Liver HMG-CoA Reductase Activity Research Articles

Ganoderma terpenoid extract exhibited anti-plasmodial activity by a mechanism involving reduction in erythrocyte and hepatic lipids in Plasmodium berghei infected mice

Bioactive components of Ganoderma lucidum has recently gained intense research attention due to their acclaimed nutritional and medicinal properties. Thus, the terpenoid extract from the fruit bodies of G. lucidum (GT) was evaluated for activity against Plasmodium berghei in mice in two separate experiments. In addition, the effects of the extract on erythrocyte and hepatic lipids as well as liver HMG-CoA reductase activity before and after the treatments were also assessed. Mice with established infection were administered 100 and 250 mg/kg/day GT alone and in combination with chloroquine (CQ), in either case two separate controls designated: CQ (30 mg/kg chloroquine) and INF-CTR (1 mL DMSO) were also included. Treatment was administered orally for 12 days and parasitemia determined every three days. Percentage survival was significantly increased to 87% from 66% due to combination of GT100 with CQ compared to GT100 alone and to 75% from 62% when GT250 was administered with CQ compared to GT250 alone. Erythrocyte triglycerides, total cholesterol (TC), LDL and phospholipids contents were significantly lower in GT + CQ-treated mice compared to CQ alone and INF-CTR. Similarly, hepatic TC and phospholipid levels were significantly lower in the GT + CQ-treated mice compared to CQ alone and INF-CTR and HMG-CoA reductase activity in the liver was significantly inhibited due to administration of GT + CQ. Data from this study suggest that the anti-plasmodial action of GT could involve mechanisms associated with its hypolipidemic activity. It was also demonstrated that chloroquine, when administered in combination with GT, potentiates its curative effect in P. berghei-infected mice.

Hypocholesterolemic activity of cornelian cherry (Cornus mas L.) fruits

Background Lipid profile disturbances are important risk factors for cardiovascular events in patients with diabetes mellitus and finding safe and multifaceted agents is persuaded in this regard. This study aimed to evaluate the effect of cornelian cherry dried powder (CCDP) on serum lipid profile as well as liver antioxidant capacity, HMG-CoA reductase level and activity, and LDL receptor level in streptozotocin-induced diabetic rats. Methods Forty-eight male adult Wistar rats were randomly allocated into eight equal groups and were treated for 4 weeks as follows: negative control (normal rats, basic diet); positive control (diabetic rats, basic diet), T1 to T4 groups: diabetic rats fed with basic diet containing 0.25, 0.5, 1 and 2 g/ 100 g BW CCDP, respectively; T5: diabetic rats fed with basic diet plus 10 mg/kg lovastatin in drinking water and T6: normal rats fed with basic diet containing 1 g/ 100 g BW CCDP. Results Administration of CCDP had no significant effect on serum glucose levels in diabetic rats however decreased total cholesterol, low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) levels and liver antioxidant capacity as compared to positive control rats (p<0.05). Although HMG-CoA reductase level showed a significant decrease only in T3 group, its activity was reduced in all diabetic CCDP and lovastatin-treated groups as compared to positive control. LDL receptor level remained statistically the same among positive control and CCDP-treated groups. Conclusions In conclusion, the present study confirms hypocholesterolemic effect of CCDP in diabetic rats and demonstrated that this effect was at least partly due to inhibition of liver HMG-CoA reductase activity.

Hypolipidemic activity of Phellinus rimosus against triton WR-1339 and high cholesterol diet induced hyperlipidemic rats

Patients with the risk for atherosclerotic disease will be targeted to reduce the existing hyperlipidemia. The hypolipidemic activity of Phellinus rimosus was studied using triton WR-1339 and high cholesterol diet (HCD) induced models. The triton induced elevated lipid profile was attenuated by P. rimosus or standard drug atorvastatin. Similarly, administration of P. rimosus along with HCD significantly decline serum triglyceride, total cholesterol, low-density lipoprotein, with elevating the high-density lipoprotein. Thiobarbituric acid reacting substances in heart and liver significantly decreased; where as activity of enzymatic antioxidants and level of reduced glutathione were significantly increased. In both models, P. rimosus extract showed a significant ameliorative effect on the elevated atherogenic index as well as LDL/HDL-C ratio. The hypolipidemic activity of P. rimosus can be ascribed to its inhibitory effect on the liver HMG CoA reductase activity. The results suggest the possible therapeutic potential of this fungus as hypolipidemic agent.

