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Susumu Tazuma

Publications and source records attributed to Susumu Tazuma.

11 recordsLinked to original sources
PubMed2003

AT1A-deficient mice show less severe progression of liver fibrosis induced by CCl(4).

The renin-angiotensin system has been shown to contribute to fibrogenesis in varieties of organs, including the liver. Here, we investigated whether the angiotensin II type 1A receptor (AT1A) is implicated in the development of liver fibrosis, using AT1A-deficient and wild-type (WT) mice. After single dose of carbon tetrachloride (CCl(4)), there were no significant differences between two groups with regard to hepatic inflammation and necrosis. After 4 weeks of treatment with CCl(4), histological examination revealed that AT1A-deficient mice showed less infiltration of inflammatory cells and less severe progression of liver fibrosis compared with WT mice. These findings were accompanied by the hepatic content of hydoxyproline and the expression of alpha-smooth muscle actin (alpha SMA). The level of transforming growth factor-beta 1 (TGF-beta 1) messenger RNA was markedly higher in WT mice when compared with AT1A-deficient mice. These results confirm that signaling via AT1A plays a pivotal role in hepatic fibrogenesis.

Animals↗
PubMed2003

Inhibition of cholesterol crystallization under bilirubin deconjugation: partial characterization of mechanisms whereby infected bile accelerates pigment stone formation.

Pigment gallstones have been reported to be closely associated with biliary tract infection. We previously reported that addition of unconjugated bilirubin (UCB), which is deconjugated by beta-glucuronidase in infected bile, could enhance cholesterol crystal formation in supersaturated model bile (MB). The present study evaluated the effect of beta-glucuronidase on the processes of pigment gallstone formation and cholesterol crystallization. Supersaturated MB (taurocholate/lecithin/cholesterol at 71:18:11, a total lipid concentration of 10.0 g/dl and a cholesterol saturation index (CSI) of 2.0) and native rat bile were mixed at a ratio of 3:1. Then, mixed bile was incubated with or without beta-glucuronidase and changes of the following parameters were investigated over time: (1) the UCB/total bilirubin ratio; (2) cholesterol crystal formation; (3) the precipitate weight and the cholesterol concentration in the precipitate and supernatant; and (4) the lipid distribution of vesicles in the supernatant. Compared with beta-glucuronidase-free bile, (1) beta-glucuronidase-containing bile showed a significant increase of the UCB/total bilirubin ratio, (2) as well as a significantly longer nucleation time (96+/-17.0 vs. 114+/-20.0) and fewer cholesterol crystals. (3) The precipitate weight and the cholesterol concentration in the precipitate were significantly increased, while the cholesterol concentration in supernatant was decreased. (4) When mixed bile was incubated with beta-glucuronidase, the cholesterol concentration in the vesicles was lower than in bile without beta-glucuronidase. The precipitate weight and the cholesterol concentration in the precipitate was increased by incubation with beta-glucuronidase, while cholesterol concentration was decreased in the supernatant (especially in the vesicles). This means that bile vesicles were more stable and it was more difficult for cholesterol crystals to form. Thus, the presence of beta-glucuronidase may inhibit the formation of pure cholesterol stones even in the presence of cholesterol supersaturation.

Animals↗
PubMed2003

Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse.

We explored the influence of the hydrophilic-hydrophobic balance of a series of natural bile acids on cholesterol absorption in the mouse. Male C57L/J mice were fed standard chow or chow supplemented with 0.5% cholic; chenodeoxycholic; deoxycholic; dehydrocholic; hyocholic; hyodeoxycholic; alpha-, beta-, or omega-muricholic; ursocholic; or ursodeoxycholic acids for 7 days. Biliary bile salts were measured by reverse-phase HPLC, and hydrophobicity indices were estimated by Heuman's method. Cholesterol absorption efficiency was determined by a plasma dual-isotope ratio method. In mice fed chow, natural proportions of tauro-beta-muricholate (42 +/- 6%) and taurocholate (50 +/- 7%) with a hydrophobicity index of -0.35 +/- 0.04 produced cholesterol absorption of 37 +/- 5%. Because bacterial and especially hepatic biotransformations of specific bile acids occurred, hydrophobicity indices of the resultant bile salt pools differed from fed bile acids. We observed a significant positive correlation between hydrophobicity indices of the bile salt pool and percent cholesterol absorption. The principal mechanism whereby hydrophilic bile acids inhibit cholesterol absorption appears to be diminution of intraluminal micellar cholesterol solubilization. Gene expression of intestinal sterol efflux transporters Abcg5 and Abcg8 was upregulated by feeding cholic acid but not by hydrophilic beta-muricholic acid nor by hydrophobic deoxycholic acid. We conclude that the hydrophobicity of the bile salt pool predicts the effects of individual fed bile acids on intestinal cholesterol absorption. Natural alpha- and beta-muricholic acids are the most powerful inhibitors of cholesterol absorption in mice and might act as potent cholesterol-lowering agents for prevention of cholesterol deposition diseases in humans.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2003

Hydrophilic bile salts have a cytoprotective effect against cyclosporine A-induced cholestasis through enhanced canalicular membrane fluidity and transporter activity.

