江頭 祐嘉合

Abstract UV-irradiated red perilla demonstrated promising protective effects against carbon tetrachloride-induced liver injury in mice. UV exposure significantly enhanced the accumulation of rosmarinic acid, malonylshisonin and shisonin in red perilla, and increased DPPH radical scavenging capacity. The hepatoprotective effect of UV-irradiated red perilla may be attributed to the high level of its polyphenolic compounds, which exhibit antioxidant activity.

Obesity is a major risk factor for some metabolic disorders including type 2 diabetes. Enhancement of peroxisome proliferator-activated receptor (PPAR) γ, a master regulator of adipocyte differentiation, is known to increase insulin-sensitive small adipocytes. In contrast, decreased PPARγ activity is also reported to improve insulin resistance. We have previously identified erucic acid as a novel natural component suppressing PPARγ transcriptional activity. In this study, we investigated the effect of erucic acid-rich yellow mustard oil (YMO) on obese/diabetic KK-Ay mice. An in vitro luciferase reporter assay and mesenchymal stem cell (MSC) differentiation assay revealed that 25 µg/mL YMO significantly inhibited PPARγ transcriptional activity and differentiation of MSCs into adipocytes but promoted their differentiation into osteoblasts. In KK-Ay mice, dietary intake of 7.0% (w/w) YMO significantly decreased the surrogate indexes for insulin resistance and the infiltration of macrophages into adipose tissue. Furthermore, 7.0% YMO increased bone mineral density. These results suggest that YMO can ameliorate obesity-induced metabolic disorders.

It is well known that dietary fiber helps to relieve and prevent constipation, and there are a number of scientific papers, including systematic reviews and meta-analyses on the effects of naturally derived dietary fiber on bowel movements. In recent years, there has been an increase in the manufacture of dietary fiber ingredients obtained from food raw materials, and these are now commonly available in the market. Resistant maltodextrin (RMD), a soluble dietary fiber, is manufactured from starch, and industrially produced soluble dietary fiber is used worldwide. While there are many reports on the effects of RMD on bowel movements, no systematic review or meta-analysis has been reported. We conducted a systematic review and meta-analysis to clarify the effect of RMD on bowel movements based on stool frequency and stool volume. We also investigated the subjective evaluation of RMD effects on bowel movements. Of a total of 314 potentially relevant articles, 28 articles met the eligibility criteria, and 29 randomized controlled trials were identified. As a result of integration analyses, we found that the intake of RMD significantly increased stool volume and stool frequency compared with placebo intake. Furthermore, RMD intake tended to improve sensation of complete/incomplete evacuation. In conclusion, the evidence suggests that RMD has a positive effect on bowel movements, contributing to normal bowel function. This finding will help in the development of new criteria for choice of dietary fiber in the process of developing food products.

Aims: Food-derived peptides have been reported to yield a variety of health promoting activities. Pyroglutamyl peptides are contained in the wheat gluten hydrolysate. In the present study, we investigated the effect of pyroglutamyl dipeptides on the lipopolysaccharide (LPS)-induced inflammation in macrophages. Main methods: RAW 264.7 macrophages were treated with LPS and various concentrations of pyroglutamyl-leucine (pyroGlu-Leu), -valine (pyroGlu-Val), -methionine (pyroGlu-Met), and -phenylalanine (pyroGlu-Phe). Cell viability/proliferation and various inflammatory parameters were measured by the established methods including ELISA and western blotting. The binding of fluorescein isothiocyanate-labeled LPS to RAW 264.7 cells was also measured fluorescently. Key findings: All the tested dipeptides significantly inhibited the secretion of nitric oxide, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 from LPS-stimulated RAW 264.7 macrophages. Above all, pyroGlu-Leu inhibited the secretion of all these inflammatory mediators even at the lowest dose (200 mu g/ml). PyroGlu-Leu dose-dependently suppressed I kappa B alpha degradation and MAPK (JNK, ERK, and p38) phosphorylation in LPS-stimulated RAW 264.7 cells. On the other hand, it did not affect the binding of LPS to the cell surface. Significance: Our results indicated that pyroGlu-Leu inhibits LPS-induced inflammatory response via the blocking of NF-kappa B and MAPK pathways in RAW 264.7 macrophages. (C) 2014 Elsevier Inc. All rights reserved.