Evaluation of Ayurvedic plants for anti-atherosclerotic and anti-hyperlipidemic effects

AIM: To study effects of Ayurvedic plants, Plumbago zeylanicus (Pz), Phyllanthus emblica (Pe), Cyperus rotundus (Cr) and Embelia ribes (Er) on prevention of atherosclerosis and hyperlipidemia. Methodology: The study was carried out in two parts after Animal Ethics Committee approval. In both the parts, animals were assigned to groups viz. Normal control, Disease control, Atorvastatin (AT), Pe, Pz, Cr and Er. Standardized aqueous extracts of test drugs in doses equivalent to human therapeutic dose were administered orally. In Part 1, male adult New-Zealand strain rabbits were administered high cholesterol diet pellets along with test drugs/vehicle for 45 days. On 46th day, lipid profile and histopathology of aorta were studied. In Part 2, male wistar rats (150–200 gm) received test drug/vehicle with cholesterol supplementation (CS: 400mg/kg with choline in coconut oil p.o.) for 35 days. Lipid profile and liver HMG-CoA reductase activity and aortic MDA were estimated on 36th day. Data was analysed using ANOVA followed by post hoc tests. Results: In part 1, only AT and Pe prevented hyperlipidemia induced by HCD. However, all the test drugs exhibited anti-atherosclerotic potential as seen from significant reduction in mean plaque area and percent luminal encroachment by the plaques. The best results were observed with AT and Pz, followed by Cr. In Part 2, AT prevented hyperlipidemia and increased HDL-C (p<0.01). Of the test drugs, Pz reduced triglycerides and VLDL-C (p<0.05) and increased HDL-C (p<0.05). Pe reduced LDL-C (p<0.01) and showed trend to reduce total cholesterol. AT, Pz and Pe also decreased HMG-CoA reductase activity and prevented rise in vascular MDA in response to CS. Conclusion:Pz showed the best anti-atherosclerotic effect comparable to AT. Anti-hyperlipidemic effects of Pz and Pe appear to be responsible for the anti-atherosclerotic activity. The mechanisms responsible for anti-atherosclerotic potential of Cr and Er need to be explored. Acknowledgement: 1. Dept. of AYUSH Govt. of India 2. Zandu Pharmaceuticals Works Ltd.

Effects of administration of α-tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity

