Preferential suppression of insulin‐stimulated proliferation of cultured hepatocytes by somatostatin: Evidence for receptor‐mediated growth regulation

Kothary, Piyush C.; Kokudo, Norihiro; Eckhäuser, Frederic E.; DelValle, John; Raper, Steven E.

doi:10.1002/jcb.240590214

Cited by 5 publications

(4 citation statements)

References 26 publications

(13 reference statements)

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“…Somatostatin is actually widely known to inhibit, to a certain degree, "standard" liver regeneration [37][38][39], though its use in the context of extremely SFS livers ultimately has the opposite effect, as we have seen in the present report. Without any form of portal inflow reduction-be it mechanical or pharmacological-the initial regenerative stimulus and, consequentially, response in SFS livers is great (excessive).…”

Section: Discussionsupporting

confidence: 57%

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy

Hessheimer

Vengohechea

Maza

et al. 2021

Cancers

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Liver resection treats primary and secondary liver tumors, though clinical applicability is limited by the remnant liver mass and quality. Herein, major hepatic resections were performed in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes with somatostatin therapy. Three experimental groups were performed: 75% hepatectomy (75H), 90% hepatectomy (90H), and 90% hepatectomy + somatostatin (90H + SST). Animals were followed for 24 h (N = 6) and 5 d (N = 6). After hepatectomy, portal pressure gradient was higher in 90H versus 75H and 90H + SST (8 (3–13) mmHg vs. 4 (2–6) mmHg and 4 (2–6) mmHg, respectively, p < 0.001). After 24 h, changes were observed in 90H associated with stellate cell activation and collapse of sinusoidal lumen. Collagen chain type 1 alpha 1 mRNA expression was higher, extracellular matrix width less, and percentage of collagen-staining areas greater at 24 h in 90H versus 75H and 90H + SST. After 5 d, remnant liver mass was higher in 75H and 90H + SST versus 90H, and Ki-67 immunostaining was higher in 90H + SST versus 75H and 90H. As well, more TUNEL-staining cells were observed in 90H versus 75H and 90H + SST at 5 d. Perioperative somatostatin modified portal pressure, injury, apoptosis, and stellate cell activation, stemming changes related to hepatic fibrogenesis seen in liver remnants not receiving treatment.

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Section: Discussionsupporting

confidence: 57%

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy

Hessheimer

Vengohechea

Maza

et al. 2021

Cancers

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“…The onset of DNA synthesis is well synchronized in hepatocytes, beginning in cells that surround the portal vein of the liver lobule and proceeding towards the central vein (Minuk, 2003). Many growth factors are involved in the regeneration of the liver: hepatocyte growth factor (HGF) (Nishino et al, 2008), epidermal growth factor (EGF) (Natarajan et al, 2007), transforming growth factors (TGFs) (Weymann et al, 2009), insulin (Stefano et al, 2006), glucagon (Kothary et al, 1995) and insulin like growth factor (Sanz et al, 2005). …”

Section: Introductionmentioning

confidence: 99%

The identification of stem cells in human liver diseases and hepatocellular carcinoma

Oliva

French

Qing

et al. 2010

Experimental and Molecular Pathology

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Liver stem cells are thought to preside in bile ducts and the canals of Hering. They extend into the liver parenchyma at a time when normal liver cell proliferation is suppressed and liver regeneration is stimulated. In the present study 69 liver biopsies and surgically excised liver tumors were studied for the presence of liver stem cells. It was found that human cirrhotic livers and hepatocellular carcinomas (HCC) frequently exhibited isolated single scattered hepatocyte stem cells within the liver parenchyma rather than in the portal tract, bile duct or the canal of Hering. These cells expressed liver stem cell markers. HCCs also contained isolated tumor cell which expressed the same stem cell markers. The markers used were GST-P, OV-6, CK-19, Oct-3/4 and FAT10. They were identified by immunofluorescent antibody staining. HGF, EGF, CK19, AIR, H19, Nanog, Oct-3/4 and FAT10 were identified by RNA-FISH. H19 is a non-coding RNA, which is expressed in most HCCs. Results: Immunohistochemistry and RNA-FISH performed on human livers identified isolated stem cells in liver parenchyma as follows: Stem cells identified by immunohistochemical markers (OV-6 and GST-P) and RNA-FISH markers (HGF, EGF, CK19 and H19) were found scattered in the liver parenchyma of cirrhotic livers and within hepatocellular carcinomas (HCCs). Precirrhotic ASH or NASH all stained negative for these stem cells. In HCCs, 13 out of 15 had stem cells located within the tumor (78%). In cirrhotic livers, 12 out of 28 (37%) had liver parenchymal stem cells present. In one case of stage 3 precirrhosis, stem cells were also found. Double staining for the markers showed colocalization of the markers in stem cells. Stem cells were found in 33% of HBV, 47% of HCV, 25% of alcoholic steatohepatitis (ASH) and 17% of non-alcoholic steatohepatitis (NASH). The frequency of stem cells found in the different disease categories correlates with the frequency of HCC occurring in these different diseases.

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“…Based on the fact that it lowers PVF and suppresses the release and action of several hepatotrophic factors, somatostatin is known to suppress hepatic regeneration (38)(39)(40). While some authors argue that SFSS arises primarily due to the failure of a partial liver to regenerate (41,42), other groups have made observations to the contrary.…”

Section: Discussionmentioning

confidence: 99%

Somatostatin Therapy Protects Porcine Livers in Small-for-Size Liver Transplantation

Hessheimer

Escobar

Muñoz

et al. 2014

American Journal of Transplantation

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Small-for-size (SFS) injury occurs in partial liver transplantation due to several factors, including excessive portal inflow and insufficient intragraft responses. We aim to determine the role somatostatin plays in reducing portal hyperperfusion and preventing the cascade of deleterious events produced in small grafts. A porcine model of 20% liver transplantation is performed. Perioperatively treated recipients receive somatostatin and untreated controls standard intravenous fluids. Recipients are followed for up to 5 days. In vitro studies are also performed to determine direct protective effects of somatostatin on hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). At reperfusion, portal vein flow (PVF) per gram of tissue increased fourfold in untreated animals versus approximately threefold among treated recipients (p ¼ 0.033). Postoperatively, markers of hepatocellular, SEC and HSC injury were improved among treated animals. Hepatic regeneration occurred in a slower but more orderly fashion among treated grafts; functional recovery was also significantly better. In vitro studies revealed that somatostatin directly reduces HSC activation, though no direct effect on SEC was found. In SFS transplantation, somatostatin reduces PVF and protects SEC in the critical postreperfusion period. Somatostatin also exerts a direct cytoprotective effect on HSC, independent of changes in PVF.

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Preferential suppression of insulin‐stimulated proliferation of cultured hepatocytes by somatostatin: Evidence for receptor‐mediated growth regulation

Cited by 5 publications

References 26 publications

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy

Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy

The identification of stem cells in human liver diseases and hepatocellular carcinoma

Somatostatin Therapy Protects Porcine Livers in Small-for-Size Liver Transplantation

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