A hepatoprotective peptide, pyroglutamyl leucine (pyroGlu-Leu), was identified in wheat gluten hydrolysate through an in vivo activity-guided fractionation approach based on D-galactosamine-induced acute hepatitis in rats and fractionation of peptides with large-scale preparative ampholine-free isoelectric focusing. The active acidic fraction predominantly consisted of pyroglutamyl peptides and free pyroglutamic acid. Pyroglutamyl peptides were derivatized with phenyl isothiocyanate after removal of a pyroglutamyl residue by pyroglutamate aminopeptidase. The derivatives were purified by reversed-phase HPLC and subjected to sequence analysis. The active fraction contained pyroGlu-Ile, pyroGlu-Leu, pyroGlu-Gln, pyroGlu-Gln-Gln, and free pyroGlu. Ingestion of pyroGlu-Leu at 20 mg/kg body weight significantly decreased serum aspartate and alanine aminotransferases to approximately 30% and 20% of those values of the vehicle group, respectively, which were near the normal levels. Thirty minutes after ingestion of pyroGlu-Leu at 20 mg/kg, the concentration of pyroGlu-Leu in portal blood plasma increased to approximately 2 mu M.

Psyllium, a dietary fibre rich in soluble components, has both cholesterol- and TAG-lowering effects. Many studies have verified these actions using liver samples, whereas little information is available on the effects of psyllium treatment on other organs. The purpose of the present study was to evaluate the possible beneficial effects of psyllium. We investigated the gene expression profiles of both liver and skeletal muscle using DNA microarrays. C57BL/6J mice were fed a low-fat diet (LFD; 7% fat), a high-fat diet (HFD; 40% fat) or a HFD with psyllium (40% fat+5% psyllium; HFD+Psy) for 10 weeks. Body weights and food intake were measured weekly. After 10 weeks, the mice were killed and tissues were collected. Adipose tissues were weighed, and plasma total cholesterol and TAG blood glucose levels were measured. The expression levels of genes involved in glycolysis, gluconeogenesis, glucose transport and fatty acid metabolism were measured by DNA microarray in the liver and skeletal muscle. In the HFD+Psy group, plasma total cholesterol, TAG and blood glucose levels significantly decreased. There was a significant reduction in the relative weight of the epididymal and retroperitoneal fat tissue depots in mice fed the HFD+Psy. The expression levels of genes involved in fatty acid oxidation and lipid transport were significantly up-regulated in the skeletal muscle of the HFD+Psy group. This result suggests that psyllium stimulates lipid transport and fatty acid oxidation in the muscle. In conclusion, the present study demonstrates that psyllium can promote lipid consumption in the skeletal muscle; and this effect would create a slightly insufficient glucose state in the liver.

Benifuuki contains unique methylated catechins such as epigallocatechin- 3- O-(3 -O-methyl) gallate (EGCG Me). The hot-water extract of Benifuuki (BE) is an ingredient useful for food industrial applications. In this study, we evaluated the suppressive effect of BE on postprandial hypertriglyceridemia in rats. Rats were fed CE-2 diet for 1 week and deprived of food overnight. A solution containing corn oil (1 mL/head) and BE (50 or 100 mg/head) was given orally. Corn oil (1 mL/head) was given in the control group. Blood was withdrawn via the jugular vein after administration. After the separation of plasma, triglyceride was measured. Increase of plasma triacylglycerol after the administration of corn oil in rats was delayed by BE. The area under the curve (AUC) of plasma triglycerides was significantly decreased (by 43%) in the 100 mg per head BE group, as compared with the control group. BE suppressed postprandial hypertriglyceridemia, which is a risk factor for coronary heart disease. These results suggest that BE may help to prevent postprandial hypertriglyceridemia.