Male hamsters were fed on semi-synthetic diets containing commercial corn oil (CO), isolated corn oil triglycerides (COTG), COTG supplemented with 30 ppm of α -tocopherol (COTGT L) and COTG supplemented with 81 ppm of α -tocopherol (COTGT H) as the dietary lipid for 45 days. Male albino guinea pigs were fed on commercial chow pellets and treated with different dosages of tocopherol and tocotrienols intra-peritoneally for 6 consecutive days. Serum and liver were taken for analysis. Our results show that stripping corn oil of its unsaponifiable components resulted in COTG which yielded lower serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and raised high-density lipoprotein cholesterol (HDL-C) and serum triglycerides (TG) levels. These results indicate that the COTG with its fatty acids are responsible for the hypocholesterolemic effect exhibited by corn oil. However, supplementing the COTG diet with α -tocopherol (α -T) at 30 ppm significantly raised the serum TC, LDL-C and TG levels, but did not alter the HDL-C level, indicating that α -T is hypercholesterolemic. Supplementing the COTG diet with α -T at 81 ppm raised the serum TC level but to a lesser extent as compared to that obtained with 30-ppm α -T supplementation. The increased TC, in this case, was reflected mainly by an increased in HDL-C level as the LDL-C level was unchanged. The TG level was also raised but to a lesser extent than that obtained with a lower α -T supplementation. The liver HMG CoA reductase (HMGCR) activity was exhibited (56%) by the COTG as compared to CO. Supplementation of α -T at 30 ppm to the COTG diet resulted in further inhibition (76%) of the liver HMGCR activity. On the contrary, supplementation of α -T at 81 ppm to COTG diet resulted in a highly stimulatory effect (131%) on the liver HMGCR activity. Short-term studies with guinea pigs treated intra-peritoneally with α -T showed that at low dosage (5 mg) the HMGCR activity was inhibited by 46% whereas increasing the dosage of α -T to 20 mg yielded lesser inhibition (18%) as compared to that of the control. Further increase in the dosage of α -T to 50 mg actually resulted in 90% stimulation of the liver HMGCR activity as compared to the control. These results clearly indicate that the effect of α -T on HMGCR activity was dose-dependent. Treatment of the guinea pigs with 10 mg of tocotrienols (T3) resulted in 48% inhibition of the liver HMGCR activity. However, treatment with a mixture of 5 mg of α -T with 10 mg of T3 resulted in lesser inhibition (13%) of the liver HMGCR activity as compared to that obtained with 10 mg of T3. The above results indicate that the α -T is hypercholesterolemic in the hamster and its effect on liver HMGCR is dose-dependent. T3 exhibited inhibitory effect on liver HMGCR and α -T attenuated the inhibitory effect of T3 on liver HMGCR.

Effects of administration of α-tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity

Male hamsters were fed on semi-synthetic diets containing commercial corn oil(CO), isolated corn oil triglycerides (COTG), COTG supplemented with 30 ppm ofα-tocopherol (COTGTL) and COTG supplemented with 81 ppm of α-tocopherol(COTGTH) as the dietary lipid for 45 days. Male albino guinea pigs were fed oncommercial chow pellets and treated with different dosages of tocopherol andtocotrienols intra-peritoneally for 6 consecutive days. Serum and liver were takenfor analysis. Our results show that stripping corn oil of its unsaponifiablecomponents resulted in COTG which yielded lower serum total cholesterol (TC)and low-density lipoprotein cholesterol (LDL-C) and raised high-density lipoproteincholesterol (HDL-C) and serum triglycerides (TG) levels. These results indicate thatthe COTG with its fatty acids are responsible for the hypocholesterolemic effectexhibited by corn oil. However, supplementing the COTG diet with α-tocopherol(α-T) at 30 ppm significantly raised the serum TC, LDL-C and TG levels, but didnot alter the HDL-C level, indicating that a-T is hypercholesterolemic. Supplementingthe COTG diet with α-T at 81 ppm raised the serum TC level but to a lesserextent as compared to that obtained with 30-ppm α-T supplementation. Theincreased TC, in this case, was reflected mainly by an increased in HDL-C level asthe LDL-C level was unchanged. The TG level was also raised but to a lesser extentthan that obtained with a lower α-T supplementation. The liver HMG CoAreductase (HMGCR) activity was exhibited (56%) by the COTG as compared toCO. Supplementation of α-T at 30 ppm to the COTG diet resulted in furtherinhibition (76%) of the liver HMGCR activity. On the contrary, supplementation ofα-T at 81 ppm to COTG diet resulted in a highly stimulatory effect (131%) on theliver HMGCR activity. Short-term studies with guinea pigs treated intra-peritoneallywith α-T showed that at low dosage (5mg) the HMGCR activity was inhibited by46% whereas increasing the dosage of α-T to 20 mg yielded lesser inhibition (18%)as compared to that of the control. Further increase in the dosage of α-T to 50 mgactually resulted in 90% stimulation of the liver HMGCR activity as compared tothe control. These results clearly indicate that the effect of α-T on HMGCR activitywas dose-dependent. Treatment of the guinea pigs with 10 mg of tocotrienols (T3)resulted in 48% inhibition of the liver HMGCR activity. However, treatment with amixture of 5 mg of α-T with 10 mg of T3 resulted in lesser inhibition (13%) of theliver HMGCR activity as compared to that obtained with 10mg of T3. The aboveresults indicate that the α-T is hypercholesterolemic in the hamster and its effect onliver HMGCR is dose-dependent. T3 exhibited inhibitory effect on liver HMGCRand α-T attenuated the inhibitory effect of T3 on liver HMGCR.

