Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat

Geier, Andreas; Dietrich, Christoph G.; Grote, Tobias; Beuers, Ulrich; Prüfer, Thomas; Fraunberger, Peter; Matern, Siegfried; Gartung, Carsten; Gerbes, Alexander L.; Bilzer, Manfred

doi:10.1016/j.jhep.2005.05.031

Cited by 58 publications

(60 citation statements)

References 55 publications

(77 reference statements)

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“…In accordance with these data from systemic Fxr −/−, the same increase in Cyp7a1 expression in combination with decreased Bsep can be observed in ΔL Fxr mice in the present study. In this context, bile acid retention due to reduced bile acid transporter expression as observed in various rodent models of fatty liver (19,20) (25). In accordance with previous data SHP is not induced in 1% cholesterol diet animals since it has been shown that SHP induction is repressed by free fatty acids (FFA) in NAFLD patients and hepatoma cells (28).…”

Section: Discussionsupporting

confidence: 83%

“…In this regard, it is also unclear whether bile acid retention and subsequent hepatic FXR activation in fatty livers represents a causal event in the pathogenesis or rather an attempt of adaptation (19,20). Following these pertinent questions we studied organspecific liver (ΔL) and intestinal (ΔIE) Fxr knockout mice under a 1% cholesterol diet.…”

Section: Introductionmentioning

confidence: 99%

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Protective effects of FXR on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal

Schmitt¹,

Kong²,

Stieger³

et al. 2012

Z Gastroenterol

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Protective effects of FXR on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal

Schmitt¹,

Kong²,

Stieger³

et al. 2012

Z Gastroenterol

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“…The cumulative bile flow was significantly elevated in high-fat rats but only at the later time points. Each of these groups is a contrast to the obese Zucker rat (a model of insulin resistance and obesity) in which bile secretory function in fatty liver is impaired, nonetheless in the absence of cholestatic injury (Pizarro et al, 2004;Geier et al, 2005). This is the first study to examine liver efflux transporter expression in high-fat and MCD dietary models of simple hepatic steatosis and NASH in rats.…”

Section: Discussionmentioning

confidence: 99%

Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease

Lickteig

Fisher

Augustine

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:Efflux transporters are responsible for the excretion of numerous xenobiotics and endobiotics and thus play an essential role in proper liver and kidney function. Nonalcoholic fatty liver diseases (NAFLDs) comprise a spectrum of disorders that range from simple fatty liver (SFL) to nonalcoholic steatohepatitis (NASH). Although the precise events leading to NAFLD are unclear, even less is known about the effects on efflux transporter expression and drug disposition. The purpose of this study was to determine the effect of NAFLD on efflux transporter expression in rat liver as well as on acetaminophen (APAP) metabolite excretion. To simulate SFL and NASH, rats were fed either a high-fat (HF) or a methionine-and choline-deficient (MCD) diet for 8 weeks. In the livers of MCD rats, there were striking increases in both mRNA and protein levels of multidrug resistance-associated protein (Mrp) 3, Mrp4, and breast cancer resistance protein, as well as increased Mrp2 protein. After administration of a nontoxic dose of APAP, biliary concentrations of APAP-sulfate, APAP-glucuronide (APAP-GLUC), and APAP-glutathione were reduced in MCD rats. The effects of the HF diet on both transporter expression and APAP disposition were by comparison far less dramatic than the MCD diet-induced alterations. Whereas APAP-sulfate levels were also decreased in MCD rat plasma, the levels of the Mrp3 substrate APAP-GLUC were elevated. Urinary elimination of APAP metabolites was identical between groups, except for APAP-GLUC, the concentration of which was 80% higher in MCD rats. These studies correlate increased hepatic Mrp3 protein in the MCD model of NASH with increased urinary elimination of APAP-GLUC. Furthermore, the proportional shift in elimination of APAP metabolites from bile to urine indicates that MCD-induced alterations in efflux transporter expression can affect the route of drug elimination.

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“…In obesity and NAFLD animal models, Mrp2 has been shown to have altered hepatic expression and function (Geier et al, 2005;Cheng et al, 2008). In addition, Mrp2, Mrp3, and Mrp4 protein expression were significantly increased in a rodent model of NAFLD (Lickteig et al, 2007).…”

Section: Cohortmentioning

confidence: 99%

“…In obesity and NAFLD animal models, Mrp2 has been shown to have altered hepatic expression and function (Geier et al, 2005;Cheng et al, 2008). In addition, functional genetic polymorphisms in MRP2 have been associated with susceptibility to NAFLD and disease severity (Sookoian et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Schrieber¹,

Hawke²,

Zhao³

et al. 2011

Drug Metabolism and Disposition

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ABSTRACT:Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single-and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC 0-8 h ) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC 0-8 h was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC 0-8 h (p < 0.05) and 42% lower C max (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.

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Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat

Cited by 58 publications

References 55 publications

Protective effects of FXR on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal

Protective effects of FXR on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal

Efflux Transporter Expression and Acetaminophen Metabolite Excretion Are Altered in Rodent Models of Nonalcoholic Fatty Liver Disease

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

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