Trapping of oxidized <scp>LDL</scp> in lysosomes of <scp>K</scp>upffer cells is a trigger for hepatic inflammation

Bieghs, Veerle; Walenbergh, Sofie M. A.; Hendrikx, Tim; Gorp, Patrick J. van; Verheyen, Fons; Damink, Steven W. M. Olde; Masclee, Ad; Koek, Ger H.; Hofker, Marten H.; Binder, Christoph J.; Shiri-Sverdlov, Ronit

doi:10.1111/liv.12170

Cited by 75 publications

(80 citation statements)

References 31 publications

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“…We speculate that the OxPLs on the r-apo(a) constructs are likely derived from OxPLs generated from apoptotic cells in cell culture ( 52 ). In vivo, OxPLs on Lp(a) may be derived from hepatocytes during Lp(a) assembly, particularly if there is enhanced hepatocyte oxidative stress, such as in nonalcoholic steatohepatitis ( 53 ), or transferred to Lp(a) in plasma from atherosclerotic plaques, as suggested by prior human studies in patients undergoing percutaneous coronary intervention ( 22,54 ). Importantly, however, our studies of OxPLs on apo(a), expressed both in cell culture and found in mouse plasma, show a similar dependence on an intact LBS in KIV 10 , suggesting that the OxPLs acquired by apo(a) in vitro are a relevant model for those acquired by the apo(a) component of Lp(a) in vivo.…”

Section: Discussionmentioning

confidence: 99%

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Leibundgut

Scipione

Yin

et al. 2013

Journal of Lipid Research

190

146

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Section: Discussionmentioning

confidence: 99%

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Leibundgut

Scipione

Yin

et al. 2013

Journal of Lipid Research

190

146

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“…The other indicators of great importance are Kupffer cells, resident macrophages occurring between the endothelial cells in the wall of sinusoids [7,14,15]. Apart from them, abnormalities due to NAFLD (and thus NASH) may be localized also within other cells, i.e.…”

Section: Degree Of Lipid Unsaturation In Lds From C57bl/6j Mice Fed Hmentioning

confidence: 98%

Raman spectroscopy analysis of lipid droplets content, distribution and saturation level in Non‐Alcoholic Fatty Liver Disease in mice

Kochan

Maślak

Krafft

et al. 2014

Journal of Biophotonics

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Non-Alcoholic Fatty Liver Disease (NAFLD) is a common liver disorder, characterized by an excessive lipids deposition within the hepatic tissue. Due to the lack of clear-cut symptoms and optimal diagnostic method, the actual prevalence of NAFLD and its pathogenesis remains unclear, especially in the early stages of progression. In the presented work confocal Raman microspectroscopy was used to investigate alterations in the chemical composition of the NAFLD-affected liver. We have investigated two NAFLD models, representative for macrovesicular and microvesicular steatosis, induced by High Fat Diet (60 kcal %) and Low Carbohydrate High Protein Diet (LCHP), respectively. In both models we confirmed the development of NAFLD, manifested by the presence of lipid droplets (LDs), but of different sizes. Model of macrovesicular steatosis was characterized by large LDs, whereas in the microvesicular steatosis model small droplets were found. In both models, however, we observed a significant decrease in the degree of unsaturation of lipids, in comparison to the control. In addition, for both models, the impact of medical treatment with selected drugs (perindopril and nicotinic acid, respectively) was tested, indicating a significant influence of medicine not only on the occurrence and size of the droplets, but also on their composition. In both cases the drug treatment resulted in an increase of the degree of unsaturation of lipids forming droplets. Confocal Raman microspectroscopy was proven to be a powerful tool providing detailed insight into selected areas of hepatic tissue, following the NAFLD pathogenesis and diagnostic potential of the applied drugs.

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“…Importantly, our approach to depleting macrophages by using GdCl 3 in the liver was based on identifying the precise origin of the inflammatory cytokines, especially IL-1b, IL-12, IL-23, and Dectin-1; we were well aware that IL-1b release has other cellular sources in the liver as well. Our results with CYP2E1-mediated M1 polarization in NASH provide insight into the mechanisms of macrophage responses, which had been scarce aside from a few isolated studies where morbidly obese patients with NASH etiology were shown to produce increased T H 1 cytokines and Kupffer cell responses (Fukushima et al, 2009;Bertola et al, 2010;Bieghs et al, 2013). There has been preclinical evidence for the involvement of Kupffer cells with an M1 phenotype, the former being responsible for NASH progression, but those studies did not clarify the role of oxidative stress, especially mediated by CYP2E1, in causing a M1 polarization bias (Fukushima et al, 2009;Bieghs et al, 2013).…”

Section: No Donor Attenuates Inflammation In Nash Livermentioning

confidence: 99%

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

Seth

Das

Pourhoseini

et al. 2014

J Pharmacol Exp Ther

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Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1b (IL-1b) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl 3 ), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASHabrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH.

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Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation

Cited by 75 publications

References 31 publications

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

Raman spectroscopy analysis of lipid droplets content, distribution and saturation level in Non‐Alcoholic Fatty Liver Disease in mice

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

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