Tocotrienols inhibit liver HMG CoA reductase activity in the guinea pig

Male guinea pigs were treated intraperitoneally with different dosages of tocotrienols isolated from palm oil fatty acid distillate (PFAD) for 6 consecutive days. Control animals were treated with vitamin E-free palm oil triglycerides. Commercial animal pellets and water were given ad libitum during the treatment period. The guinea pigs were sacrificed at around 2400 hr. Liver HMG CoA reductase was assayed by a combination of conventional TLC and liquid scintillation spectrophotometry using 14C-HMG CoA as the substrate. Our results show that tocotrienols isolated from PFAD inhibited liver HMG CoA reductase activity in the guinea pig and the inhibitory effect of tocotrienols on HMG CoA reductase appeared to be dose-dependent. Analysis of the serum tocol profiles indicate that only α-tocopherol was found in the serum and there was no tocotrienol in the serum after 6 consecutive treatments with tocotrienols. These results indicate a rapid clearance of tocotrienols from the blood circulation. On the contrary, the liver retained much of the tocotrienols administered. The levels of tocotrienols in the liver appear to increase with increased dosages of tocotrienols in the treatment.

Cholesterol and fatty acid metabolism in piglets fed sow milk or infant formula with or without addition of cholesterol

Several studies have reported that plasma cholesterol and phospholipid (PL) levels of arachidonic acid (20:4n−6) are lower and PL levels of linoleic acid (18:2n−6) are higher in infants fed formula than in infants fed human milk. Plasma cholesterol level and possibly the dietary intake of cholesterol could be related to plasma PL n−6 fatty acid metabolism because plasma PL 18:2n−6 is used for esterification of plasma free cholesterol. Whether the low cholesterol content of infant formula as compared with human milk is related to the difference in plasma n−6 fatty acid levels between infants fed human milk and infants fed formula is not known. This study determined the effect of feeding formula with 0.05 mmol cholesterol/L, formula with 1.09 mmol cholesterol/L, or sow milk with 0.34 mmol cholesterol/L on plasma, liver, and bile lipid fatty acid levels and liver low-density lipoprotein (LDL) receptor mass in piglets. Liver microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and plasma lathosterol were assayed as indices of liver and body cholesterol synthesis, respectively. Formula with or without cholesterol added, or sow milk, was fed from birth to 18 days of age. Providing cholesterol in the formula did not correct the significantly lower plasma cholesterol or plasma and liver PL 20:4n−6 levels associated with formula feeding. The liver total cholesterol and cholesteryl esters (CE), biliary bile acid, and PL concentrations were significantly higher and the liver HMG CoA reductase activity and plasma lathosterol:cholesterol ratio were significantly lower in piglets fed the formula with cholesterol than in piglets fed the formula without cholesterol added. No evidence of fewer hepatic LDL receptors was found in piglets fed sow milk compared with piglets fed formula. The results show marked differences in hepatic and bile n−6 fatty acid concentrations between artificially and naturally fed piglets that were not explained by the difference in dietary cholesterol intake alone. The significance of the changes in bile lipid composition due to formula feeding should be studied further.

