Effect of dietary lipids on hepatic and extrahepatic sterol 27-hydroxylase activity in high- and low-responding baboons.

Chen LD, Kushwaha RS, Rice KS, Carey KD, McGill HC Jr.

Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.

Our previous studies found that low low-density lipoprotein (LDL)-responding baboons compared with high LDL-responding baboons have higher hepatic sterol 27-hydroxylase activity when consuming a high-cholesterol and high-fat (HCHF) diet. The present studies were conducted to determine whether the extrahepatic activity of sterol 27-hydroxylase is also higher in low-responding baboons and to assess whether the enzyme is regulated at the protein level. We measured the hepatic sterol 27-hydroxylase activity and protein level and plasma 27-hydroxycholesterol concentration in six low- and six high-responding baboons on both the basal and the HCHF diet. We also compared the sterol 27-hydroxylase activity in the adrenal gland and 27-hydroxycholesterol concentration in blood lymphocytes from high- and low-responding baboons consuming the HCHF diet. With the HCHF diet, the plasma 27-hydroxycholesterol concentration and hepatic sterol 27-hydroxylase activity and protein level increased rapidly in low responders, but not in high responders. Blood lymphocytes of low-responding baboons cultured in the presence of lipoprotein-deficient serum (LPDS) had lower cholesterol concentrations than those from high-responding baboons. Addition of exogenous 27-hydroxycholesterol to the culture medium of blood lymphocytes decreased the cellular cholesterol concentration. Plasma 27-hydroxycholesterol and hepatic sterol 27-hydroxylase activity and protein levels were negatively correlated with the plasma VLDL + LDL cholesterol concentration and VLDL + LDL/HDL cholesterol ratio after 6 weeks on the HCHF diet, but not on the chow diet. The results suggest that sterol 27-hydroxylase activity in both hepatic and extrahepatic tissues attenuates the dietary responsiveness in baboons, and the enzyme activity is not regulated by the specific activity of the protein.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9627374&dopt=Abstract cholesterol




Postmarketing analysis of lovastatin use in the VA Northern California System of Clinics: a retrospective, computer-based study.

Swislocki AL, Lin K, Cogburn D, Fann KY, Khuu DT, Noth RH.

VA Northern California Health Care System, Martinez 94553, USA.

Prevention of coronary heart disease is a major public health goal. The efficacy of lovastatin in lowering serum cholesterol has been proven in research studies, but its efficacy in practice is unclear. To evaluate our practice patterns and outcome in the Veterans Administration Northern California System of Clinics, we reviewed computer-based records of 203 unselected patients issued lovastatin; 193 (95%) were men, and the average patient age was 66 +/- 9 years. The average daily dose of lovastatin was 24 +/- 10 mg, and average duration of therapy was 22 +/- 11 months. Only 72 patients (35%) were instructed on the prescription to take their medication with the evening meal, and only 59 patients (29%) had seen a dietitian during the observed (1 to 3 years) treatment period. Nevertheless, among the 124 patients with pretreatment lipid data, total serum cholesterol decreased by 18% from 271 +/- 45 to 221 +/- 41 mg/dL (P < 0.001), and low density lipoprotein (LDL)-cholesterol decreased by 23% from 185 +/- 43 to 143 +/- 37 (P < 0.001) mg/dL. High density lipoprotein-cholesterol and triglycerides were unchanged. Of the 168 patients with LDL-cholesterol data during the treatment period, only 74 (44%) achieved an LDL-cholesterol level of less than 130 mg/dL, the minimum goal for a population of older males with a high incidence of other cardiac risk factors. Safety surveillance with liver function testing was performed at least once in 192 patients (95%), but with creatine phosphokinase (CPK) testing in only 123 patients (61%) during the survey period. Enzyme elevations were minor, but occurred at least intermittently in approximately one quarter of patients. Only 5.7% of patients on lovastatin manifested an increase in transaminases on therapy. Due to incomplete baseline data, it is unclear how many patients had elevated CPK as a result of lovastatin. We conclude that: (1) lovastatin is effective in lowering total and LDL-cholesterol in practice, but is often used in dosage insufficient to lower LDL-cholesterol to goal levels; (2) patients are not being adequately educated on dosing schedules; (3) toxicity may be underestimated by infrequent and inconsistent surveillance; and (4) nonpharmacologic therapy is underutilized.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10178460&dopt=Abstract cholesterol




Long-term effects of cis and trans monounsaturated (18:1) and saturated (16:0) fatty acids on the synthesis and secretion of apolipoprotein A-I- and apolipoprotein B-containing lipoproteins in HepG2 cells.

