Choleretic activity and biliary elimination of lipids and bile acids induced by an artichoke leaf extract in rats

The therapeutic properties of artichoke (Cynara scolymus L.) preparations have been known since ancient times. The traditional use of artichoke leaf extract (ALE) in gastroenterology is mainly based upon its strong antidyspeptic actions which are mediated by its choleretic activity. The aim of this study was to investigate the effects of ALE on bile flow and the formation of bile compounds in anaesthetised Wistar rats after acute and repeated (twice a day for 7 consecutive days) oral administration. A significant increase in bile flow was observed after acute treatment with ALE as well as after repeated administration. The choleretic effects of ALE were similar to those of the reference compound dehydrocholic acid (DHCA). Total bile acids, cholesterol and phospholipid were determined by enzymatic assays. There was a strong ALE-induced increase in total bile acid concentration over the entire experiment. With the highest dose (400 mg/kg), a significant increase was obtained after single and repeated administration. The bile acids-increased effects of ALE were much more pronounced than those of reference (DHCA). No significant differences in cholesterol and phospholipid content could be found.     

Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits

The preventive effects of simvastatin (MK-733) and pravastatin (CS-514), 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors, on hypercholesterolemia induced by 0.25% cholesterol feeding were compared in rabbits. MK-733 (6, 2 and 0.7 mg/kg) was found to prevent the increase in serum total cholesterol levels dose-dependently. High dose CS-514 (18 mg/kg) also limited the increase in the cholesterol levels, but medium (6 mg/kg) and low doses (2 mg/kg) of CS-514 were ineffective in preventing it. MK-733 inhibited the increase in VLDL and LDL cholesterol levels dose-dependently. MK-733 suppressed the increase in serum phospholipid levels. MK-733 inhibited the accumulation of cholesterol in the liver. The high dose of CS-514 also limited it. High dose MK-733 (6 mg/kg) reduced the cholesterol concentration in gallbladder bile. Neither MK-733 nor CS-514 affected bile acid excretion in the gallbladder bile. High dose MK-733 decreased the lithogenic index. MK-733 increased the number of LDL receptors, and high dose CS-514 also increased it. The suppressive effect of CS-514 on serum cholesterol levels at 18 mg/kg was found to be less than that of MK-733 at 0.7 mg/kg.     

Pituitary control of cholesterol metabolism in normal and LDL receptor knock-out mice: effects of hypophysectomy and growth hormone treatment

The pituitary is important in the control of lipid metabolism and studies of hypophysectomized (Hx) rats have shown strong effects of growth hormone (GH) on bile acid synthesis, hepatic LDL receptor (LDLR) expression and on the sensitivity to dietary cholesterol. It is unclear if mice may be used in such studies. The aim of the current study was to evaluate if Hx mice may be used to further explore how GH modulates cholesterol and bile acid metabolism, and to define the importance of the LDLR in this regulation by studying LDLR-deficient mice (LDLRko). Experiments on three mouse strains showed that, following Hx, HDL were reduced and LDL increased. Cholesterol/fat feeding of Hx mice increased serum cholesterol levels 2- to 3-fold. Serum triglycerides were reduced 50% in Hx mice; a further 30% reduction was seen after dietary cholesterol/fat. A serum marker for CYP7A1-mediated bile acid synthesis (C4) increased 2-fold in intact mice on cholesterol/fat diet. In Hx mice C4 levels were reduced by 50% as compared to intact controls, but were unexpectedly increased to levels seen in normal mice upon cholesterol/fat feeding. Hx of LDLRko mice moderately increased LDL-cholesterol and reduced triglycerides and GH treatment attenuated these effects; serum C4 levels were increased by GH treatment in all groups. In conclusion, mice can be used to explore the role of the pituitary in lipid metabolism. CYP7A1 is generally reduced in Hx mice but has a normal stimulatory response following dietary cholesterol suggesting that faulty regulation of CYP7A1 is not important for the reduced resistance to dietary cholesterol in Hx mice. Further, the LDLR is only to a minor part involved in the pituitary regulation of serum cholesterol in mice.     

Hypolipidemic activity of Achyranthus aspera Linn in normal and triton induced hyperlipemic rats.

The alcoholic extract of A. aspera, at 100 mg/kg dose lowered serum cholesterol (TC), phospholipid (PL). triglyceride (TG) and total lipids (TL) levels by 60, 51, 33 and 53% respectively in triton induced hyperlipidemic rats. The chronic administration of this drug at the same doses to normal rats for 30 days, lowered serum TC, PL, TG and TL by 56, 62, 68 and 67% respectively followed by significant reduction in the levels of hepatic lipids. The faecal excretion of cholic acid and deoxycholic acid increased by 24 and 40% respectively under the action of this drug. The possible mechanism of action of cholesterol lowering activity of A. aspera may be due to rapid excretion of bile acids causing low absorption of cholesterol.     

