Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease

Asanuma, Taketoshi; Ono, Masafumi; Kubota, Kei; Hirose, Akira; Hayashi, Yoshihiro; Saibara, Toshiji; Inanami, Osamu; Ogawa, Yasuhiro; Enzan, Hideaki; Onishi, Saburo; Kuwabara, Mikinori; Oben, Jude A.

doi:10.1136/gut.2009.176651

Cited by 63 publications

(69 citation statements)

References 32 publications

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“…Namely, it has been considered to represent the phagocytic activity of KCs. However, recent studies have reported that impairment of KC phagocytic activity is dependent on the level of activity in each KC and is not dependent on a reduction in the total number of KCs in studies of animal models of non-alcoholic steatohepatitis (29,30).…”

Section: Discussionmentioning

confidence: 96%

Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin

Tonan

Fujimoto

Qayyum

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Kupffer cells contribute to the pathogenesis of liver injury in chronic liver disease, yet it is difficult to assess Kupffer cell function either ex vivo or in vivo, since supporting data are limited. The aim of this study was to clarify the relation between Kupffer cell function and hepatocyte function by analyzing the correlation between conventional indices of hepatic functional reserve and both superparamagnetic iron oxide-enhanced MRI (SPIO-MRI) and technetium-99m-galactosyl human serum albumin scintigraphy (Tc-99m-GSA) in patients with chronic viral hepatitis. Consecutive 46 patients (16 patients with chronic hepatitis and 30 patients with cirrhosis) who underwent both SPIO-MRI and Tc-99m-GSA were examined. The patients were aged 46-83 years (median 70) and included 29 men and 17 women. Spearman correlation coefficient was used to analyze the correlations between functional reserve indices and both reduction percentages of liver-to-muscle signal intensity ratio (reduction-%LMR), as a surrogate parameter of Kupffer cell function and Tc-99m-GSA parameters. The usefulness of each parameter as a marker to differentiate Child-Pugh A from Child-Pugh B/C was evaluated using receiver operating characteristic (ROC) analysis. The reduction-%LMR correlated more closely with Child-Pugh score (r=0.77; P<0.001) than did Tc-99m-GSA parameters. For predicting Child-Pugh B/C, ROC analysis revealed that reduction-%LMR (AUC=0.91, P<0.001) was the most useful parameter and at a cutoff value of 50% or less, sensitivity, specificity, positive and negative predictive values were 0.79, 0.91, 0.94 and 0.71, respectively. SPIO-MRI may be a helpful non-invasive method for the evaluation of hepatic functional reserve, and this study suggests that Kupffer cell function is closely correlated with hepatocyte function in patients with chronic viral hepatitis. IntroductionProper assessment of hepatic functional reserve is crucial to the selection of patients for hepatic surgery, particularly in liver transplantation and the management of liver cirrhosis. The Child-Pugh score (1,2) is now used worldwide as the standard in the assessment of hepatic functional reserve (3). Given the relation between this score and survival in patients with cirrhosis of the liver, it has recently been listed as one of the parameters in the minimal criteria of the liver transplant Abbreviations: SPIO, superparamagnetic iron oxide; Tc-99m-GSA-scintigraphy, scintigraphy using technetium-99m-labelled galactosyl human serum albumin; GRE, gradient-recalled echo; ROIs, regions of interest; %LMR, percentages of liver-to-muscle signal intensity ratio; H15, uptake ratio of the heart at 15 min after Tc-99m-GSA injection; H3, uptake ratio of the heart at 3 min after Tc-99m-GSA injection; HH15, index of blood clearance = H15/H3; L15, radioactivity of the liver at 15 min after Tc-99m-GSA injection; LHL15, the receptor index = L15/(H15 + L15); ICG15, indocyanine green retention rate at 15 min; ROC analysis, receiver operating characteristic analysisKey words: chro...

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Section: Discussionmentioning

confidence: 96%

Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin

Tonan

Fujimoto

Qayyum

et al. 2011

Experimental and Therapeutic Medicine

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“…17 In contrast to USPIO, SPIONs are characterized by enhanced liver accumulation, thereby constituting a superb hepatic MRI contrast agent. Low concentrations of SPIONs (0.5 mg Fe/kg of carboxydextran-coated ferucarbotran (Resovist/Ferrixan, 45-60 nm [18][19][20], or dextran-coated ferumoxides (Endorem/Feridex), 21 have been used to noninvasively distinguish between benign liver condition (simple steatosis) and nonalcoholic steatohepatitis (NASH), which is highly associated with cardiovascular and renal comorbidities. 22 Despite promising results in humans, the marketing of intravenous iron oxide-containing contrast agents is currently at a standstill.…”

Section: Introductionmentioning

confidence: 99%

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Unterweger

Janko

Schwarz

et al. 2017

IJN

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Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent.

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“…These observations suggest that K-604 inhibited ACAT-1 and thus modulated the cholesterol levels in the Kupffer cells. As previously reported, impaired Kupffer cell function is important in the pathogenesis of NASH [29][30][31]. Thus, within the paradigm of the NASH etiology, it appears plausible that the inhibition of ACAT-1 by K-604 may suppress foam cell formation and lead to the normalized phagocytic function and morphology of the Kupffer cells.…”

Section: Body Weights Plasma Profiles Plasma Concentrations Of K-60mentioning

confidence: 60%

An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

Shibata¹,

Shibuya²

2016

JGPLD

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A high level of cholesterol activates Kupffer cells, which subsequently triggers inflammation and ultimately leads to steatohepatitis. The number of Kupffer cells correlates with the inflammatory grade of Non-Alcoholic Fatty Liver Disease (NAFLD). In this study, we studied the role of 'foamy' Kupffer cells in the nexus between inflammation and steatosis and investigated whether K-604, a selective Acyl-Coenzyme A: Cholesterol Acyltransferase-1 (ACAT-1) inhibitor ameliorates hepatic steatosis and inflammation in rodent models of NAFLD and Non-Alcoholic Steatohepatitis (NASH). Methionine-and Choline-Deficient (MCD) diet-fed KK-Ay mice, High-Fat and High-Cholesterol (HFC) diet-fed Low-Density Lipoprotein Receptor-Deficient (Ldlr(−/−)) mice and Zucker fatty rats were evaluated after 16, 16 and 12 weeks of K-604 treatment. The biochemical parameters, hepatic lipid levels, histopathological changes and gene expression levels were assessed. In the MCD dietfed KK-Ay mice, K-604 significantly improved the NASH symptoms. In the HFC diet-fed Ldlr (−/−) mice, K-604 suppressed the inflammatory gene expression and reduced the number of inflammatory foci. Moreover, K-604 decreased the area and size of foamy Kupffer cells. In the Zucker fatty rats, K-604 could also inhibit hepatic steatosis. These results indicated that K-604 acts directly on Kupffer cells and inhibits hepatic inflammation, suggesting that ACAT-1 is involved in the progression of steatohepatitis. Therefore, ACAT-1 inhibition may be a new therapeutic target for NAFLD and NASH.

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Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease

Abstract: KC uptake function is significantly impaired in patients with NAFLD and experimental animals with NASH, worsens with the degree of steatosis and is not due to a reduction of KC numbers.

Cited by 63 publications

References 32 publications

Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin

Correlation of Kupffer cell function and hepatocyte function in chronic viral hepatitis evaluated with superparamagnetic iron oxide-enhanced magnetic resonance imaging and scintigraphy using technetium-99m-labelled galactosyl human serum albumin

Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

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