Characterization of heparan sulfate on hepatocytes in regenerating rat liver

Kimura, Akitoshi; Toyoki, Yoshikazu; Hakamada, Kenichi; Yoshihara, Shuichi; Sasaki, Mutsuo

doi:10.1007/s00534-007-1321-7

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…Preparation of Hepatic Sulfated Glycosaminoglycans (sGAGs)-Hepatic sGAGs were isolated essentially as described previously (18,19) with some modification. Briefly, bovine liver was boiled and homogenized, and acetone precipitate was prepared.…”

Section: Methodsmentioning

confidence: 99%

Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho

Nakamura

Uehara

Asada

et al. 2011

Journal of Biological Chemistry

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Secreted from intestine, human fibroblast growth factor 19 (hFGF19) is an endocrine metabolic regulator that controls bile acid synthesis in the liver. Earlier studies have suggested that hFGF19 at 10 -100 nM levels signals through FGF receptor 4 (FGFR4) in the presence of a co-receptor, betaKlotho, but its activity and receptor specificity at physiological concentrations (picomolar levels) remain unclear. Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. Importantly, sGAGs isolated from liver are highly active in enhancing the picomolar hFGF19 signaling. At nanomolar levels, in contrast, hFGF19 activates all types of human FGFRs, i.e. FGFR1c, FGFR2c, FGFR3c, and FGFR4 in the co-presence of betaKlotho and heparin and activates FGFR4 even in the absence of betaKlotho. These results show that sGAGs play crucial roles in specific and sensitive hFGF19 signaling via FGF receptors and suggest that hepatic sGAGs are involved in the highly potent and specific signaling of picomolar hFGF19 through FGFR4 and betaKlotho. The results further suggest that hFGF19 at pathological concentrations may evoke aberrant signaling through various FGF receptors.In both humans and mice, the fibroblast growth factor (FGF) family is composed of 22 structurally related proteins that can be divided into several subfamilies (1). The endocrine FGF subfamily, which function as metabolic regulators (2-5), is composed of FGF19, FGF21, and FGF23 in humans and FGF15, FGF21, and FGF23 in mice. Mouse (m)Fgf15 is an ortholog for human (h)FGF19 (6). Both mFGF15 and hFGF19 are expressed in the distal small intestine. Their secretion into the circulation is induced by bile acid, and after reaching the liver via the portal vein they suppress a key liver enzyme involved in bile acid biosynthesis, thereby closing a feedback loop regulating bile acid homeostasis (7). hFGF19/mFGF15 also reportedly contributes to the regulation of blood glucose levels, along with other metabolic regulators, including FGF21 and insulin (8 -11).Endocrine FGFs act via receptor tyrosine kinases but also require the presence of a co-receptor, alphaKlotho (KLA) 4 or betaKlotho (KLB) (12). In humans, FGF23 signaling via several FGF receptor (FGFR) subtypes is thought to specifically require KLA, whereas hFGF19 and FGF21 reportedly require . But other studies have shown that KLA can also act as a co-receptor for hFGF19 (15). It has thus been unclear how the receptor specificity of hFGF19 is achieved, or even what its precise receptor specificity is. Results from Fgf15 knockout mice suggest that mFGFR4 is the sole functional receptor for mFGF15 (7).Moreover, the potential applicability of hFGF19 to the treatment of metabolic diseases such as diabetes (8 -11) has prompted attempts to develop protocols for its clinical application, but these have been discouraged by the finding that transgenic mice expressing high le...

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Section: Methodsmentioning

confidence: 99%

Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho

Nakamura

Uehara

Asada

et al. 2011

Journal of Biological Chemistry

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“…Human hepatocellular carcinoma Huh7, HepG2, and Hep3B cell lines were cultured with DMEM, containing 10% FCS, antibiotics (100 U/mL penicillin and 100 U/mL streptomycin), and 2 mM glutamine, at 37 °C in a humidified atmosphere with 5% CO 2 . The rat hepatocytes were isolated through collagenase perfusion from 250-350 g Sprague-Dawley rats and cultured in 12-well plates in DMEM supplemented with 2% fetal bovine serum (FBS) with some modification (19). The culture medium was changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

Methyl Antcinate A from Antrodia camphorata Induces Apoptosis in Human Liver Cancer Cells through Oxidant-Mediated Cofilin- and Bax-Triggered Mitochondrial Pathway

Hsieh

Rao

et al. 2010

Chem. Res. Toxicol.

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We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the activation of the ROS-dependent cofilin- and Bax-triggered mitochondrial pathway as a critical mechanism of MAA-induced cell death in liver cancer cells.

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“…Using [35S] sulfuric acid incorporation, Otsu et al showed that, in the hepatic regeneration phase after hepatectomy, the synthesis of heparin sulfate proteoglycans, and to a lesser extent, of chondroitin/dermatan sulfate proteoglycans, increases up to 3-5 days and is temporally shifted compared to the stage of maximum mitosis that occurs 1-2 days following the surgical procedure [94]. However, Kimura et al have reported that heparan sulfate appears just hours after hepatectomy, suggesting a possible role of this GAG as an initiator of hepatocyte proliferation [95].…”

Section: Proteoglycans and Liver Regenerationmentioning

confidence: 99%

Proteoglycans in Cancer: Friends or Enemies? A Special Focus on Hepatocellular Carcinoma

Dituri

Gigante

Scialpi

et al. 2022

Cancers

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Proteoglycans are a class of highly glycosylated proteins expressed in virtually all tissues, which are localized within membranes, but more often in the pericellular space and extracellular matrix (ECM), and are involved in tissue homeostasis and remodeling of the stromal microenvironment during physiological and pathological processes, such as tissue regeneration, angiogenesis, and cancer. In general, proteoglycans can perform signaling activities and influence a range of physical, chemical, and biological tissue properties, including the diffusivity of small electrolytes and nutrients and the bioavailability of growth factors. While the dysregulated expression of some proteoglycans is observed in many cancers, whether they act as supporters or limiters of neoplastic progression is still a matter of controversy, as the tumor promoting or suppressive function of some proteoglycans is context dependent. The participation of multiple proteoglycans in organ regeneration (as demonstrated for the liver in hepatectomy mouse models) and in cancer suggests that these molecules actively influence cell growth and motility, thus contributing to key events that characterize neoplastic progression. In this review, we outline the main roles of proteoglycans in the physiology and pathology of cancers, with a special mention to hepatocellular carcinoma (HCC), highlighting the translational potential of proteoglycans as targets or therapeutic agents for the treatment of this disease.

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Characterization of heparan sulfate on hepatocytes in regenerating rat liver

Abstract: These results suggested that this HS molecule, which contained about ten disaccharide units during proliferation, may be an initiator of hepatocyte proliferation.

Cited by 8 publications

References 38 publications

Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho

Sulfated Glycosaminoglycans Are Required for Specific and Sensitive Fibroblast Growth Factor (FGF) 19 Signaling via FGF Receptor 4 and betaKlotho

Methyl Antcinate A from Antrodia camphorata Induces Apoptosis in Human Liver Cancer Cells through Oxidant-Mediated Cofilin- and Bax-Triggered Mitochondrial Pathway

Proteoglycans in Cancer: Friends or Enemies? A Special Focus on Hepatocellular Carcinoma

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