental groups. The level of liver cholesterol was significantly lower in LCR1 and LCR2 groups than HF-control. Serum levels of TBARS were significantly lower only in LCR2 group when compared with HF-control group. From the observed results, we concluded that LCR can be utilized as a hypocholesterolemic ingredient in combination with ginger, especially for functional foods.

Effect of Fermented Bean Paste on Serum Lipids in Rats Fed a Cholesterol-Free Diet

We examined the effects of fermented bean pastes derived from bean vinegar by-products on serum cholesterol in rats. The rats were fed boiled paste from adzuki (A), kintoki (K), or tebou (T), or fermented paste from adzuki (AP), kintoki (KP), or tebou (TP) for 4 weeks. The serum non-high-density lipoprotein (HDL) cholesterol levels in all the experimental groups, except for A group, were significantly lower than in the control (CN) group. Likewise, the serum triglyceride levels in K and all the fermented bean groups were significantly lower than in the CN group. The levels of hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase mRNA in all the experimental groups except for A were significantly lower than in the CN group. These findings indicate that fermented bean pastes also suppress cholesterol synthesis, resulting in a reduced serum cholesterol concentration. These effects might be related not only to the resistant starch but also to the protein or peptide in the fermented bean paste.

Cinnamate supplementation enhances hepatic lipid metabolism and antioxidant defense systems in high cholesterol-fed rats.

This study investigated the effect of cinnamate, a phenolic compound found in cinnamon bark and other plant materials, on lipid metabolism and antioxidant enzyme activities in rats fed a high cholesterol diet. Three groups of rats were given a diet containing 1 g of cholesterol/kg for 6 weeks. The control group only received the high cholesterol diet, whereas the other two groups received a diet supplemented with lovastatin or cinnamate (0.1 g/100 g of diet). The plasma high-density lipoprotein-cholesterol levels were significantly higher in the cinnamate group than in either the control or lovastatin groups, and the atherogenic index was significantly lower in rats with cinnamate supplementation. Supplementation with cinnamate resulted in significantly lower hepatic cholesterol and triglyceride levels. Accumulation of hepatic lipid droplets was higher in the control group than in the rats supplemented with either cinnamate or lovastatin. Hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was significantly lower in the cinnamate group compared with the other groups, whereas only acyl-CoA:cholesterol acyltransferase activity was significantly lower in the lovastatin group compared with the control group. Cinnamate supplementation resulted in higher catalase and glutathione peroxidase activities, while hepatic thiobarbituric acid-reactive substances were significantly lower in both the cinnamate and lovastatin groups. The fecal acidic sterol was higher in the lovastatin group than in the control or cinnamate groups. These results suggest that dietary cinnamate inhibits hepatic HMG-CoA reductase activity, resulting in lower hepatic cholesterol content, and suppresses lipid peroxidation via enhancement of hepatic antioxidant enzyme activities.

The Hypocholesterolemic Effect of High Amylose Cornstarch in Rats Is Mediated by an Enlarged Bile Acid Pool and Increased Fecal Bile Acid Excretion, Not by Cecal Fermented Products

Sham-operated and cecectomized rats were fed for 21 d a cholesterol-free purified diet containing (200 g/kg) either normal cornstarch (CS) or high amylose cornstarch (HACS). In both types of rats, those fed the HACS diet had a significantly lower plasma total cholesterol concentration and a significantly larger intestinal bile acid pool than those fed the CS diet. In cecectomized rats, those fed the HACS diet had significantly lower plasma HDL and LDL cholesterol concentrations, a significantly greater fecal bile acid excretion and a significantly lower hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase mRNA concentration than those fed the CS diet. The plasma triglyceride concentration and LDL-receptor mRNA concentration were not affected by the diet or cecectomy. In sham-operated rats, the propionate concentration in the cecal contents was significantly greater in those fed the HACS diet than in those fed the CS diet. Compared with sham-operated rats, cecectomized rats had significantly enhanced cholesterol 7alpha-hydroxylase activity. In intact rats, biliary bile acid flux into the small intestine was significantly greater in those fed the HACS diet than in those fed the CS diet. Thus, the hypocholesterolemic effect of HACS appears to be mediated by accelerated fecal excretion of bile acids and increases in the intestinal pool and biliary flux of bile acids, and not by cecal fermentation products.

Quercetin dihydrate and gallate supplements lower plasma and hepatic lipids and change activities of hepatic antioxidant enzymes in high cholesterol-fed rats.