This study was performed to examine the effect of rutin in buckwheat noodle on lipid metabolism in rats fed a high-fat, high-sucrose diet. Buckwheat noodles were prepared by traditional Japanese methods, and the experimental diets contained 40% dried buckwheat noodle powder. In experiment 1, rats from CLEA were fed Control (0), Low-rutin (182), Medium-rutin (385), High-rutin (980 mg rutin/100 g) or Catechin (352 mg catechin/100 g) diet for 3 weeks, and in experiment 2, rats from Charles River Laboratories were fed Control or High-rutin diets for 4 weeks. Results indicated that serum total cholesterol level in Medium- and High-rutin groups and the level of free fatty acids in the High-rutin group were significantly lower than that in the Control group (experiment 1). The former result was shown to be reproducible in experiment 2. These results suggested that the rutin in buckwheat noodle has beneficial effects on lipid metabolism.

We investigated in this study the effect of modified arabinoxylan from rice bran (MGN-3) and its fractions on D-galactosamine (D-GalN)-induced IL-18 expression and hepatitis in rats. Male Wistar rats were pretreated with MGN-3 or fractions of the MGN-3 hydrolysate, or with saline 1 h before administering D-GalN (400 mg/kg B.W.). The serum transaminase activities, IL-18 mRNA expression level in the liver and IL-18 concentration in the serum were determined 24 h after injecting D-GalN. Both the oral and intraperitoneal administration of MGN-3 (20 mg/kg B.W.) alleviated D-GalN-induced hepatic injury under these experimental conditions. The low-molecular-weight fraction (LMW) of MGN-3 showed the strongest protective effect on D-GalN-induced liver injury, its main sugar component being glucose. Moreover, the D-GalN-induced IL-18 expression was significantly reduced by treating with MGN-3 and LMW. The results suggest that MGN-3 and LMW could provide significant protection against D-GalN liver injury, and that IL-18 might be involved in their protective influence.

Water spinach (Ipomoea aquatica Forsk; I. aquatica) of the green-stemmed type (green type) is widely consumed, but there also exists a red-stemmed variety (red type). In the present study, the antioxidant capacity of the red type was compared to that of the green type in carbon tetrachloride (CCl4)-treated mice. CCl4-induced thiobarbituric acid reactive substrate (TBARS) formation in the liver was significantly suppressed in mice fed 5% red-type I. aquatica, while the green type showed no effect. Hydrophobic oxygen radical absorbance capacity (H-ORAC(FL)) in the red type showed a lower level than that in the green type: however, lipophilic ORAC (L-ORAC(FL)) and total-ORAC(FL) levels were significantly higher in the red type than in the green type. alpha-Tocopherol, anthocyanidin/proanthocyanidin, and beta-carotene contents were all significantly higher in the red type than in the green type. These results suggest that the wild red-type I. aquatica contains certain lipophilic components that exert antioxidant capacities not only in vitro but also in vivo. Such effective components in the red type would be beneficial phytochemicals for suppressing several diseases related to oxidative stress.

Val-Glu-Pro (VEP) is an angiotensin I-converting enzyme (ACE) inhibitory peptide derived from Spirulina platensis. The antihypertensive effect of VEP in spontaneously hypertensive rats (SHRs) was investigated in 24 h after one single dose and in one-week with one single dose per day. The expression regulation of VEP on major components of the renin-angiotensin system (RAS) in the kidney and serum of the SHRs was also explored with Real-Time PCR and enzyme-linked immunosorbent assay (ELISA). The results indicated that the least effective dose of VEP was 5 mg/kg and it exhibited a dose-dependent manner with increased dosages. The lowest weighted systolic blood pressure (WSBP) and weighted diastolic blood pressure (WDBP) occurred in 6 h and 4 h after administration, respectively. During the one-week experiment course, the WSBP of the VEP-treated group (10 mg/kg) was significantly lower than that of the negative control group from the 5th day. Furthermore, the VEP treatment significantly down-regulated the mRNA expression of renin, ACE, and the angiotensin II(Ang II) type 1 (AT1) receptor, and up-regulated the mRNA expression of the Ang II type 2 (AT2) receptor in the kidney of the SHRs, suggesting that the antihypertensive effect of VEP might be related to its inhibition on the RAS and that it might be of great prospects in prevention and treatment of hypertension.