Comparison of the effects of condensed tannin and pectin on cecal fermentations and lipid metabolism in the rat

The aim of the study was to compare the effect of a soluble fiber (citrus pectin) and prefermented condensed tannin (Quebracho) on the cecal fermentations, bile acids excretion and lipid metabolism in rats fed semi-purified diets. Analysis of the fermented tannin established than it is rich in monomers and trimers with little highly condensed polymers. Food intake and weight gain were not affected by addition of 5% citrus pectin or 1% Quebracho tannin in the diet. In the cecum, there was evidence of a depolymerization of polymers and of degradation of monomers, together with an accumulation of polar phenolic compounds. There was a significant enlargement of the cecum and of the volatile fatty acids (VFA) pool in rat fed the pectin diet; the Quebracho diet depressed the cecal VFA concentrations, compared to controls. The 1% Quebracho diet enhanced bile acids excretion, but the 5% pectin diet did not. In contrast, plasma cholesterol was depressed more effectively by pectin than by Quebracho. Both diets increased the activity of liver HMG-CoA reductase, a rate limiting enzyme of cholesterogenesis. The data show that, at a relatively low level in the diet, condensed tannins and soluble fibers may affect lipid metabolism by distinct mechanisms, which could be complementary in natural product diets.

The mechanism underlying the hypolipemic effect of perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid

The influence of the peroxisomal proliferators perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid on lipid metabolism in rats was studied. Dietary treatment of male Wistar rats with these three compounds resulted in rapid and pronounced reduction in both cholesterol and triacylglycerols in serum. The concentration of liver triacylglycerols was increased by about 300% by PFOSA. Free cholesterol was increased by both perfluoro compounds. Cholesteryl ester was reduced to 50% by PFOSA as well by clofibrate. In hepatocytes from fed rats, all the compounds resulted in reduced cholesterol synthesis from acetate, pyruvate and hydroxymethyl glutarate, but there was no reduction of synthesis from mevalonic acid. The oxidation of palmitate was also increased in all groups. The perfluoro compounds, but not clofibrate, caused some reduction in fatty acid synthesis. The activity of liver HMG-CoA reductase was reduced to 50% or less in all treatment groups and all three compounds led to lower activity of acyl-CoA: cholesterol acyltransferase (ACAT). Changes in other enzymes related to lipid metabolism were incosistent. The present data suggest that the hypoliponic effect of these compounds may, at least partly, be mediated via a common mechanism; impaired production of lipoprotein particles due to reduced synthesis and esterification of cholesterol together with enhanced oxidation of fatty acids in the liver.

Changes in cholesterol accumulation and steroid excretion in response to cellulose, alfalfa or oats in cholesterol-fed rats

Experiments were conducted to investigate the mechanisms by which some sources of dietary fiber reduce accumulation of liver cholesterol in rats fed a cholesterol-containing diet. Male Wistar rats were fed a semipurified diet containing no fiber (sucrose replacing dietary fiber) or 15% cellulose, alfalfa or whole ground oats as a source of dietary fiber with a without 0.25% cholesterol added. Serum and liver cholesterol level, liver HMG CoA reductase activity, and fecal bile acid and neutral steroid excretion were measured after 21 days. Serum cholesterol levels were not different in any of the diet groups. In cholesterol-fed rats, alfalfa resulted in a reduction in the level of liver cholesterol accumulation in comparison to cellulose or the fiber-free diet but oats did not. Daily bile acid and neutral steroid excretion were increased in response to cholesterol feeding but little difference was observed among the groups fed the various dietary fiber sources except that alfalfa resulted in lower excretion rates compared to other fiber-containing diets. HMG CoA reductase activity was reduced by cholesterol feeding and was significantly increased in response to alfalfa in the absence of dietary cholesterol. The relative amounts of bile acids excreted was altered both by cholesterol feeding and by the source of dietary fiber. Cholesterol feeding resulted in an increase in the amount of chenodeoxycholic acid derivatives excreted, especially in the 6β-hydroxylated, muricholic acids. Dietary fiber appeared to increase the contribution of chenodeoxycholic and lithocholic acids to the resultant increase in response to dietary cholesterol. These changes in the relative amounts of bile acids excreted in response to this cholesterol challenge are suggested as a partial explanation of the reduction in accumulation of liver cholesterol in rats in response to dietary cholesterol.