This study was designed to test the lipid-lowering and antioxidant activity of two bioflavonoids, quercetin dihydrate and gallate. Four groups of rats were given a semisynthetic diet containing 10 g cholesterol/kg for six weeks. The control group received only a high-cholesterol diet, whereas the other three groups received a diet including 1 g lovastatin, 1 g quercetin dihydrate, or 1 g gallate/kg. The quercetin dihydrate and gallate supplements both significantly lowered the plasma lipid and hepatic cholesterol levels compared to those of the control. The hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was significantly lowered by the quercetin dihydrate when compared to the other groups, while the hepatic acyl CoA: cholesterol acyltransferase (ACAT) activity was only significantly higher in the control group. The overall potential for antioxidant protection was significantly enhanced by the quercetin dihydrate and gallate supplements through lowering the plasma and hepatic thiobarbituric acid reactive substances (TBARS) levels and increasing the hepatic superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in high-cholesterol-fed rats. These results suggest that the supplementation of quercetin dihydrate and gallate promotes an increase in fecal sterols, which in turn leads to a decreased absorption of dietary cholesterol as well as lower plasma and hepatic cholesterol.

Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism.

Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) activity, 39.6 (SEM 2.8) v. 171.0 (SEM 47.3) pmol/min per mg protein. Cholesterol 7 alpha-hydroxylase (EC 1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA:cholesterol acyl transferase (ACAT; EC 2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs 0.72 (P < 0.005), and rs 0.68 (P < 0.01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.

Prickly Pear (Opuntia sp.) Pectin Alters Hepatic Cholesterol Metabolism without Affecting Cholesterol Absorption in Guinea Pigs Fed a Hypercholesterolemic Diet

Prickly pear pectin intake decreases plasma LDL concentrations by increasing hepatic apolipoprotein B/E receptor expression in guinea pigs fed a hypercholesterolemic diet. To investigate whether prickly pear pectin has an effect on cholesterol absorption and on enzymes responsible for hepatic cholesterol homeostasis, guinea pigs were fed one of three semipurified diets, each containing 15 g lard/100 g diet: 1) the lard-basal diet with no added cholesterol or prickly pear pectin (LB diet); 2) the LB diet with 0.25 g added cholesterol/100 g diet (LC diet); or 3) the LC diet containing 2.5 g prickly pear pectin/100 g diet, added at the expense of cellulose (LC-P diet). Animals fed the LB diet had the lowest plasma LDL and hepatic cholesterol concentrations, followed by animals fed the LC-P diet (P < 0.001). Hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was highest in the group fed the LB diet, with similar values for animals in the other two groups. A positive correlation existed between plasma LDL cholesterol concentration and hepatic acyl CoA:cholesterol acyltransferase activity (r = 0.87, P < 0.001). Cholesterol absorption was not different among the three dietary groups. These results indicate that the decreased plasma and hepatic cholesterol concentrations of animals fed prickly pear pectin are not explained by differences in cholesterol absorption but rather are due to mechanisms that alter hepatic cholesterol homeostasis, resulting in lower plasma LDL concentrations.

Regulation of Cholesterol and Lipoprotein Metabolism in Guinea Pigs Mediated by Dietary Fat Quality and Quantity

The effects of dietary fat quality and quantity on regulation of cholesterol and lipoprotein metabolism were measured in guinea pigs. The animals were fed 7.5 or 15% (wt/wt) fat diets containing either polyunsaturated corn oil (CO), monounsaturated olive oil (OL) or saturated lard as the fat source. Dietary fat quality had a number of significant effects: animals fed the CO-based diet had lower plasma LDL levels and LDL particles of higher density with decreased ratios of core-to-surface components. Apoprotein B/E receptor-mediated binding of LDL to hepatic membranes was twofold higher for animals fed the CO-based diet. Animals fed the OL-based diet had lower hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity and increased levels of hepatic cholesterol. Hepatic cholesteryl ester levels were lowest for animals fed the lard-based diet. Increasing dietary fat quantity resulted in increased plasma LDL levels and hepatic cholesterol, HMG-CoA reductase activity and receptor affinity for LDL. No changes were observed in LDL binding. These data demonstrate that, independent of dietary fat quantity, CO-based diets lower plasma LDL levels, modify LDL composition and increase hepatic apoprotein B/E receptor number.