The antihypertensive effect of an angiotensin I-converting enzyme (ACE) inhibitory peptide lie-Gin-Pro (IQP), whose sequence was derived from Spirulina platensis, was investigated in spontaneously hypertensive rats (SHRs) for 1 week. The weighted systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the peptide IQP-treated group were significantly lower than those of the negative control group from the third and fourth days, respectively. Accompanying the blood pressure reduction, a significant regulation of the expression of major components of the renin angiotensin system (RAS) was found in the treatment group, including downregulation of the mRNA levels of renin, ACE, and the angiotensin II type 1 (AT1) receptor in the kidney, as well as serum angiotensinogen (Ang), ACE, and angiotensin II (Ang II) concentrations. The treatment group also showed upregulation of mRNA expression of the angiotensin II type 2 (AT2) receptor in the kidney. Our findings suggested that IQP might be of potential use in the treatment of hypertension.

Increasing attention has been paid to Spirulina for its potential clinical uses. The present study investigated the protection by dietary Spirulina platensis against D-galactosamine (D-GaIN)- and acetaminophen (APAP)-induced hepatitis in ICR mice. Mice in each group (n 6) were fed with a standard diet (American Institute of Nutrition (AIN)-93G), a positive control diet containing 0.5 % butylated hydroxytoluene (BHT), or a diet containing 3, 6 or 9% S. platensis for 1 week. On the last day the mice were treated with D-GaIN (300 mg/kg body weight, intraperitoneally) or APAP (150 mg/kg body weight, intraperitoneally) and 24 h later the mice were killed. The doses of both 6 and 9 % S. platensis were found to significantly alleviate the increase of serum glutamate oxaloacetoacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) activities in D-GaIN- or APAP-intoxicated mice. The observation was very similar to that of the positive control groups. Two more experiments were carried out to investigate the involvement of thiobarbituric acid-reactive substances (TBARS) and IL-18 in the suppression of 6% S. platensis on D-GaIN- and APAP-induced hepatitis. The significant increase of GOT and OPT activities was found to be accompanied with the elevation of hepatic TBARS level, IL-18 mRNA expression and serum IL-18 concentration, and was significantly alleviated by supplementation with 6% S. platensis in diets. These results showed that dietary S. platensis could provide a significant protection against D-GaIN- and APAP-induced liver injuries, and IL-18 and lipid peroxidation might be involved in the protective influence of S. platensis.

To elucidate the mechanism by which dietary amino acids suppress the d-galactosamine (d-GalN)-induced hepatitis, we examined the involvement of Kupffer cells, tumor necrosis factor-alpha (TNF-alpha) and apoptosis in the mechanism. In experiment 1, the rats were fed with 10%l-glutamine or 5% glycine diet injected with d-GalN with or without gadolinium chloride (GdCl(3))-pretreatment. The results indicated that these amino acids suppressed the d-GalN-induced elevation of serum transaminase activities, irrespective of GdCl(3)-pretreatment. In experiment 2, rats were fed with 10% of l-glutamine, l-serine, l-alanine or l-glutamic acid diets injected with d-GalN. The results demonstrated that all these amino acids suppressed the d-GalN-induced elevation of serum transaminase activities, but that serum TNF-alpha concentrations and hepatic caspase-3 activities in the rats were not appreciably changed. In conclusion, the suppressive effects of amino acids on d-GalN-induced hepatitis were suggested not to be always mediated by the inhibition of Kupffer cells -> TNF-alpha -> apoptosis pathway.