Lipid lowering and antioxidant effects of Amomum subulatum seeds (Family Zingiberaceae) in cholesterol fed rabbits

In the present study, hypolipidemic activity of fraction (50:50; CHCl₃:CH₃OH) of Amomum subulatum (Zingiberaceae) seeds was evaluated in cholesterol-fed rabbits. Hyperlipidemia induced by feeding atherogenic diet for 120 days resulted in a significant increase in serum total cholesterol, phospholipid and triglyceride levels when compared with control group. The levels of LDL and VLDL-cholesterol were increased significantly, but the HDL-cholesterol ratio was decreased. The changes in the antioxidant parameters were accompanied by an increase in lipid peroxidation and reduction in glutathione (GSH) and catalase activity. The level of lipid peroxidation was reduced whereas GSH content and catalase activity were elevated after the treatment with A. subulatum fraction at the dose level of 100 mg/kg.b.wt/day. A significant reduction was observed in total cholesterol, triglyceride, phospholipid, LDL and VLDL cholesterol where as HDL-cholesterol ratio was increased after administration of A. subulatum. The results of the present study indicate that fraction of A. subulatum possesses lipid-lowering and antioxidant activity and could be beneficial in the treatment of hyperlipidemia.     

Effects of short-term treatment with a combined oestrogen-progestin oral contraceptive on biliary lipids and cholesterol saturation index in young women

The effect of daily ingestion for 7 days of ethinyloestradiol (30 micrograms) plus DL-norgestrel [0.5 mg] (Eugynon-30) on the lipid composition of duodenal bile in 8 healthy young women was investigated from the fifth day after onset of menstrual bleeding. This treatment did not significantly affect the concentrations of cholesterol, phospholipid and total bile acids expressed as mmol/l, nor the mean molar percentage of phospholipid. However, the treatment caused a significant increase in the mean molar percentage of cholesterol which was accompanied by a significant decrease in the mean molar percentage of total bile acids. The cholesterol saturation index of the bile of 7 subjects was elevated after treatment while both serum cholesterol and testosterone were significantly reduced. The results show that administration to healthy young women, not previously exposed to oral contraceptives, with a low oestrogen-progestin preparation for only 7 days produces a more lithogenic bile, accompanied by a decrease in serum cholesterol and plasma testosterone concentrations.     

Thyroid hormone differentially augments biliary sterol secretion in the rat. II. The chronic bile fistula model.

To further define thyroid hormone effects on bile acid synthesis and biliary lipid secretion, studies were done in chronic bile fistula rats. Euthyroid and methimazole-hypothyroid rats, with and without triiodothyronine (T3) injection, had total bile diversion for timed bile collections. With interrupted enterohepatic circulation, cholesterol absorption is negligible and bile acid secretion equals bile acid synthesis rate. Hypothyroid rats had diminished levels of bile acid synthesis and biliary secretion of cholesterol and phospholipid. Single dose T3 injection produced a 13-fold increase in bile cholesterol secretion and a 3-fold increase in phospholipid secretion, both initiated 12 h after T3. Bile acid synthesis increased by 50%, but the increase did not begin until 24 h after T3. Neither hypothyroidism nor T3 treatment abolished diurnal rhythms of bile acid synthesis and biliary lipid secretion. Inhibition of cholesterol synthesis with lovastatin resulted in a persistent 33% decrease in bile acid synthesis in euthyroid and hypothyroid rats, while bile cholesterol secretion only transiently decreased. Inhibition of cholesterol synthesis did not alter T3-induced bile cholesterol secretion, with a 10-fold increase seen. However, bile acid synthesis was not stimulated by T3 in the presence of lovastatin. We conclude that facilitated bile acid synthesis and biliary cholesterol secretion are early effects of T3 and may account for the hypocholesterolemia of T3. Cholesterol synthesis does not appear to be required for the T3-induced bile cholesterol secretion.     