Dashti N, Feng Q, Franklin FA.

Division of Gastroenterology and Nutrition, Department of Nutrition Sciences, and Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

The objective of this study was to compare the long-term effects of oleic (cis 18:1), elaidic (trans 18:1), and palmitic (16:0) acids on hepatic lipoprotein production, using HepG2 cells as an experimental model. The net accumulation in the medium of apolipoprotein A-I (apoA-I) was not significantly altered by fatty acids, whereas that of apoB was increased with oleic and elaidic acids. Oleic acid, and to a lesser extent elaidic and palmitic acids, increased the mass of triglycerides in the medium and the incorporation of [(3)H]glycerol into secreted triglycerides. The incorporation of [(14)C]acetate into cellular and secreted total cholesterol was stimulated by 96% and 83%, respectively, with elaidic acid but was not significantly modified by oleic or palmitic acid. Relative to oleic acid, the secretion of (14)C-labeled phospholipids and triglycerides was decreased 28% to 31% with elaidic and palmitic acids whereas that of free cholesterol and cholesteryl esters was enhanced 93% and 73%, respectively, with elaidic acid but remained unchanged with palmitic acid. Compared with oleic acid, elaidic acid stimulated the secretion of very low density lipoprotein cholesterol (VLDL-Chol), low density lipoprotein cholesterol (LDL-Chol), and high density lipoprotein cholesterol (HDL-Chol) by 43%, 70%, and 34%, respectively, whereas palmitic acid decreased VLDL-Chol but had no significant effect on LDL-Chol and HDL-Chol. The ratios of total cholesterol to HDL-Chol were 3.17, 3.60, and 3.25 with oleic, elaidic, and palmitic acids, respectively; the corresponding ratios of LDL-Chol to HDL-Chol were 0.87, 1.10, and 0.93, respectively. Compared with oleic and palmitic acids, the LDL and HDL particles secreted in the presence of elaidic acid contained higher levels of free cholesterol and cholesteryl esters and a lower content of phospholipids. The phospholipid-to-total cholesterol ratios of HDL were 1.05, 0.40, and 0.76 with oleic, elaidic, and palmitic acids, respectively.Our results indicate that in comparison with cis monounsaturated and saturated fatty acids, trans fatty acids have more adverse effects on the concentration and composition of lipoproteins secreted by HepG2 cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11108731&dopt=Abstract cholesterol




Characterization of the ovariectomized rat model for the evaluation of estrogen effects on plasma cholesterol levels.

Lundeen SG, Carver JM, McKean ML, Winneker RC.

Women's Health Research Institute, Wyeth-Ayerst Research, Radnor, Pennsylvania 19087, USA. lundees war.wyeth.com

Estrogens protect against cardiovascular disease in women through effects on the vascular wall and liver. Here we further characterize the rat as a model for the evaluation of estrogenic effects on plasma lipid levels vs. uterine wet weight. In adult ovariectomized female rats treated for 4 days s.c., 17alpha-ethinyl estradiol (EE) was the most potent agent to lower plasma total and high density lipoprotein cholesterol levels, followed by 17beta-estradiol and 17alpha-estradiol. However, 17alpha-estradiol had the greatest separation of uterotropic vs. cholesterol-lowering effects. EE had the same lipid-lowering potency whether administered s.c. or orally to adult rats. It had no effect on cholesterol levels in immature rats, even though the uterotropic response was dramatic. Testosterone propionate, dexamethasone, and progesterone did not significantly lower cholesterol levels. The antiestrogens tamoxifen and raloxifene lowered cholesterol levels, but with less efficacy and potency than the estrogens. ICI 182780 had no effect on cholesterol levels. When coadministered with EE, ICI 182780 inhibited the cholesterol-lowering and uterotropic activities of EE, suggesting that the estrogen receptor pathway is involved. In conclusion, although the information from the rat is limited as a model of the low density lipoprotein-lowering effects of estrogens in humans, it can be used to study the effects and mechanism of action of estrogen and antiestrogens on plasma cholesterol levels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9075715&dopt=Abstract cholesterol




Native and partially hydrolyzed psyllium have comparable effects on cholesterol metabolism in rats.

Arjmandi BH, Sohn E, Juma S, Murthy SR, Daggy BP.

University of Illinois at Chicago, 60612, USA.