In sire determination of the functional size of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase by radiation inactivation analysis

Radiation inactivation analysis of liver pieces yieided a target size of 210 kDa for hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (( S)-mevalonate:NADP + oxidoreductase (CoA-acylating), EC 1.1.1.34) from rats fed a normal diet. Feeding a diet containing mevinolin and colestipol, which causes a marked increase in enzyme activity, resulted in a reduction of the target size to 120 kDa. These results are consistent with those obtained by radiation inactivation and immunoblotting analysis of isolated microsomes and suggest that the increase in HMG-CoA reductase activity caused by these dietary agents is accompanied by a change from a dimer to a monomer form of the enzyme.

Effects of n-(4-methylbenzylthiocarbonyl)-l-phenylalanine (kf 1492), a new phenylalanine derivative, on lipid synthesis in vivo inhibition of hepatic cholesterol synthesis and 3-hydroxy-3-methylglutaryl-Co a reductase.

KF 1492, a new phenylalanine derivative, was administered at a dose of 100 mg/kg or 0.25% (w/w) diet to Wistar rats. After different periods of drug administration, incorporation of 14 C-acetate or 14 C-mevalonic acid into digitonin-precipitable sterols and hepatic 3-hydroxy-3-methylglutaryl-Co A (HMG-CoA) reductase activity were measured. KF 1492 feeding was associated with depressed incorporation of 14 C-acetate into sterols in liver slices or homogenate. There was no effect on incorporation of 14 C-mevalonic acid into sterols. Thus, KF 1492 administration induced inhibition of hepatic HMG-CoA reductase correlated with reduction of incorporation of 14 C-acetate into digitonin-precipitable sterols. KF 1492 feeding also inhibited in vivo sterol synthesis in rats, which was intraperitoneally injected with 14 C-acetate. Stereoisomers, metabolites adn chemically similar compounds of KF 1492 reduced HMG-CoA reductase activity, and this was correlated with lowering the activity of plasma cholesterol. These findings indicate that a major site of the action of KF 1492 in the inhibition of sterol synthesis may be at the level of HMG-CoA reductase.

Comparison of hydrophobic surfactant and cholestyramine on lipid and sterol balance in the rat

The effects of dietary supplement with hydrophobic surfactant, Pluronic L-81, on sterol and lipid metabolism in rats consuming a high-fat high-cholesterol diet was determined. Results were compared both to rats on the high-fat high-cholesterol diet alone and to other rats on a similar diet supplemented with cholestyramine. All treatment programs were well tolerated. Pluronic L-81 therapy produced reductions of plasma and hepatic cholesterol levels compared to rats on the diet alone. Additionally, plasma triglycerides were reduced. These changes were associated with relatively high fecal outputs of neutral steroids but acidic steroid excretion was less than observed for rats on diet alone. No malabsorption of neutral lipid was observed for detergent-treated rats. Cholestyramine was also effective in limiting hepatic cholesterol accumulation. Fecal losses of both neutral and acidic steroids were greater in this group compared to rats on diet alone. This was associated with a marked increase of hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity in the cholestyramine-treated group. Both types of treatment limit cholesterol accumulation in rats on a high cholesterol diet. Pluronic L-81 treatment, however, does not significantly increase endogenous cholesterol synthesis while it is greatly increased in response to cholestyramine as reflected by hepatic activities of HMG-CoA reductase.

Hepatic cholesterol metabolism in normo- and hyperlipidemic patients with cholesterol gallstones.

In vivo studies have shown abnormalities in cholesterol and bile acid metabolism in primary hyperlipoproteinemia (HLP). The aim of the present investigation was to determine if the increased production of cholesterol in HLP type IV can be attributed to a correspondingly high level of the hepatic 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity and if the low cholic acid: chenodeoxycholic acid synthesis ratio in HLP type II is due to some hydroxylase deficiency. Liver biopsies from 26 normolipidemic and 25 hyperlipidemic (10 type IIa, 6 type IIb, and 9 type IV) patients undergoing elective cholecystectomy were assayed for HMG CoA reductase activity, 12 alpha-hydroxylase activity, and 25-hydroxylase activity. The HMG CoA reductase activity was normal in HLP type IIa and type IIb and was increased about twice HLP type IV (P less than 0.001). The 12 alpha- and 25-hydroxylase activities were normal in all groups of patients. The results are compatible with a normal cholesterol synthesis in the liver in HLP type II. A reduced 12 alpha- or 25-hydroxylase activity cannot explain the low production of cholic acid relative to chenodeoxycholic acid in this type of HLP. The elevated HMG CoA reductase activity found in the liver of type IV patients may, however, be part of the explanation for the elevated synthesis of cholesterol often seen in these patients.