Enterostatin (VPDPR) and its peptide fragment DPR reduce serum cholesterol levels after oral administration in mice

We found that enterostatin (VPDPR), an anorexigenic peptide for a high-fat diet, significantly reduces serum cholesterol levels after oral administration of 100 mg/kg for 3 days in mice fed a high cholesterol-cholic acid diet. DPR, a peptide fragment of VPDPR, also had hypocholesterolemic activity at a dose of 50 mg/kg. Food intake was not suppressed under these dietary conditions. Fecal excretion of cholesterol and bile acids was increased significantly by both VPDPR and DPR. Interestingly, DPR induced hypocholesterolemic effects just two hours after a single oral administration at a dose of 100 mg/kg.     

Enterostatin (VPDPR) and Its Peptide Fragment DPR Reduce Serum Cholesterol Levels after Oral Administration in Mice

We found that enterostatin (VPDPR), an anorexigenic peptide for a high-fat diet, significantly reduces serum cholesterol levels after oral administration of 100 mg/kg for 3 days in mice fed a high cholesterol-cholic acid diet. DPR, a peptide fragment of VPDPR, also had hypocholesterolemic activity at a dose of 50 mg/kg. Food intake was not suppressed under these dietary conditions. Fecal excretion of cholesterol and bile acids was increased significantly by both VPDPR and DPR. Interestingly, DPR induced hypocholesterolemic effects just two hours after a single oral administration at a dose of 100 mg/kg.     

Biliary lipid secretion in patients with heterozygous familial hypercholesterolemia and combined hyperlipidemia. Influence of bezafibrate and fenofibrate

Serum and biliary lipid metabolism were examined in 13 patients with different types of hyperlipoproteinemia before and after 4 weeks of treatment with either bezafibrate or fenofibrate. In patients with heterozygous familial hypercholesterolemia (FH), bezafibrate (n = 5) and fenofibrate (n = 7) produced a similar significant reduction of total cholesterol, LDL-cholesterol, and triglycerides by 21, 23, and 32%, respectively. In patients with familial combined hyperlipidemia (CHL), only triglycerides decreased markedly. Biliary lipid secretion rates in patients with heterozygous FH were not different from those of young male volunteers, indicating that a reduction of hepatic LDL receptors did not affect hepatic elimination of cholesterol or bile acids. Biliary cholesterol secretion increased significantly from 57 to 75 mg/hr during bezafibrate therapy (n = 8) and from 62 to 71 mg/hr during fenofibrate therapy (n = 9). No consistent change in bile acid or phospholipid secretion was observed. The elevated output of biliary cholesterol increased cholesterol saturation significantly from 147 to 185% and from 152 to 173% during administration of bezafibrate and fenofibrate, respectively. The present study indicates that treatment with bezafibrate or fenofibrate is effective in lowering LDL cholesterol in patients with heterozygous FH, but both drugs increase cholesterol saturation of bile, which might enhance the risk of cholesterol gallstone formation.     

Influence of cyclic Ovosiston therapy on plasma lipid fractions of free cholesterol, total cholesterol and phospholipid

Serum levels of free and total cholesterol and phospholipids were st udied in 84 women (average age 43.8 years) treated with Ovosiston for 1 to more than 9 months. Controls were 19 untreated women (average age 45 years). Total cholesterol and phospholipid levels were significantly greater in women treated for more than 3 months, but no significant change in free cholesterol levels was observed. Serum lipid levels were examined continuously in 6 women during several treatment cycles, and a trend toward increasing phospholipid levels was seen in 5 women; this trend reversed when treatment was interrupted. It is concluded that the characteristic increases in total cholesterol and phospholipid levels occur after the 2nd or 3rd treatment cycle.     

Biliary lipid secretion in hypercholesterolemia.

A report on the effects of primary bile acid ingestion alone or in combination with plant sterols on serum cholesterol levels, biliary lipid secretion, and bile acid metabolism. Biliary bile acid and cholesterol secretion were measured in four patients with type IIa hypercholesterolemia before and after randomized treatment periods. During these periods either a bile acid mixture (cholic-chenodeoxycholic 2:1, a proportion similar to that endogenously synthesized in health), at a level of 20 mg/kg, or the same mixture plus sitosterols, 200 mg/kg, was fed. Serum cholesterol and the cholesterol saturation of fasting-state bile was also measured. Pretreatment biliary lipid secretion was within normal limits. Bile acid kinetic measurements were also recorded before treatment and showed that cholic acid synthesis was disproportionately decreased relative to that of chenodeoxycholic acid, a finding previously reported by others. Administration of the bile acid mixture increased biliary bile acid secretion in 3 of 4 patients, but did not influence biliary cholesterol secretion. The combination of sitosterol-bile acid, however, caused a relative decrease in cholesterol secretion in bile, and fasting-state bile became unsaturated in all patients. No change in fecal neutral sterol excretion occurred during the beta-sitosterol-bile acid regimen, suggesting that simultaneous bile acid feeding blocks the compensatory increase in cholesterol synthesis known to be induced by beta-sitosterol feeding in hypercholesterolemic patients. Serum cholesterol levels also fell modestly during the sitosterol-bile acid regimen, the decrease averaging 15%. We conclude that the abnormally low rate of bile acid synthesis in patients with type IIa hyperlipoproteinemia does not influence biliary lipid secretion; that increasing the input of the two primary bile acids into the enterohepatic circulation does not increase biliary cholesterol secretion or lower serum cholesterol levels in such patients; and that the usual increase in cholesterol synthesis induced by beta-sitosterol feeding does not occur if bile acids are administered simultaneously.     