Antischistosomal action of mevinolin: evidence that 3-hydroxy-methylglutaryl-coenzyme a reductase activity in Schistosoma mansoni is vital for parasite survival

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase) plays an important role in regulating egg production in the human parasitic trematode Schistosoma mansoni. Infected mice treated with a low dose of mevinolin, an inhibitor of this enzyme, stopped egg production by the parasite and blocked the pathology associated with the infection. As an extension of this work, we exposed adult and developing schistosomes to higher doses of mevinolin for an extended period of time and observed the following: administration of 0.2% mevinolin in the diet of infected mice for 14 days resulted in 96-100% elimination of adult parasites. Administration of the same dose for 2 days before, and for 15 days after infection, resulted in 93-96% reduction of adult parasites. Co-administration of mevinolin with 0.5% mevalonate, but not 0.5% cholesterol, blocked the antischistosomal activity of mevinolin. We monitored schistosomal and mouse liver HMG-CoA reductase activity during the course of treatment and observed that HMG-CoA reductase activity was elevated in the liver but significantly reduced in the parasite. In vitro incubation of paired schistosomes with mevinolin, for up to 11 days, resulted in a dose- and time-dependent reduction of parasite motility and lactate production with eventual death. These in vitro effects were no evident when mevalonate was added to the culture system in place of, or in addition to, mevinolin. Collectively, the evidence suggests that mevalonate and/or metabolite not only plays a vital role in schistosome egg production, but is vital for survival of the parasite.

Effect of Dietary Fat Content and Composition during Pregnancy on Fetal Hepatic HMG CoA Reductase Activities and Lipids in Rats

The effects of diets containing 20% (wt/wt) safflower, olive or palm oil or 5% (wt/wt) safflower oil when fed throughout gestation on hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and on plasma and liver lipids were studied in fetal rats at d 21 of gestation. Hepatic total and active HMG CoA reductase activity, plasma free cholesterol and liver triglyceride and phospholipid 18:2(n-6) levels were higher in fetuses of rats fed 20% than in those of rats fed 5% safflower oil. Fetuses of rats fed olive oil had higher active HMG CoA reductase levels than fetuses of rats fed 20% safflower or palm oil; their total reductase activity was similar to that of the safflower oil group and higher than that for the palm oil group. Fetal liver and plasma cholesterol and triglyceride, as well as liver phospholipid concentrations, were not altered by the type of oil fed. The diets containing safflower oil resulted in higher 18:2(n-6) and lower 18:1 levels in fetal liver phospholipid and triglycerides than did the diets containing palm or olive oil. These studies demonstrate that fetal liver HMG CoA reductase activity is influenced by the maternal diet fat content and composition although the effect of specific fatty acids is unknown.

Pharmacological investigation of bezafibrate, a hypolipidemic agent (2). Mechanism of the hypolipidemic action of bezafibrate in rats

The mechanism of the hypolipidemic action of bezafibrate was investigated in rats. Bezafibrate decreased the incorporation of 14C-acetic acid into the liver and serum triglyceride and inhibited liver acetyl CoA carboxylate activity. Bezafibrate increased liver beta-oxidation, but it had no effect on lipolysis and triglyceride secretion from the liver. Bezafibrate accelerated the elimination of serum triglyceride in Intralipid injected rats and increased tissue lipoprotein lipase activity. Bezafibrate decreased the incorporation of 14C-acetic acid into liver cholesterol and inhibited liver HMG-CoA reductase activity. Bezafibrate had no effect on cholesterol absorption and excretion. These results suggest that the hypotriglyceridemic actions of bezafibrate are due to inhibition of triglyceride synthesis and acceleration of triglyceride elimination and that the hypocholesterolemic action of bezafibrate is mainly due to inhibition of liver HMG-CoA reductase activity.