Cyclosporine A (CsA) reduces liver canalicular membrane (CM) fluidity to cause a disproportionate reduction of biliary lipid secretion (the uncoupling phenomenon) without affecting adenosine triphosphate-dependent (ABC) transporters except for Mdr1. This study investigated whether hydrophilic bile salts inhibit CsA-induced cholestasis, focusing on CM fluidity and ABC transporter expression. Male Sprague-Dawley rats were infused with taurocholate (TC) (200 nmol/min/100 g body weight) for 2 h, flowed by infusion with tauroursodeoxycholate (TUDC), tauroalphamuricholate, or taurobetamuricholate (100 nmol/min/100 g body weight plus TC at 100 nmol/min/100 g body weight). Thereafter, CsA (20 mg/kg body weight) was injected as a bolus and bile was collected for 2 h. Canalicular membrane vesicles were prepared for analysis of cholesterol (CH), phospholipid (PL), CM fluidity, and expression of ABC transporters (Mdr1, Bsep, Mdr2, and Mrp2). CsA administration reduced biliary lipid secretion along with a disproportionately smaller decline of bile salt secretion. Hydrophilic bile salts significantly inhibited cholestasis after CsA injection by increasing CM fluidity and by increasing the expression of Mrp2 and Bsep, whereas Mdr1 and Mdr2 were unaltered. (1) Hydrophilic bile salts inhibit CsA-induced cholestasis, presumably by increasing CM fluidity, and this action was greatest with TUDC. (2) The fact that ABC transporters, except for Mdr1 and Mdr2, were overexpressed in the CM after infusion of these bile salts suggests that cytoprotective bile salts functions may increase transporter mass as well as enhancing transporter activity.

Journal Article↗
PubMed2003

Choleretic action of diosgenin is based upon the increases in canalicular membrane fluidity and transporter activity mediating bile acid independent bile flow.

It is known that diosgenin alters the lipid composition of hepatic plasma membranes as well as bile lipids. We recently reported that changes in the lipid composition of the canalicular membrane bilayer were associated with alterations of membrane fluidity. Therefore, the present study was performed to determine the effect of diosgenin on bile secretion, focusing on canalicular membrane composition, membrane fluidity, transporter expression, and transporter activity. METHODS: SD rats were fed a diet with or without diosgenin. Bile duct cannulation was done and the bile acid pool was depleted, followed by infusion of sodium taurocholate for 120 min to collect bile samples. Bile flow and the biliary output of cholesterol (Ch), phospholipids, bile salt, and total glutathione (GSH+GSSG) were estimated. Liver canalicular membrane vesicles (CMV) were prepared for the assessment of lipid composition, ATP-dependent transporters, and membrane fluidity. RESULTS: Bile flow, especially bile acid-independent fraction, was increased significantly by diosgenin. Biliary output of Ch and total glutathione were significantly increased by diosgenin. CMV fluidity and Mrp2 expression were increased by diosgenin. CONCLUSION: The fact that diosgenin increased bile flow and biliary cholesterol and glutathione output indicates a choleretic action along with enhancement of solute secretion. The increase of CMV fluidity and Mrp2 suggests that the choleretic action of diosgenin was based upon both the direct stimulation of transporter expression and indirect transporter activation by an increase of membrane fluidity.

Journal Article↗
PubMed2003

Unique reciprocal changes of hepatocellular membrane transporter expression and fluidity in rats with selective biliary obstruction.

BACKGROUND AND AIMS: The localized occlusion of bile ducts by intrahepaticlithiasis and intrahepatic neoplasms dose not cause severe jaundice, although the reason is unclear. The aim of this study was to clarify the molecular change of the liver in partial cholestasis, especially with respect to transporter expression (Mrp2, Mrp3, Bsep, P-gps) and membrane fluidity. METHODS AND RESULTS: After 3 days of selective bile duct ligation in Sprague-Dawley rats, the obstructed lobe (OL) and non-OL were analyzed. Canalicular and sinusoidal membrane fluidity were decreased in the OL compared with the non-OL. Mrp2 protein expression was significantly lower in the OL (by 62.9+/-6.9%) when compared with the non-OL. Mdr1b and Mdr2 mRNA were up-regulated in the OL when compared with the non-OL. Interestingly, Mrp3 protein and mRNA were induced in both the non-OL and OL of rats without hyperbilirubinemia. CONCLUSIONS: It seems that the reduction of membrane fluidity in the OL is a local response to localized cholestasis, while the induction of Mrp3 observed in both the OL and non-OL may be a response of the whole liver to localized impairment of bile secretion, although the regulatory mechanism is yet to be established.