Influence of hydrocortisone acetate administered to the lactating rat on lipid composition of the milk and serum lipid levels in dams and pups

The influence of i.m. administration of hydrocortisone acetate to the mother (doses of 0.4, 0.8 or 2 mg/100 g body weight/day) during the first 15 days of lactation on milk composition in fatty acids mother and pups serum levels of lipids and their effect on pups' growth is studied. Serum levels of cholesterol and triglycerides in mothers increase at any of the experimental doses. Daily injections of 2 mg/100 g bw to the mother cause an increase in the percentage of C16 as well as in the level of fatty acids derived from linoleic and linolenic acids while reducing the percentage of C18:1. The treatment brings about a higher level in total lipids in the milk which is proportional to the dose. Doses of 0.4 and 0.8 mg increase the percentage of C8 and C10, while the dose of 2 mg enhances the % of C16. A fall in the uptake of linoleic acid by the mammary gland is observed when using any of the experimental doses. No change is observed either in the weight of pups or in serum cholesterol levels while triglyceride level is increased by the effect of treatment. The higher dose increases the level of linolenic acid and some of its derivates.     

Selective inhibition of CYP27A1 and of chenodeoxycholic acid synthesis in cholestatic hamster liver

The aim of this study was to explore the regulation of serum cholic acid (CA)/chenodeoxycholic acid (CDCA) ratio in cholestatic hamster induced by ligation of the common bile duct for 48 h. The serum concentration of total bile acids and CA/CDCA ratio were significantly elevated, and the serum proportion of unconjugated bile acids to total bile acids was reduced in the cholestatic hamster similar to that in patients with obstructive jaundice. The hepatic CA/CDCA ratio increased from 3.6 to 11.0 (P<0.05) along with a 2.9-fold elevation in CA concentration (P<0.05) while the CDCA level remained unchanged. The hepatic mRNA and protein level as well as microsomal activity of the cholesterol 7alpha-hydroxylase, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase and 5beta-cholestane-3alpha,7alpha,12alpha-triol 25-hydroxylase were not significantly affected in cholestatic hamsters. In contrast, the mitochondrial activity and enzyme mass of the sterol 27-hydroxylase were significantly reduced, while its mRNA levels remained normal in bile duct-ligated hamster. In conclusion, bile acid biosynthetic pathway via mitochondrial sterol 27-hydroxylase was preferentially inhibited in bile duct-ligated hamsters. The suppression of CYP27A1 is, at least in part, responsible for the relative decreased production of CDCA and increased CA/CDCA ratio in the liver, bile and serum of cholestatic hamsters.     

Effect of melatonin on hyperlipidemic nephropathy under constant light exposure

Studies have shown anti-hyperlipidemic actions of melatonin, with pharmacological doses inducing changes in cholesterol levels. This study was designed to evaluate the effect of melatonin on adriamycin-induced (25mg/kg b.w., i.p.) hyperlipidemia under constant light exposure. Melatonin was injected i.p. (1,000 microg/kg b.w./day). Triglycerides, total cholesterol, high-density lipoprotein cholesterol, light-density lipoprotein cholesterol, non-proteic nitrogen compounds (urea and creatinine levels), total protein in serum, proteins eliminated in the urine and melatonin levels in serum and kidney were determined. Results show a decrease in melatonin levels induced by both adriamycin and constant light. Likewise, adriamycin induced significant increases in triglycerides, total cholesterol and light-density lipoprotein cholesterol, and lowered high-density lipoprotein cholesterol levels. Constant light exposure also prompted an increase in LDL-c levels and a decrease in HDL-c values, and intensified the effects of adriamycin on these two lipoproteins. All changes induced by adriamycin and constant light were reverted toward normality by melatonin administration.     

