Hepatocyte Growth Factor In Liver Research Articles

The protective effects of Nigella sativa, thymoquinone and bentonite in experimental aflatoxicosis model in broilers

The aim of this study was to determine the preventive efficacy of black seed (Nigella sativa L.), thymoquinone and Na bentonite on biomarkers of tissue degeneration in the liver and other organs induced by aflatoxin (AF) in broilers. One hundred broiler chicks were divided into 10 equal groups and fed for 28 days. The animals received feed with 2 mg/kg total aflatoxin, Nigella sativa (NS; 5%), thymoquinone (TMQ; 300 mg/kg) and Na bentonite (BNT; 10 g/kg) both individually and in combination. At the end of the experiment, blood and liver tissue samples were collected. AF treatment significantly increased serum and liver 8-hydroxy-2’-deoxyguanosine(8-OHdG), serum transforming growth factor β (TGF-β), and liver total antioxidant capacity (TAC) levels, whereas it significantly decreased liver TGF-β and serum TAC levels compared to the control. However, there were no changes in the serum and liver hepatocyte growth factor (HGF) levels from AF. Both individual and combined addition of NS, BNT and TMQ to AF-contaminated feed significantly improved liver 8-OHdG, liver TAC and serum TGF-β levels. Serum 8-OHdG levels were ameliorated only in the AF+BNT+TMQ group. In addition, the AF+BNT+NS and AF+BNT+TMQ groups showed significant improvement in liver 8-OHdG, liver TGF-β and liver TAC levels. We conclude that NS and TMQ supplementation to AF-contaminated feed may be beneficial against aflatoxicosis in broilers.

Hepatocyte growth factor, vascular endothelial growth factor, glial cell-derived neurotrophic factor and nerve growth factor are differentially affected by early chronic ethanol or red wine intake

Ethanol intake during pregnancy and lactation induces severe changes in brain and liver throughout mechanisms involving growth factors. These are signaling molecules regulating survival, differentiation, maintenance and connectivity of brain and liver cells. Ethanol is an element of red wine which contains also compounds with antioxidant properties. Aim of the study was to investigate differences in hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) in brain areas and liver by ELISA of 1-month-old male mice exposed perinatally to ethanol at 11 vol.% or to red wine at same ethanol concentration. Ethanol was administered before and during pregnancy up to pups' weaning. Ethanol per se elevated HGF in liver and cortex, potentiated liver VEGF, reduced GDNF in the liver and decreased NGF content in hippocampus and cortex in the offspring. We did not find changes in HGF or NGF due to red wine exposure. However, we revealed elevation in VEGF levels in liver and reduced GDNF in the cortex of animals exposed to red wine but the VEGF liver increase was more marked in animals exposed to ethanol only compared to the red wine group. In conclusion the present findings in the mouse show differences in ethanol-induced toxicity when ethanol is administered alone or in red wine that may be related to compounds with antioxidant properties present in the red wine.

Evaluation of hepatocyte growth factor in patients with biliary atresia

Background Hepatocyte growth factor (HGF) is a potent mitogen for mature hepatocytes in primary culture and seems to be a trigger factor for liver regeneration and proliferation after liver injury. The aim of this study was to evaluate the expression of HGF in patients with biliary atresia (BA). Methods Plasma levels of HGF were determined using an enzyme-linked immunosorbent assay from 19 patients with BA, 10 at the time of Kasai procedure (KP) and 9 at liver transplantation (LT), and 10 patients with nonicteric choledochal cyst served as control. Hepatic HGF level was quantitatively estimated using enzyme-linked immunosorbent assay and Western blotting. Hepatocyte growth factor messenger RNA (mRNA) expression of liver was measured with quantitative reverse transcriptase polymerase chain reaction. Immunohistochemical study of liver sections was evaluated by HGF staining. Results Plasma HGF levels in LT patients were significantly higher than in KP patients (2977.30 ± 1251.42 vs 960.17 ± 559.82 pg/mL, P < .01). Western blots showed increased hepatic HGF levels in LT group than in KP group (2.02 ± 0.86 vs 1.44 ± 0.72 pg/ μg total protein, P < .05). However, there were no differences in HGF mRNA expression. Immunohistochemical study showed significantly increased HGF staining in hepatocytes of LT livers than of KP livers. Conclusions Elevation of plasma and liver HGF levels could be related to the progression of liver cirrhosis in patients with BA. Hepatocyte growth factor might have a protective role, probably through the induction of hepatocyte proliferation, during the development of BA-associated liver cirrhosis.