This study was conducted to determine whether the storage conditions and the levels of psyllium in the diet modulate its hypocholesterolemic effects. Seventy-five male Sprague-Dawley rats, age 90 d, were randomly divided into five treatment groups and were fed cholesterol-containing diets for 21 d. Diets included 10% cellulose (control); 5 or 10% psyllium stored 8 mo at 5 degrees C (PS5); or 5 or 10% psyllium stored 8 mo at 40 degrees C (PS40). The higher storage temperature caused a gradual decrease in molecular weight of the psyllium, as measured by changes in solution viscosity. Hepatic rates of sterol synthesis were significantly (P < 0.001) higher in all of the psyllium-fed rats compared with control rats [21 +/- 2, 312 +/- 35, 464 +/- 40, 328 +/- 49 and 439 +/- 57 nmol [3H]digitonin-precipitable sterol (DPS)/(g liver x h), respectively, for control, 5% PS5, 10% PS5, 5% PS40 and 10% PS40]. A similar trend was observed in intestinal rates of sterol synthesis, and the difference was significant (P < 0.05) for all treatment groups except the 5% PS5-fed group compared with the control group. Liver total cholesterol and total lipid concentrations were significantly lower in all psyllium-fed rats compared with controls. There were no significant differences in serum total cholesterol concentrations among the psyllium-fed groups, although serum cholesterol levels in both the PS5-fed groups were significantly (P < 0.05) lower than that in the control group (2.66 +/- 0.18, 2.62 +/- 0.15 and 3.26 +/- 0.12 mmol/L, respectively, for 5% PS5, 10% PS5 and control). Serum triglyceride and HDL cholesterol concentrations did not vary significantly among groups. The findings of this study indicate that the cholesterol-lowering activity of psyllium is unaltered by storage conditions shown to cause a moderate degree of hydrolysis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9082031&dopt=Abstract cholesterol




Replacing dietary palmitic acid with elaidic acid (t-C18:1 delta9) depresses HDL and increases CETP activity in cebus monkeys.

Khosla P, Hajri T, Pronczuk A, Hayes KC.

Foster Biomedical Research Laboratory, Brandeis University, Waltham, MA 02254, USA.

The question whether dietary trans fatty acids affect lipoprotein metabolism similarly to specific saturated fatty acids was investigated in 11 normolipemic cebus monkeys by exchanging 5% dietary energy (%en) between elaidic (t-C18:1 delta9) and palmitic acid (16:0) in two test diets (30%en fat + 100 mg cholesterol/1000 kcal diet) conforming to the American Heart Association (AHA) Step 1 guidelines. These were compared with a normal control diet rich in saturated fat and cholesterol (38%en fat + 180 mg cholesterol/1000 kcal diet). The control diet was fed initially for 14 wk, followed by each of the the two test diets in a crossover design. Plasma lipid concentrations were determined four times between the 6th and 14th wk. Turnover studies (using 125I-HDL and 131I-LDL) were conducted after 9 wk in each dietary period. Relative to the control diet, both test diets significantly reduced plasma total cholesterol (TC), HDL cholesterol (HDL-C) and VLDL plus LDL cholesterol (LDL-C) concentrations; triglyceride (TG) concentrations tended to be lower. However, the trans diet resulted in a significantly greater reduction in HDL-C than the palmitate diet (124 +/- 17, 117 +/- 18 and 106 +/- 13 mg/dL for the control, palmitate and trans diets, respectively). The palmitate diet significantly decreased the TC/HDL-C ratio by 11% when compared with the control diet (1.68 +/- 0.17 vs. 1.89 +/- 0.30), whereas the trans diet had no effect (1.81 +/- 0.20 vs. 1.89 +/- 0.30). Kinetic studies revealed that, relative to the control diet, both test diets significantly lowered the LDL apolipoprotein B (apoB) pool size, principally reflecting an increase in the LDL apoB fractional catabolic rate (FCR) related to the reduced cholesterol intake. Between the two test diets, no significant differences in LDL kinetic parameters were observed. Both test diets significantly decreased HDL apoA1 concentrations in comparison with the control diet, which was partly explained by an increase in the fractional catabolic rate of HDL. Of the two test diets, the trans diet was associated with a 9.5% greater HDL FCR than the palmitate diet (P < 0.08) and a significant increase in plasma cholesteryl ester transfer protein (CETP) activity (% transfer 114 +/- 7 vs. 91 +/- 7; P < 0.03). Thus, palmitic acid- and elaidic acid-rich diets produced identical effects on LDL metabolism in normocholesterolemic cebus monkeys fed diets with low levels of cholesterol, whereas elaidic acid depressed HDL-C, attributable to both increased CETP activity and HDL clearance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9082041&dopt=Abstract cholesterol




Simvastatin further enhances the hypocholesterolemic effect of soy protein in rabbits.

Giroux I, Lavigne C, Moorjani S, Jacques H.

