Insulin Receptor, Insulin Receptor Substrate-1, Raf-1, and Mek-1 during Hormonal Hepatocarcinogenesis by Intrahepatic Pancreatic Islet Transplantation in Diabetic Rats

Evert, Matthias; Sun, Jianping; Pichler, Sabine; Slavova, N.; Schneider‐Stock, Regine; Dombrowski, Frank

doi:10.1158/0008-5472.can-04-2040

Cited by 33 publications

(48 citation statements)

References 45 publications

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“…There are serine/threonine phosphorylation sites in IRS-1, and the phosphorylation of these sites inhibits IRS-1 [15][16][17], leading to insulin resistance. IRS-1 is therefore related to obesity and diabetes [18,19].…”

Section: Introductionmentioning

confidence: 99%

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Wang

Zhou

et al. 2008

Cell Res

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cAMP and protein kinase A (PKA) are widely known as signaling molecules that are important for the induction of adipogenesis. Here we show that a strong increase in the amount of cAMP inhibits the adipogenesis of 3T3-L1 fibroblast cells. Stimulation of PKA activity suppresses adipogenesis and, in contrast, inhibition of PKA activity markedly accelerates the adipogenic process. As adipogenesis progresses, there is a significant increase in the expression level of PKA regulatory subunits and a corresponding decrease in PKA activity. Moreover, treatment of 3T3-L1 cells with epidermal growth factor (EGF) stimulates PKA activity and blocks adipogenesis. Inhibition of PKA activity abolishes this suppressive effect of EGF on adipogenesis. Moreover, activation of PKA induces serine/threonine phosphorylation, reduces tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) and the association between PKA and IRS-1. Taken together, our study demonstrates that PKA has a pivotal role in the suppression of adipogenesis. cAMP at high concentrations can suppress adipogenesis through PKA activation. These findings could be important and useful for understanding the mechanisms of adipogenesis and the relevant physiological events.

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Section: Introductionmentioning

confidence: 99%

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Wang

Zhou

et al. 2008

Cell Res

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“…1,4,6 Moreover, we recently demonstrated increased insulin signalling within the FAH, reflected in a translocation of the insulin receptor and overexpression of several insulin signal transduction proteins, such as insulin receptor substrate-1, Raf-1 and Mek-1. 7 The carbohydrate metabolism in FAH has also been …”

mentioning

confidence: 99%

“…4 Previous results indicate that insulin is the primary trigger for the development of FAH and hepatocarcinogenesis in this model. 1,[4][5][6][7] In the beginning of the carcinogenic process, however, these FAH can be regarded as purely adaptative in nature. At this stage, insulin effects manifested in several aspects, that is, an increase in glycogen storage and proliferative activity, lipid accumulation, and altered expression of several insulinrelated proteins, including IGF-I and its binding proteins, such as IGFBP-1 and IGFBP-4.…”

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confidence: 99%

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Evert

Schneider‐Stock

Dombrowski

2005

Laboratory Investigation

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Fatty acid synthase (FAS) is the key enzyme of de novo fatty acid synthesis and has been shown to be involved in carcinogenesis of numerous human malignancies, including breast, colorectal, and prostate carcinomas, often associated with a worse prognosis. Although FAS is mainly expressed in the liver, an implication of FAS in hepatocarcinogenesis, has not yet been investigated. FAS expression is stimulated by insulin and glucose, and insulin is also the primary trigger of hepatocarcinogenesis in an endocrine experimental model, which is induced by low-number transplantation of islets of Langerhans into the livers of diabetic rats. We therefore investigated, whether FAS is implicated in hepatocarcinogenesis in this model and in comparison to chemically induced hepatocarcinogenesis after N-nitrosomorpholine (NNM) treatment in diabetic and normoglycemic rats. Preneoplastic clear-cell foci of altered hepatocytes (FAH), harvested after laser-microdissection of kryostat sections, showed an overexpression of FAS messenger RNA in gene expression profiles, done by arrayhybridization, and in quantitative RT-PCR (Light-Cycler). Virtually, all (96-98%) of the subsequently investigated FAH and the glycogenotic hepatocellular adenomas and carcinomas showed an additional strong FAS protein overexpression. In the NNM-model, FAS protein was also overexpressed in the vast majority (87%) of glycogenotic FAH and neoplasms, in particular in the diabetic animals. Also two spontaneous glycogenotic FAH in control animals displayed strong FAS overexpression. Basophilic lesions and neoplasms, which occasionally develop out of the primary clear-cell FAH at later stages of carcinogenesis, however, lost FAS overexpression. In conclusion, FAS overexpression is an early phenonemon in spontaneous, hormonally and chemically induced rat hepatocarcinogenesis, demonstrable in early clear-cell (glycogenotic) FAH and hepatocellular neoplasms. Keywords: fatty acid synthase; glucose; hepatocarcinogenesis; insulin; islet transplantatation; N-nitrosomorpholine After low-number transplantation of islets of Langerhans into the livers of diabetic rats, the liver acini draining the blood from the islet grafts show cellular alterations, the foci of altered hepatocytes (FAH). 1 FAH resemble the glycogen-storing or clear-cell phenotype of preneoplastic foci known from experimental and human hepatocarcinogenesis. 2,3 In the transplantation model, these preneoplastic FAH may develop into hepatocellular adenomas (HCA) and carcinomas (HCC) within 6-24 months after islet transplantation. 4 Previous results indicate that insulin is the primary trigger for the development of FAH and hepatocarcinogenesis in this model. 1,[4][5][6][7] In the beginning of the carcinogenic process, however, these FAH can be regarded as purely adaptative in nature. At this stage, insulin effects manifested in several aspects, that is, an increase in glycogen storage and proliferative activity, lipid accumulation, and altered expression of several insulinrelated proteins, including IGF-I a...