Recently the l-tryptophan (Trp) metabolites such as l-kynurenine(Kyn), l-kinurenic acid, quinolinic acid (QA) and picolinic acid (PA) have been shown physiologically important in central nervous and immune system, and various enzyme activities concerning their production were reported to be affected by insulin-dependent diabetes mellitus. However, the states of these metabolites in diabetes have not been clarified enough yet. The present study was performed to make clear the states of the productions of l-Kyn, QA, PA and nicotinamide (Nam) in vitro in the hepatocytes prepared from streptozotocin (STZ)-induced diabetic rats using [5-(3)H]l-Trp. The diabetic model rats were made by STZ injection (60 mg/kg) and the hepatocytes isolated from the rats were incubated with [5-(3)H] l-Trp. The amounts of metabolites derived from l-Trp were determined by the isotope-dilution methods. The alpha-amino-beta-carboxymuconate-epsilon-semiarldehyde decarboxylase (ACMSD) mRNA level in the diabetic group was greatly higher than that in the control group. In the STZ-induced diabetes group, the amount of [5-(3)H]l-Trp converted to tritiated water, l-Kyn or QA were found to be more than 3 times of that in the control group, respectively. The produced amounts of PA and Nam were not significantly different between the diabetic and the control groups. It is suggested that STZ-diabetes mellitus causes augmentations of both l-Kyn and QA generations but not those of PA and Nam in liver, indicating the possibility that the immune and neuronal systems of insulin dependent diabetes mellitus would be influenced by the increased amounts of lKyn and QA but not by those of PA and Nam.

D-Galactosamine (GaIN) induces acute hepatitis in experimental animals and this hepatitis has been shown to be suppressed by preceding ingestion of amino acids such as Gly, L-Ser, and L-GIn. However, little is known about the mechanism of its action. The present study shows for the first time that IL-18 reduction is involved in the suppressive actions Of L-GIn and L-Ser on GaIN-induced hepatitis. Elevation of IL-18 mRNA expression in liver and its concentration in serum in GaIN-treated rats were found to be suppressed by preceding ingestion of 10% L-Gln- or 10% L-Ser diets, and resulted in the attenuation of the increase in serum transaminase (ALT and AST) activities, indexes of hepatic injury. These results suggest that suppressive effects of some dietary amino acids on the GaIN-induced hepatitis are mediated by IL-18 reduction. (c) 2008 Elsevier Inc. All rights reserved.

Hepatic α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) plays a key role in regulating NAD biosynthesis. In normal rats, ACMSD has been generally detectable only in the liver and kidneys. Therefore, there is a possibility that liver or kidney injury affects tryptophan-niacin metabolism. We previously reported the significant change of tryptophan-niacin metabolism in rats with liver cirrhosis or in rats with d-galactosamine injected liver injury. In this experiment, we investigated the change of tryptophan-niacin metabolism in rats treated with puromycin aminonucleoside (PAN)-induced nephrosis, the mechanisms responsible for their change of urinary excretion of nicotinamide and its metabolites, and the role of the kidney in tryptophan-niacin conversion. In PAN-treated rats, the sum of urinary excretion of nicotinamide and its metabolites was significantly lower compared with controls. Although kidney ACMSD activity was reduced, the conversion of tryptophan to niacin tended to be lower in the PAN-treated rats. The reduction of urinary excretion of niacin in nephrotic rats may be due to the reduction of blood tryptophan concentration. The role of the kidney ACMSD may be insignificant concerning tryptophan-niacin conversion under this experimental condition. © 2006 Elsevier B.V. All rights reserved.

Dietary polyunsaturated fatty acid (PUFA) suppresses hepatic α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) [EC4.1.1.45] activity and mRNA level in rats. In this study, to examine whether down-regulation of ACMSD mRNA by PUFA involves PPARα-mediated mechanism or not, we investigated the effect of PUFA on the ACMSD level by using primary cultured rat hepatocytes. The primary cultured hepatocytes which were isolated from rats were incubated with fatty acids, WY-14,643 (a PPARα agonist) and/or MK-886 (a PPARα antagonist). ACMSD and acyl-CoA oxidase (ACO) as peroxisome marker enzyme mRNA level levels were determined by competitive RT-PCR method. These results lead us to the conclusion that the mechanism of decreased level of ACMSD mRNA by PUFA was different from that by WY-14,643, suggesting that there would be pathways other than a PPARα-mediated one for PUFA to regulate ACMSD mRNA level. © 2007 Elsevier B.V. All rights reserved.