Expression of growth factors in colorectal carcinoma liver metastatic patients after partial hepatectomy: implications for a functional role in cell proliferation during liver regeneration

Liver has a remarkable ability to replace lost cell mass. Surgical resection of hepatic lobes triggers hepatocyte replication. Normally hepatocytes have a quiescent, highly differentiated phenotype and rarely divide in adult humans [1,2]. However, their capacity to replicate is readily activated after liver resection or after toxic injury. A number of studies have demonstrated the involvement of specific cytokines and growth factors in liver regeneration. The intact liver is relatively unresponsive to exogenous factors but partial hepatectomy provides some critical element that makes hepatocytes competent to fully respond to these substances [3,4]. Many growth factors play important roles in liver regeneration, most notably hepatocyte growth factor (HGF) and transforming growth factor a (TGF-alpha) [5,6]. HGF is an important multifunctional cytokine involved in liver repair after an injury. It acts as a motogen, a morphogen and a mitogen. Mesenchymal cells are responsible for the production of HGF whereas epithelial cells of various organs and tissues including the liver normally express HGF receptor cMET. In the liver HGF is produced by nonparenchymal cells especially perisinusoidal cells (PC), Kupffer cells (KC) and endothelial cells (EC). The expression of HGF mRNA during liver regeneration is also seen in mesenchymal cells in the lung and spleen and level of HGF increases in the blood after partial hepatectomy [7-9]. In contrast to HGF, which stimulates hepatocyte replication by a paracrine mechanism, TGF-alpha is an autocrine growth factor that is produced by hepatocytes and acts on these cells through binding the epidermal growth factor receptor (EGF-R) [10]. It is not known whether HGF and TGF-alpha have identical or complementary functions in hepatocyte replication. Human liver regeneration is known to be influenced by the size of resection and also by the condition of the liver. Vascular complications and ischemic injury in hepatectomized patients could result in adequate regeneration, leading to hepatic insufficiency [11]. Moreover, regeneration of human liver is influenced by coexisting liver diseases. Clinical experience has shown that resection of diseased liver sometimes results in postoperative liver failure due to limited hepatic functional reserve. While considerable interest has been focused on the tumor recurrence in liver cancer patients who underwent partial hepatectomy (PH) no data have been reported regarding the regenerating process after PH in liver tumor-bearing patients. The growth factors released by cancer cells may possibly regulate the growth of other cells in paracrine manner. The aim of the present study was initiated to determine the hepatocyte proliferation in relation to the expression of HGF and TGF-alpha in blood and liver tissue of patients with benign and malignant liver tumors after liver resection.

Hepatocyte Growth Factor and c-Met Inhibition by Hepatic Cell Hypoxia: A Potential Mechanism for Liver Regeneration Failure in Experimental Cirrhosis

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Hepatocyte growth factor levels in liver and serum increase during chemical hepatocarcinogenesis

