Insulinlike growth factor—ii/mannose 6-phosphate receptor is expressed on ccl4-exposed rat fat-storing cells and facilitates activation of latent transforming growth factor-β in cocultures with sinusoidal endothelial cells

Bleserc, Pieter J. De; Jannes, Peggy; Buul-Offers, S. C. van; Hoogerbrugge, C. M.; Schravendijk, C. F. H. Van; Niki, Toshiro; Rogiers, Vera; Brande, J. L. Van den; Wisse, Eddie; Geerts, Albert

doi:10.1002/hep.1840210529

Cited by 75 publications

(82 citation statements)

References 44 publications

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“…This is in contrast to our recent findings on the biodistribution of 33 P-TFO, where we observed significant decrease in the hepatic uptake of 33 P-TFO when injected into fibrotic rats (16). This may be due to the fact that M6P/IGF-II receptors are upregulated during fibrosis (18,19), which should increase uptake by HSCs via receptor-mediated endocytosis and cancel out any adverse effect created by decrease in sinusoidal gap.…”

Section: Discussioncontrasting

confidence: 99%

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Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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Excessive production of extracellular matrix, predominantly type I collagen results in liver fibrosis. Earlier we synthesized mannose 6-phosphate-bovine serum albumin (M6P-BSA) and conjugated to the type I collagen specific triplex forming oligonucleotide (TFO) for its enhanced delivery to hepatic stellate cells (HSCs), which is the principle liver fibrogenic cell. In this report, we demonstrate a time-dependent cellular uptake of M6P-BSA-33 P-TFO by HSC-T6 cells. Both cellular uptake and nuclear deposition of M6P-BSA-33 P-TFO were significantly higher than those of 33 P-TFO, leading to enhanced inhibition of type I collagen transcription. Following systemic administration into rats, hepatic accumulation of M6P-BSA-33 P-TFO increased from 55% to 68% with the number of M6P per BSA from 14 to 27. Unlike 33 P-TFO, there was no significant decrease in the hepatic uptake of (M6P) 20 -BSA-33 P-TFO in fibrotic rats. Prior administration of excess M6P-BSA decreased the hepatic uptake of (M6P) 20 -BSA-33 P-TFO from 66% to 40% in normal rats, and from 60% to 15% in fibrotic rats, suggesting M6P/insulin-like growth factor II (M6P/IGF-II) receptor-mediated endocytosis of M6P-BSA-33 P-TFO by HSCs. Almost 82% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, by conjugation with M6P-BSA, the TFO could be potentially used for the treatment of liver fibrosis.

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Section: Discussioncontrasting

confidence: 99%

“…M6P is a ligand for M6P/IGF II receptor, which is upregulated in fibroblast-like cells such as activated HSCs during liver fibrosis (18,19). Coupling of M6P to albumin increased selective uptake of this modified albumin by HSCs during liver fibrosis (30).…”

Section: Discussionmentioning

confidence: 99%

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Cheng

Guntaka

et al. 2006

Bioconjugate Chem.

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“…An up-regulation of M6P/IGF-II receptors on HSC has been reported after induction of liver fibrosis in rats. [12][13][14] We therefore synthetized M6P-modified HSA with different degrees of sugarloading. We show that albumins modified with M6P groups, especially the highly substituted albumins, accumulate in the HSC of fibrotic rat livers.…”

Section: Discussionmentioning

confidence: 99%

“…13,18 The membrane form of the M6P/IGF-II receptor is involved in the activation of L-TGF␤. 12,19,20 L-TGF␤ has three glycosylation sites, two of which contain M6P. 21 TGF␤ is a fibrogenic cytokine with many functions, including induction of extracellular matrix synthesis and the inhibition of its degradation.…”

mentioning

confidence: 99%

Albumin Modified With Mannose 6–Phosphate: A Potential Carrier for Selective Delivery of Antifibrotic Drugs to Rat and Human Hepatic Stellate Cells

et al. 1999

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The hallmark of liver fibrosis is an increased extracellular matrix deposition, caused by an activation of hepatic stellate cells (HSC). Therefore, this cell type is an important target for pharmacotherapeutic intervention. Antifibrotic drugs are not efficiently taken up by HSC or may produce unwanted side-effects outside the liver. Cell-specific delivery can provide a solution to these problems, but a specific drug carrier for HSC has not been described until now. The mannose 6-phosphate/insulin-like growth factor II (M6P/ IGF-II) receptor, which is expressed in particular upon HSC during fibrosis, may serve as a target-receptor for a potential carrier. The aim of the present study was to examine if human serum albumin (HSA) modified with mannose 6-phosphate (M6P) is taken up by HSC in fibrotic livers. A series of M6P x -modified albumins were synthetized: x ‫؍‬ 2, 4, 10, and 28. Organ distribution studies were performed to determine total liver uptake. The hepatic uptake of M6P x -HSA increased with increasing M6P density. M6P x -HSA with a low degree of sugar loading (x ‫؍‬ 2-10) remained in the plasma and accumulated for 9% ؎ 0.5% or less in fibrotic rat livers. An increase in the molar ratio of M6P: HSA to 28:1 caused an increased liver accumulation to 59% ؎ 9% of the administered dose. Furthermore, we determined quantitatively the in vivo intrahepatic distribution of M6P x -HSA using double-immunostaining techniques. An increased substitution of M6P was associated with an increased accumulation in HSC; 70% ؎ 11% of the intrahepatic staining for M6P 28

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“…The mannose 6-phosphate͞insulin-like growth factor-II receptor (M6P͞IGF2R) plays a critical role in regulating cell growth by facilitating the activation of the growth inhibitor transforming growth factor ␤ (TGF␤) (4,5) and inactivating the growth stimulator insulin-like growth factor-II (IGF2) (6). Loss of this receptor is therefore predicted to both increase cell proliferation and reduce apoptosis, consistent with the M6P͞ IGF2R gene functioning as a tumor suppressor.…”

mentioning

confidence: 98%

Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis

Yamada

Souza

Finkelstein

et al. 1997

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

191

151

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This report shows that loss of heterozygosity at the mannose 6-phosphate͞insulin-like growth factor II receptor (M6P͞IGF2R) locus occurred in 5͞8 (63%) dysplastic liver lesions and 11͞18 (61%) hepatocellular carcinomas (HCCs) associated with the high risk factors of hepatitis virus infection and liver cirrhosis. Mutations in the remaining allele were detected in 6͞11 (55%) HCCs, including deletions in a polydeoxyguanosine region known to be a target of microsatellite instability. M6P͞IGF2R allele loss was also found in cirrhotic tissue of clonal origin adjacent to these dysplastic lesions and HCCs, demonstrating that M6P͞IGF2R inactivation occurs early in liver carcinogenesis. In conclusion, HCCs frequently develop from clonal expansions of phenotypically normal, M6P͞IGF2R-mutated hepatocytes, providing further support for the idea that M6P͞IGF2R functions as a liver tumor-suppressor gene.

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Insulinlike growth factor—ii/mannose 6-phosphate receptor is expressed on ccl4-exposed rat fat-storing cells and facilitates activation of latent transforming growth factor-β in cocultures with sinusoidal endothelial cells

Cited by 75 publications

References 44 publications

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Receptor-Mediated Hepatic Uptake of M6P−BSA-Conjugated Triplex-Forming Oligonucleotides in Rats

Albumin Modified With Mannose 6–Phosphate: A Potential Carrier for Selective Delivery of Antifibrotic Drugs to Rat and Human Hepatic Stellate Cells

Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis

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