Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis

Schneiderhan, Wilhelm

doi:10.1053/jhep.2001.27828

Cited by 76 publications

(61 citation statements)

References 56 publications

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“…48 Alernatively, oxLDL and necrotic/apoptotic hepatocytes may exhibit a fibrogenicity triggered by stimulation of scavenger receptors expressed on stellate cells. 24,49 This was supported, at least in part, by our immunohistochemical result that showed CD36 expression on activated stellate cells in NASH/NAFLD livers. Taking these evidences into consideration, oxPC may be a key mediator connecting hepatic steatosis and neutrophil MPOderived oxidative stress to hepatic fibrogenesis in NASH/ NAFLD.…”

Section: Discussionsupporting

confidence: 59%

Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Ikura¹,

Ohsawa²,

Suekane³

et al. 2006

Hepatology

127

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Nonalcoholic steatohepatitis/nonalcoholic fatty liver disease is considered to be a hepatic manifestation of various metabolic disorders. However, its precise pathogenic mechanism is obscure. Oxidative stress and consequent lipid peroxidation seem to play a pivotal role in disease progression. In this study, we analyzed the localization of oxidized phosphatidylcholine (oxPC), a lipid peroxide that serves as a ligand for scavenger receptors, in livers of patients with this steatotic disorder. Specimens of nonalcoholic fatty liver disease (15 autopsy livers with simple steatosis and 32 biopsy livers with steatohepatitis) were examined via immunohistochemistry and immunoelectron microscopy using a specific antibody against oxPC. In addition, scavenger receptor expression, hepatocyte apoptosis, iron deposition, and inflammatory cell infiltration in the diseased livers were also assessed. Oxidized phosphatidylcholine was mainly localized to steatotic hepatocytes and some macrophages/Kupffer cells. A few degenerative or apoptotic hepatocytes were also positive for oxPC. Immunoelectron microscopy showed oxPC localized to cytoplasmic/intracytoplasmic membranes including lipid droplets. Steatotic livers showed enhanced expression of scavenger receptors. The number of oxPC cells was correlated with disease severity and the number of myeloperoxidasepositive neutrophils, but not with the degree of iron deposition. In conclusion, distinct localization of oxPC in liver tissues suggest that neutrophil myeloperoxidase-derived oxidative stress may be crucial in the formation of oxPC and the progression of steatotic liver disease. (HEPATOLOGY 2006;43:506-514.)

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Section: Discussionsupporting

confidence: 59%

Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Ikura¹,

Ohsawa²,

Suekane³

et al. 2006

Hepatology

127

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“…Consequently, identifying pathways that regulate the deposition and resolution of fibrillar collagen is vital to developing new treatments for chronic liver disease. Products of oxidative stress, such as oxidized-low density lipoproteins (oxLDLs), can directly activate HSC to an ECM-producing state thereby driving fibrogenesis (2,3). In addition to HSCs, other nonparenchymal cells contribute to the regulation of liver fibrosis.…”

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confidence: 99%

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Rantakari

Patten

Valtonen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

108

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Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1 + macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP + fibrogenic cells. Stabilin-1 −/− macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6C lo monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1 + monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage-specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1 + macrophages shape the tissue microenvironment during liver injury and healing.stabilin-1 | liver | fibrosis | macrophages | CCL3

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“…This is not surprising since, after coupling of M6P to NH2 groups of lysine, a protonated group (NH 3 ϩ ) is replaced by a negatively charged group (PO 4 3Ϫ ). Scavenger receptors are found on Kupffer and sinusoidal endothelial cells, and also on activated HSCs (Schneiderhan et al, 2001;Adrian et al, 2006). The combination of SucHSA and M6PHSA did not induce a complete blockage of liver uptake, even after administration of very high doses.…”

Section: Discussionmentioning

confidence: 91%

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

Rachmawati¹,

Reker‐Smit²,

Hooge³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Cytokines are considered a promising immunotherapy for chronic diseases, because of their potency and fundamental roles in pathological processes. However, their therapeutic use is limited because of their poor pharmacokinetics and pleiotropic effects in various organs. These problems may be overcome by cell-specific delivery of the cytokine. This approach involves chemical modification of the protein with homing devices that recognize receptors on target cells. The cytokine interleukin-10 (IL10) may be valuable as a therapeutic cytokine for patients with liver cirrhosis. However, its rapid renal elimination and general immunosuppressive activities limit therapeutic use. We therefore aim to target this cytokine in the liver, in particular to fibrogenic hepatic stellate cells (HSCs). We show that IL10 is successfully modified with mannose 6-phosphate (M6P), which is a homing device for the mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptor expressed on activated HSCs. Chemical modification did not diminish IL10 efficacy with regard to in vitro anti-inflammatory (lipopolysaccharide-stimulated tumor necrosis factor ␣ release) and antifibrotic (collagen deposition and degradation) activities. Biodistribution studies with radiolabeled M6P-IL10 and IL10 in rats with liver fibrosis showed that modification with M6P groups induced a shift in the distribution from the kidneys (IL10) to the liver (M6P-IL10). Hepatocellular binding of M6P-IL10 occurred via M6P/IGFII receptors and scavenger receptors, indicating that not only HSCs but also Kupffer and endothelial cells are target cells. IL10 did not bind to these receptors. We conclude that we prepared an active and liver-specific form of the cytokine IL10 that can be evaluated for its efficacy to treat liver diseases.

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Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis

Cited by 76 publications

References 56 publications

Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease: Impact on disease progression

Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury

Chemical Modification of Interleukin-10 with Mannose 6-Phosphate Groups Yields a Liver-Selective Cytokine

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