Hepatocyte growth factor (HGF) is mitogenic for hepatocytes and some tumor cell lines. Elevations in plasma HGF levels have been detected in patients with hepatocellular carcinoma (HCC), and it is possible that HGF is involved in the promotion and/or progression of tumor growth. We measured serum and liver tissue HGF levels during chemically induced hepatocarcinogenesis. Wistar rats were given diethylnitrosamine (DEN) in drinking water for 10 weeks with controls receiving drinking water only. Animals were killed at 10, 16, and 19 weeks. Liver HGF levels were determined from immunoblotted protein by scanning densitometry, and serum HGF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). HGF was also immunolocalized in fixed liver tissue sections. In DEN-treated animals, at 10 weeks, there was necroinflammation but no dysplasia. Serum HGF was elevated compared with controls (P < .001) but there was no increase in liver HGF. At 16 weeks, there was liver cell dysplasia with minimal necroinflammation; serum and tissue HGF levels were both significantly elevated above controls. At 19 weeks, hepatocellular carcinomas (HCC) were present in five of six DEN-treated animals; liver HGF (P < .05) and serum HGF (P < .001) were both elevated compared with controls. HGF was localized in basement membranes around bile ducts and vessels and some perisinusoidal cells. Increased HGF immunolabeling was observed at 16 and 19 weeks, but dysplastic hepatocytes and tumor cells were HGF-negative. HGF may serve as a growth promoter at early stages during liver tumor development acting through possibly endocrine and paracrine pathways. Recent observations have described HGF as being mitoinhibitory for HCC cell lines; it is possible therefore that the continued up-regulation of HGF in the latter stages of our DEN model may inhibit tumor cell growth, and thus represent a form of antitumor host response. (Hepatology 1996 Nov;24(5):1282-7)

Hepatocyte growth factor levels in liver and serum increase during chemical hepatocarcinogenesis

Hepatocyte growth factor (HGF) is mitogenic for hepatocytes and some tumor cell lines. Elevations in plasma HGF levels have been detected in patients with hepatocellular carcinoma (HCC), and it is possible that HGF is involved in the promotion and/or progression of tumor growth. We measured serum and liver tissue HGF levels during chemically induced hepatocarcinogenesis. Wistar rats were given diethylnitrosamine (DEN) in drinking water for 10 weeks with controls receiving drinking water only. Animals were killed at 10, 16, and 19 weeks. Liver HGF levels were determined from immunoblotted protein by scanning densitometry, and serum HGF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). HGF was also immunolocalized in fixed liver tissue sections. In DEN-treated animals, at 10 weeks, there was necroinflammation but no dysplasia. Serum HGF was elevated compared with controls (P < .001) but there was no increase in liver HGF. At 16 weeks, there was liver cell dysplasia with minimal necroinflammation; serum and tissue HGF levels were both significantly elevated above controls. At 19 weeks, hepatocellular carcinomas (HCC) were present in five of six DEN-treated animals; liver HGF (P < .05) and serum HGF (P < .001) were both elevated compared with controls. HGF was localized in basement membranes around bile ducts and vessels and some perisinusoidal cells. Increased HGF immunolabeling was observed at 16 and 19 weeks, but dysplastic hepatocytes and tumor cells were HGF-negative. HGF may serve as a growth promoter at early stages during liver tumor development acting through possibly endocrine and paracrine pathways. Recent observations have described HGF as being mitoinhibitory for HCC cell lines; it is possible therefore that the continued up-regulation of HGF in the latter stages of our DEN model may inhibit tumor cell growth, and thus represent a form of antitumor host response.

Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: its specific receptor c-met does.

Increased levels of expression of hepatocyte growth factor (HGF) and its specific receptor c-met have been shown in the liver of several benign and malignant pathologies, both in experimental models and humans. We investigated by immunohistochemistry the presence of both HGF and c-met protoocogene product (c-met pp) in 20 hepatocellular carcinomas (HCCs), 5 focal nodular hyperplasias (FNHs), 4 cases of fulminant hepatitis (FH), and 1 case of regenerated liver. The c-met protooncogene product was expressed in all cases with marked overexpression in the HCCs and in ductular metaplasia. HGF was detected in the Ito cells of all cases and in neoplastic hepatocytes of 9 of 20 HCCs (45%). The proliferative index of each lesion was evaluated by means of the polyclonal antibody anti-cyclin A. When the level of expression of HGF and c-met protooncogene product with the percentage of cyclin A+ nuclei were compared, the closest relationship was between c-met protooncogene product and cyclin A+ nuclei were compared, the closest relationship was between c-met protooncogene product and cyclin A. In 11 of 20 HCCs (55%), there wa no correlation between HGF positivity and cyclin A. This seems to suggest that, independently of the levels of native liver HGF, c-met protooncogene product is the most active modulator of liver cell proliferation.