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“…These alterations are typical insulin effects that have been studied in detail earlier, and were shown to be the results of insulin-induced alterations of enzymes of the carbohydrate and lipid metabolism. [14][15][16][21][22][23] Thus, the altered liver acini sharply contrasted to the hormonally unaffected surrounding liver tissue not only histologically but also even on macroscopic evaluation of unstained liver slices (see below).…”

Section: Hepatocellular Alterations In the Insulin Modelmentioning

confidence: 99%

“…[6][7] Here, we report on our observations made by examining morphologically altered liver acini in animal models that were originally designed to study hormonally induced hepatocarcinogenesis. [14][15][16][17][18][19][20][21][22][23] The altered morphology of the liver acini was induced by local action of hormones [such as insulin and tri-iodothyronine (T3)] on the hepatocellular metabolism after transplantation of endocrine tissues into the rat liver, resulting in considerable changes of the hepatocellular phenotype of the downstream liver acini, such as an excess in glycogen and/or fat storage in the insulin model [14][15][16][17][18][21][22][23] or increased basophilia and loss of glycogen in the T3 model. 20 Therefore, we were able to depict the anatomy of a simple liver acinus for the first time, conclusively proving the correctness of Rappaport's acinus model.…”

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confidence: 99%

Revelation of simple and complex liver acini after portal transplantation of pancreatic islets or thyroid follicles in rats

Dombrowski

Evert

2007

Hepatology

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The microarchitecture of the liver is still not completely understood although various concepts of structural liver organization have been proposed. Among them, Rappaport's liver acinus stands out as one of the most accepted models. The correctness of this model, however, has also been doubted, and its applicability is hampered by the fact that the outlines of the liver acinus are disguised and nobody was ever able to give visual evidence by "unmasking" a simple liver acinus from the surrounding liver tissue. After intraportal transplantation of pancreatic islets or thyroid follicles into diabetic or thyroidectomized rats, respectively, the transplants engraft in small portal tracts and morphologically alter the downstream liver tissue due to excessive hormone secretion. Using a combined approach of perfusion fixation, stereomicroscopy, and light microscopy, we demonstrate in this study that these foci of altered liver tissue represent simple and complex liver acini, exactly as described by Rappaport. We present stereomicroscopical and histological examples of all important cut levels of altered simple and complex liver acini, including their topographical relation to the supplying and draining vessels and to the "central vein" liver lobule. Moreover, by computer-aided reconstruction of serial semi-thin sections, we were able to present the first 3-dimensional images of simple and complex liver acini. Conclusion: Our results prove the correctness of Rappaport's acinus model and confirm the simple liver acinus as the principal microcirculatory unit of the liver. (HEPATOLOGY 2007;45:705-715.)

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Insulin Receptor, Insulin Receptor Substrate-1, Raf-1, and Mek-1 during Hormonal Hepatocarcinogenesis by Intrahepatic Pancreatic Islet Transplantation in Diabetic Rats

Cited by 33 publications

References 45 publications

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Protein kinase A suppresses the differentiation of 3T3-L1 preadipocytes

Overexpression of fatty acid synthase in chemically and hormonally induced hepatocarcinogenesis of the rat

Revelation of simple and complex liver acini after portal transplantation of pancreatic islets or thyroid follicles in rats

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