Journal Article↗
PubMed2003

Impaired gallbladder mucosal function in aged gallstone patients suppresses gallstone recurrence after successful extracorporeal shockwave lithotripsy.

BACKGROUND: Absorption of water, as well as emptying of bile, are important functions of the gallbladder. We studied the changes of gallbladder function with age in gallstone patients and their influence on the outcome of extracorporeal shockwave lithotripsy (ESWL). METHODS: (i) A total of 123 consecutive patients with complete stone clearance by ESWL were examined. Gallbladder emptying was assessed before treatment using intravenous cholecystography. After stone clearance, the recurrence of gallstones was monitored by using ultrasonography. Cox regression analysis was used to determine the risk factors associated with stone recurrence. (ii) Gallbladder bile was sampled from 59 gallstone patients during surgery. Biliary cholesterol, phospholipids, and total bile acids were simultaneously quantified by using gas-liquid chromatography. RESULTS: Impaired gallbladder function, but not gallstone recurrence, was more frequently observed in older patients (>/=65 years old) than in younger patients (<65 years old). Cox regression analysis revealed that poor gallbladder emptying was an independent predictor of stone recurrence after ESWL in the total study population, but not in the older patients (>/=65 years old). Analysis of bile from surgically treated patients with cholesterol stones showed a significantly higher total lipid concentration and a shorter nucleation time in the younger group (<65 years old), but the cholesterol saturation index did not differ between the younger and older groups. CONCLUSIONS: Our data suggest that the reduced concentrating function of the gallbladder in elderly gallstone patients helps to counteract stone recurrence despite their abnormal gallbladder motility. Therefore, aged gallstone patients may be preferentially treated by a non-surgical strategy.

Age Factors↗
PubMed2002

Less hydrophobic phosphatidylcholine species simplify biliary vesicle morphology, but induce bile metastability with a broad spectrum of crystal forms.

Cholesterol crystallization in bile is affected by phosphatidylcholine (PtdCho) hydrophobicity. The aim of the present study was to determine whether PtdCho species modulate the metastable-labile limit and equilibrium solubility of cholesterol in the micellar phase of bile, thereby altering the distribution of cholesterol to biliary lipid carriers and thus influencing cholesterol crystallization. Supersaturated model bile (with a cholesterol saturation index of 2.0 and a total lipid concentration of 10 g/dl) was prepared with various PtdCho/(bile salt+PtdCho) ratios (0.1-0.5) using egg yolk or soya bean PtdCho. Subsequently, the following features were determined: metastable-labile limit, equilibrium solubility of cholesterol, metastable zone, and cholesterol crystallization process. Less hydrophobic PtdCho species destabilized bile cholesterol to induce rapid crystallization, because of a broad integrated metastable zone, whereas more hydrophobic species stabilized bile cholesterol with a less integrated metastable zone and thus retarded cholesterol crystallization. Cholesterol crystallization was accelerated by a decrease in the PtdCho/(bile salt+PtdCho) ratio, whereas the final nucleated crystal mass was increased by an increase in this ratio. With decreasing hydrophobicity of the PtdCho species, the intermixed micellar/vesicular concentration of bile salts decreased in association with less formation of vesicles and increased formation of micelles, and a variety of crystal forms were detected. In conclusion, PtdCho species directly influenced the cholesterol crystallization process in model bile by remodelling the bile mesophase, and also had an indirect influence by altering the balance between bile salt micelles and vesicles.

Bile↗
PubMed2002

Effect of beta-muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice.

This study investigated whether beta-muricholic acid, a natural trihydroxy hydrophilic bile acid of rodents, acts as a biliary cholesterol-desaturating agent to prevent cholesterol gallstones and if it facilitates the dissolution of gallstones compared with ursodeoxycholic acid (UDCA). For gallstone prevention study, gallstone-susceptible male C57L mice were fed 8 weeks with a lithogenic diet (2% cholesterol and 0.5% cholic acid) with or without 0.5% UDCA or beta-muricholic acid. For gallstone dissolution study, additional groups of mice that have formed gallstones were fed chow with or without 0.5% beta-muricholic acid or UDCA for 8 weeks. One hundred percent of mice fed the lithogenic diet formed cholesterol gallstones. Addition of beta-muricholic acid and UDCA decreased gallstone prevalence to 20% and 50% through significantly reducing biliary secretion rate, saturation index, and intestinal absorption of cholesterol, as well as inducing phase boundary shift and an enlarged Region E that prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones. Eight weeks of beta-muricholic acid and UDCA administration produced complete gallstone dissolution rates of 100% and 60% compared with the chow (10%). We conclude that beta-muricholic acid is more effective than UDCA in treating or preventing diet-induced or experimental cholesterol gallstones in mice.

Animals↗
PubMed2002

[Hepatitis C].

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Age Factors↗