Departement des Sciences des Aliments et de Nutrition, Universite Laval, Sainte-Foy, Quebec, Canada.

OBJECTIVE: The effects of three dietary proteins (casein, cod, soy) and low dose simvastatin, an inhibitor of hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, on serum lipids were investigated. METHODS: New Zealand rabbits were fed purified diet (20% protein, 11% fat and 0.06% cholesterol) for 28 days. Animals received either 1.4 mg simvastatin or placebo orally during the last 14 days. A randomized 3 x 2 factorial design was used for the administration of diet and drug treatments. RESULTS: Mean food intake and body weight of the animals in all groups were similar. In placebo groups, soy protein decreased (p = 0.06) total cholesterolemia with significantly (p = 0.009) lower high-density lipoprotein (HDL) cholesterol, and significantly (p = 0.004) higher very low-density lipoprotein (VLDL) triglycerides (TG), compared to animal proteins. Addition of low dose simvastatin to soy protein induced a further decrease of serum total cholesterol, decreased VLDL and low-density lipoprotein (LDL) cholesterol, and LDL (apolipoprotein B), as well as improved VLDL-TG and HDL cholesterol levels. No similar reduction was seen when simvastatin was combined with casein or cod protein. CONCLUSION: These results show that low dose simvastatin may enhance the hypocholesterolemic effect of soy protein compared to animal proteins in the rabbit.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9100218&dopt=Abstract cholesterol




Additive hypocholesterolemic effect of psyllium and cholestyramine in the hamster: influence on fecal sterol and bile acid profiles.

Daggy BP, O'Connell NC, Jerdack GR, Stinson BA, Setchell KD.

Procter & Gamble Company, Cincinnati, OH 45040, USA.

Recent findings suggest that the effects of cholestyramine and psyllium in combination could be additive for cholesterol-lowering. We therefore examined the effect of both agents, alone and in combination, on lipoprotein cholesterol and neutral and acidic steroid excretion in the hamster. Animals (n = 8/group) were fed for 21 days, either a basal chow diet supplemented with 10% palm oil and 0.2% cholesterol, or one of four treatments consisting of the basal diet plus: 5.5% cellulose; 5% psyllium with 0.5% cellulose; 0.5% cholestyramine with 5% cellulose; or 5% psyllium with 0.5% cholestyramine. Psyllium and cholestyramine both had significant hypocholesterolemic effects, but in combination produced additive reductions in lipoprotein and hepatic cholesterol. Psyllium, cholestyramine, and the combination increased total bile acid excretion by 26%, 57%, and 79%, respectively. Psyllium affected only unconjugated bile acid excretion while cholestyramine also increased the excretion of conjugated and primary bile acids. Neither agent, nor the combination, affected fecal neutral sterol excretion. We conclude that, while both agents lower cholesterol by a mechanism of increased bile acid excretion, these studies indicate that psyllium does not bind bile acids in vivo and lend further support for the concomitant use of these agents for cholesterol-lowering.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9101430&dopt=Abstract cholesterol




Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV.

Cohen RD, Castellani LW, Qiao JH, Van Lenten BJ, Lusis AJ, Reue K.

Lipid Research Laboratory, West Los Angeles Veterans Affairs Medical Center, California 90073, USA.

Transgenic mouse lines carrying several copies of the mouse apo A-IV gene were produced. Lipoprotein composition and function, and aortic lesion development were examined. Apo A-IV levels in the plasma of transgenic mice were elevated threefold compared with nontransgenic littermates on a chow diet, and sixfold in mice fed an atherogenic diet. Plasma concentrations of total cholesterol, HDL cholesterol, triglycerides, and free fatty acids were similar in transgenic and control mice fed a chow diet. However, with the atherogenic diet, male transgenic mice exhibited significantly higher levels of plasma triglycerides (P < 0.05), total cholesterol (P < 0.01), HDL cholesterol (P < 0.0001), and free fatty acids (P < 0.05), and lower levels of unesterified cholesterol (P < 0.05), than nontransgenic littermates. Expression of the apo A-IV transgene had a protective effect against the formation of diet-induced aortic lesions, with transgenics exhibiting lesion scores of approximately 30% those seen in control mice. HDL-sized lipoproteins isolated from transgenic mice fed the atherogenic diet promoted cholesterol efflux from cholesterol-loaded human monocytes more efficiently than comparable lipoproteins from nontransgenic counterparts. Plasma from transgenics also exhibited higher endogenous cholesterol esterification rates. Taken together, these results suggest that apo A-IV levels influence the metabolism and antiatherogenic properties of HDL.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9109435&dopt=Abstract cholesterol