Previous studies in our laboratory demonstrated the repressive effect of sea-weeds (Laminaria sp., Sargassinn fulvellum, Eisenia bicyclis and Gelidium sp.) against D-galactosamine (D-GalN)-induced hepatopathy. However, the mechanism by which these four seaweeds attenuate the D-GaIN-hepatopathy has not been completely clarified. This study was carried out to determine the constituents of these seaweeds that protect rats against the D-GaIN-hepatopathy. Male Wistar rats were fed for 8 d diets containing 5% seaweeds with or without the antibiotic neomycin (NEO) in experiment 1, and typical seaweed dietary fibers (laminaran, fucoidan, alginate, agar and K-carrageenan) of these seaweeds in experiment 2. On the 7th day, the rats were treated with D-GaIN (1,900 mg in experiment I and 800 mg/ kg in experiment 2) and then sacrificed 24 h after the injection of D-GaIN. Their serum transaminase (aspartate and alanine aminotransferases: AST and ALT) activities were then determined. In experiment 1, the serum AST and ALT levels in the rats fed the four kinds of seaweeds without NEO were significantly low in comparison to that of the control group, but those with NEO were not significantly different among the groups. In experiment 2, the serum AST and ALT levels in the rats fed fucoidan were significantly low in comparison to those of the other groups fed the dietary fibers and the control. These results suggest that the protective effect of the three kinds of brown seaweeds Laininaria sp., Sargassuin fulvelluni and Eisenia bicyclis against D-GaIN-hepatopathy was caused at least in part by fucoidan.

In the present study we investigated the effects of 11 kinds of edible scaweeds (6 brown and 5 red algae) which contain characteristic seaweed dietary fibers on the induction of D-GalN (D-galactosamine)-hepatopathy in rats (Exps. 1 and 2). Then, the efficacy of various components prepared from Gelidium sp., which was found to alleviate the hepatopathy in Exps. 1 and 2, was examined (Exp. 3). The rats were fed the diets containing various kinds of seaweeds (Exps. 1 and 2), or several components of Gelidium sp. such as total dietary fiber (TDF), soluble dietary fiber (SDF), insoluble dietary fiber (IDF) and dietary fiber-free components (DFFQ (Exp. 3), for 8 d. The rats in all experiments were injected with D-GalN (800 mg/kg body weight) intraperitoneally at the 7th day to induce liver injury and were sacrificed 24 h after the injection Of D-GaIN. The serum transaminase activities (ALT and AST) and lactate dchydrogenase (LDH) were determined to evaluate the levels of hepatopathy. In Exp. 3, the total GSH concentration in the liver, plasma and cecal contents and organic acid concentration in cccal contents were also evaluated. In Exps. 1 and 2, repressive effects against D-GalN-hepatopathy were shown by four seawccds Lanlinaria sp., Gelidiuni sp., Sargasstim ftilvelluin and Eisenia bicyclis. In Exp. 3, it was found that protective activity in Gelidittin sp. against D-GalN-hepatopathy existed not only in the SDF but also in the DFFC fraction. The results in Exp. 3 also indicated that the total GSH but not organic acid concentration in the cecal contents were significantly correlated with serum AST activity, suggesting that the protective effect of Gelidiuni sp. on D-GalN-hepatopathy in rats is related to GSH metabolism in the intestine.