Liver hepatocyte growth factor does not always correlate with hepatocellular proliferation in human liver lesions: Its specific receptor c-met does.

Increased levels of expression of hepatocyte growth factor (HGF) and its specific receptor c-met have been shown in the liver of several benign and malignant pathologies, both in experimental models and humans. We investigated by immunohistochemistry the presence of both HGF and c-met protoocogene product (c-met pp) in 20 hepatocellular carcinomas (HCCs), 5 focal nodular hyperplasias (FNHs), 4 cases of fulminant hepatitis (FH), and 1 case of regenerated liver. The c-met protooncogene product was expressed in all cases with marked overexpression in the HCCs and in ductular metaplasia. HGF was detected in the Ito cells of all cases and in neoplastic hepatocytes of 9 of 20 HCCs (45%). The proliferative index of each lesion was evaluated by means of the polyclonal antibody anti-cyclin A. When the level of expression of HGF and c-met protooncogene product with the percentage of cyclin A+ nuclei were compared, the closest relationship was between c-met protooncogene product and cyclin A+ nuclei were compared, the closest relationship was between c-met protooncogene product and cyclin A. In 11 of 20 HCCs (55%), there wa no correlation between HGF positivity and cyclin A. This seems to suggest that, independently of the levels of native liver HGF, c-met protooncogene product is the most active modulator of liver cell proliferation. (Hepatology 1996 Jul;24(1):60-4)

Cell-specific expression of hepatocyte growth factor in liver. Upregulation in sinusoidal endothelial cells after carbon tetrachloride.

The cellular origin of hepatocyte growth factor (HGF), a polypeptide implicated in liver regeneration, was examined in normal liver and in hepatic regeneration induced by carbon tetrachloride. In normal liver, HGF and its mRNA were abundant in lipocytes, with smaller amounts present also in sinusoidal endothelial and Kupffer cells. In regenerating liver, HGF gene expression increased exclusively in endothelial cells. HGF mRNA levels rose sixfold in these cells, peaking at 6 h after toxin administration and returning to near normal by 24 h. The rise in HGF mRNA was accompanied by a 5.4-fold increase in HGF secretion. CCl4 did not alter HGF expression by either Kupffer cells or lipocytes; nor did it induce HGF expression by hepatocytes. Nonparenchymal liver cells contained two HGF transcripts: one predicting a full-length molecule of 728 amino acids; and the other encoding a functional five-amino acid deletion variant of HGF. The variant was less abundant than the full-length transcript, but increased in parallel with native HGF mRNA in response to CCl4. The response of nonparenchymal cells to HGF was examined by plating endothelial cells and lipocytes in the presence of recombinant human HGF. Under the conditions examined, the growth factor exerted neither mitogenic nor scatter factor activity on these cells.

Sequestration of a hepatocyte growth factor in extracellular matrix in normal adult rat liver

Perfusion of normal adult rat livers with Hanks' solution containing 1 M NaCl in situ led to the releasing of a large amount of hepatocyte growth factor (HGF). During the first 5 min of perfusion, the HGF content of the perfusate reached a maximum level, while the LDH activity due to release from the cells was negligible. The liver HGF content did not decrease with age. The liver HGF content in rats injured by CCl 4 injection decreased temporarily and then recovered rapidly to a normal level. These results indicate that HGF is sequestered in the extracellular matrix in the subendothelial space in normal adult rat liver and its effect will be either neutralized or potentiated by other local factors.