L-Carnitine treatment in the hyperlipidemic rabbit

A study was designed to examine the hypolipidemic effect of l-carnitine treatment (4 weeks, 170 mg/kg/d) in rabbits fed a high fat diet ( 5% corn oil 0.5% cholesterol , w w ). Eight weeks of exposure to the high fat diet significantly increased plasma total cholesterol and triglycerides. VLDL associated triglycerides, cholesterol, apo-B, and total protein were also significantly increased with the diet. There was no change in HDL-cholesterol levels. Plasma concentration of carnitine (free, acyl, and total) all increased significantly with the high fat diet. The content of free, short-chain, and total carnitine were decreased in the liver whereas the content of long-chain acylcarnitines was increased. The diet generated a significant steatosis within the livers of these animals. Four weeks of treatment of l-carnitine reduced the extent of the liver steatosis and significantly decreased plasma total cholesterol, triglycerides, VLDL associated triglycerides, cholesterol, and total protein. HDL-cholesterol levels were unaffected by the treatment. All plasma fractions of carnitine (free, acetyl, acyl, and total) were significantly increased above those levels seen after 8 weeks of the high fat diet alone. The content of liver carnitine and its esters was normalized following treatment. The high fat diet decreased liver HMG-CoA reductase activity and increased the activities of 7-α-hydroxylase and acylcholesterol acyltransferase (ACAT). l-Carnitine treatment blunted the magnitude of the diet induced increase in 7α-hydroxylase activity, yet overall the activity still remained elevated relative to controls. ACAT activity increased (1.5 times) with the high fat diet and increased further (4.5 times) following carnitine treatment. The mechanism(s) underlying the hypolipidemic effect of l-carnitine treatment in this animal model remain to be elucidated.

Metabolism of plasma mevalonate in rats and humans.

A circadian rhythm in plasma mevalonate was identified in human subjects. This variation, over a 5-fold range, is paralleled by a rhythm in urinary excretion. No such diurnal change in plasma mevalonate was observed in schedule-fed, light-cycled rats, despite the presence of a pronounced rhythm in liver HMG-Coa reductase and sterol synthesis. A linear correlation was found between liver HMG-CoA reductase activity and the rate of hepatic sterol synthesis. Sterol synthesis accounted for 59% of the HMG-CoA reductase activity. A 4-fold increase in plasma mevalonate following bilateral nephrectomy did not feed back on liver HMG-CoA reductase. Turnover rates for circulating R- and S-mevalonate were determined by the kinetics of tritiated tracers. S-Mevalonate exhibited first-order kinetics with a T 1/2 of 19 to 23 min, while R-mevalonate kinetics could be resolved into two phases with half-lives of 9 and 42 min. The renal uptake of circulating mevalonate was measured by the initial rate of increase in plasma mevalonate immediately following bilateral nephrectomy; this was confirmed by determination of the renal arterio-venous difference. This value ranges between 500 and 600 pmol/min for a 250-g rat.

Increased plasma cholesterol and decreased body lipid levels in wistar rats following pirinixil (BR 931) treatment

Pirinixil (BR 931), a new hypolipidemic agent, which has been reported to increase high density lipoprotein cholesterol levels in experimental animals was fed for 21 days (0.05% in the diet) to Wistar rats on a semi-sy n thetic diet. Pirinixil increased plasma cholesterol levels significantly without affecting plasma triglycerides. Liver cholesterol and triglycerides were markedly reduced by treatment, while combined plasma and liver lipid levels decreased approximately 20%. Liver HMG-CoA reductase activity was not affected, but cholesterol 7α-hydroxylase was significantly reduced, thus confirming data with other hypolipidemic agents in rats. The experimental findings do not support the recent hypothesis that hypolipidemic agents may increase total body lipid levels.