Chlorella powder (CP) has a hypocholesterolemic effect and high bile acid-binding capacity; however, its effects on hepatic cholesterol metabolism are still unclear. In the present study, male Wistar rats were divided into four groups and fed a high sucrose + 10% lard diet (H), an H + 10% CP diet (H + CP), an H + 0.5% cholesterol + 0.25% sodium cholate diet (C), or a C + 10% CP diet (C + CP) for 2 weeks. CP decreased,serum and liver cholesterol levels significantly in rats fed C-based diets, but did not affect these parameters in rats fed H-based diets. CP increased the hepatic mRNA level and activity of cholesterol 7 alpha-hydroxylase (CYP 7A1). CP increased hepatic HMG-CoA reductase (HMGR) activity in the rats fed H-based diets, but not in rats fed C-based diets. CP did. not affect hepatic mRNA levels of sterol 27-hydroxylase, HMGR, low-density lipoprotein (LDL) receptor, scavenger receptor class B1, ATP-binding cassette (ABC) A1, ABCG5, or ABCB11 Furthermore, the effect of a 3.08% Chlorella indigestible fraction (CIF, corresponding to 10% CP) on hepatic cholesterol metabolism was determined using the same animal models. CIF also decreased serum and liver cholesterol levels significantly in rats fed C-based diets. CIF increased hepatic CYP7A1 mRNA levels. These results suggest that the hypocholesterolemic effect of CP involves enhancement of cholesterol catabolism through up-regulation of hepatic CYP7A1 expression and that CIF contributes to the hypocholesterolemic effect.

Nuclear receptors are involved in regulating the expression of cholesterol 7 alpha-hydroxylase (CYP7A1), however, their roles in the up-regulation of CYP7A1 by cholestyramine (CSR) are still unclear. In the present study, male Wistar rats were divided into four groups and fed [high sucrose + 10% lard diet] (H), [H + 3% CSR diet] (H + CSR), [H + 0.5% cholesterol + 0.25% sodium cholate diet] (C), or [C + 3% CSR diet] (C + CSR) for 2 weeks. Cholestyramine decreased serum and liver cholesterol levels significantly in rats fed C-based diets, but had no effect on these parameters in rats fed H-based diets. Cholestyramine raised hepatic levels of CYP7A1 mRNA and activity in both groups. The gene expression of hepatic ATP-binding cassettes A1 and G5, regulated by liver X receptor (LXR), were unchanged and down-regulated by cholestyramine, respectively. The mRNA levels of the hepatic ATP-binding cassette B11 and short heterodimer partner (SHP), regulated by farnesoid X receptor (FXR), were not changed by cholestyramine. C-based diets, which contained cholesterol and cholic acid, increased SHP mRNA levels compared to H-based diets. Consequently, in rats fed the C + CSR diet, hepatic FXR was activated by dietary bile acids, but the hepatic CYP7A1 mRNA level was increased 16-fold compared to that in rats fed an H diet. These results suggest that cholestyramine up-regulates the expression of CYP7A1 independently via LXR- or FXR-mediated pathways in rats. (c) 2006 Elsevier Inc. All rights reserved.

Hepatic alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylate (ACMSD) [EC4.1.1.45] plays a key role in regulating NAD biosynthesis from tryptophan. The aim of this study was to evaluate the ACMSD mRNA expression after pyrazinamide or peroxisome proliferators ingestion. When rats were fed a control (pyrazinamide- and clofibrate-free) diet, 1% pyrazinamide- or 0.24% clofibrate-containing diets for 8 days, hepatic ACMSD activity and mRNA in rats consuming the clofibrate-containing diet was strongly suppressed, as compared with those fed the control and pyrazinamide diet. Pyrazinamide suppressed liver and kidney ACMSD activities, but did not affect ACMSD mRNA. Blood NAD was increased in the colfibrate and pyrazinamide groups. Shifting from the control diet to a clofibrate diet suppressed ACMSD mRNA strongly at day 1 and continued through day 4. However ACMSD activity decreased gradually. In rats fed with several kind of perozisome-proliferator-containing diets such as phthalate ester, bezafibrate, Wy-14,643, 2-(-4-chlorophenoxy) propionic acid, or dehydroisoandrosterone for 8 days, hepatic ACMSD mRNA was drastically decreased by all the peroxisome proliferators. These results suggest that the transcription level of hepatic ACMSD is modulated by peroxisome proliferators, and the fluctuation of the hepatic ACMSD mRNA expression was followed by that of the ACMSD activity. However, pyrazinamide does not affect the transcription level of hepatic ACMSD.