Effects of ethyl alcohol and acetaldehyde on certain biochemical parameters of blood in Wistar rats

Ethyl alcohol injected intraperitoneally to rats in a dose of 3 g/kg of body weight caused hypoglycaemia which was not observed after similar administration of acetaldehyde in a dose od 0.3 g/kg. The serum levels of lipids and total cholesterol were unchanged after administration of ethyl alcohol while acetaldehyde decreased to cholesterol level 0.5, 1.5 and 3 hours after administration. Both these compounds raised the serum activity of AspAT and AlAT, and this rise was observed 0.5 hour after ethyl alcohol and 6 hours after acetaldehyde.     

Modulatory effect of curcumin on methionine-induced hyperlipidemia and hyperhomocysteinemia in albino rats

The present study was designed to investigate the antioxidant effect of curcumin on methionine-induced hyperlipidemia and hyperhomocysteinemia in Wistar rats (200-250 g) of either sex. The vehicle control rats were treated with 1% Tween 80 in normal saline (2 ml/kg, po) for 30 days. Hyperlipidemia and hyperhomocysteinemia was induced by methionine administration (1 g/kg, po) for 30 days. A significant increase in total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C) and homocysteine levels in serum and thiobarbituric acid reactive substances (TBARS) levels in heart homogenates were observed with a concomitant decrease in serum high density lipoprotein (HDL-C) levels in pathogenic control (i.e. group II) rats, as compared to vehicle control (i.e. group I) rats. Further, curcumin (200 mg/kg, p.o.) treatment in methionine treated rats for 30 days significantly decreased the total cholesterol, triglycerides, LDL-C and homocysteine levels in serum and TBARS levels in heart homogenates and increased serum HDL-C levels, as compared to pathogenic control (i.e. group II) rats. The results of biochemical observations were supplemented by histopathological examination of rat's aortic section. The results of test drug were comparable to that obtained with folic acid (100 mg/kg, p.o.). The results suggest that curcumin has significant antihyperlipidemic and antihyperhomocysteinemic effect against methionine-induced hyperlipidemia and hyperhomocysteinemia in rats.     

A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis

The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9^th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for reducing hypertriglyceridemia and hepatic lipid accumulation in the presence of fructose.     

Characterization of serum and urinary bile acids in patients with primary biliary cirrhosis by gas-liquid chromatography-mass spectrometry: effect of ursodeoxycholic acid treatment

We have studied the effect of ursodeoxycholic acid on the serum and urinary bile acids in seven patients with moderate to severe primary biliary cirrhosis. Bile acids were characterized by gas-liquid chromatography-mass spectrometry and quantified by capillary gas-liquid chromatography. Serum bile acids were elevated 26-fold over control values, with 2.2 times more cholic acid than chenodeoxycholic acid. Urinary bile acid output was elevated 22-fold over control values with a cholic acid:chenodeoxycholic acid ratio of 1.6. In addition, lithocholic acid, deoxycholic acid, ursodeoxycholic acid, 1 beta-hydroxycholic acid, 1 beta-hydroxydeoxycholic acid, and hyocholic acid were identified in both serum and urine; the proportions of the 1- and 6-hydroxylated bile acids were much higher in urine than in serum of the patients (32.1% versus 4.2%). Three months of placebo administration did not change the serum and urinary bile acid composition. In contrast, ursodeoxycholic acid feeding (12-15 mg/kg body weight per day) for 6 months resulted in a 25% decline in the total serum bile acid concentration from the pretreatment values. The proportion of ursodeoxycholic acid increased from 2.1 to 41.2% of total bile acids, so that total fasting serum endogenous bile acid levels decreased 62.4%. Ursodeoxycholic acid feeding substantially increased urinary bile acid output, with ursodeoxycholic acid comprising 58.1%. The proportion of 1- and 6- hydroxylated endogenous bile acids was reduced by 45.5% from pretreatment levels and approximately 4.5% of the urinary bile acids were omega-muricholic acid, 1 beta-hydroxyursodeoxycholic acid, and 21-hydroxyursodeoxycholic acid. These results demonstrate significant changes in the serum and urinary bile acid pattern in primary biliary cirrhosis during ursodeoxycholic acid treatment. The beneficial effect of ursodeoxycholic acid may be due to reduction of the hydroxylated derivatives of endogenous bile acids together with the appearance of hydroxylated derivatives of ursodeoxycholic acid or it may be due to displacement of the more hydrophobic endogenous bile acids by the hydrophilic ursodeoxycholic acid.     

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435

Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC50 = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E-/- (apoE-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by 相似文献