Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: Role of hepatic stimulator substance

Zhang, Baohong; Gong, Daozhi; Mei, M H

doi:10.1046/j.1440-1746.1999.01992.x

Cited by 26 publications

(15 citation statements)

References 31 publications

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“…Indeed, the hepatic stimulator substance can suppress CCl 4 toxicity on mitochondrial membrane fluidity, during rat LR. 41,42 The purified hepatic stimulator substance was renamed ALR, and is considered an important secondary hepatic growth factor inducing mitosis in hepatocytes. 43 This 22-kd protein is the mammalian homolog of the yeast scERV1 gene product, which is essential for biogenesis of mitochondria during the cell cycle and in the maintenance of intact mitochondrial genomes.…”

Section: Discussionmentioning

confidence: 99%

Changes in mitochondrial adenine nucleotides and in permeability transition in two models of rat liver regeneration

et al. 2003

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Although enhanced phosphorylative activity can be a requisite for later DNA synthesis during liver regeneration (LR), mitochondrial generation of reactive oxygen species could lead to altered mitochondrial membrane permeability during the prereplicative phase of LR. Therefore, the role of mitochondrial permeability transition (MPT) was evaluated during rat LR, induced by either partial hepatectomy (PH) or after CCl 4 administration. Parameters indicative of mitochondrial function and membrane potentials, those of oxidative stress, and in vivo changes of the intramitochondrial pool of adenine nucleotides were determined. Twelve hours after PH, mitochondrial oxidative and phosphorylative activities and adenosine diphosphate (ADP) content were increased, reaching a maximal peak at 24 hours after surgery (maximal DNA synthesis). Parameters suggestive of oxidant stress were enhanced, but mitochondrial volume and membrane electrical potential remained unaltered. Interestingly, moderate mitochondrial swelling and depolarization were found at later post-PH times (72 hours). In CCl 4 -treated animals, it was found that an active liver cell necrosis delayed mitotic activity and mitochondrial uncoupled respiration. Starting 12 hours after CCl 4 intoxication, a drastic increase of inorganic phosphate occurred within swollen and strongly depolarized mitochondria, suggesting changes in the MPT. Despite expression of messenger RNA (mRNA) for mitochondrial transcription, factor A showed a similar time course in both experimental models. The so-called augmenter liver regeneration was found significantly elevated only in PH rats. In conclusion, onset of MPT could be associated with cell necrosis and inflammation after CCl 4 treatment, whereas this mitochondrial event could constitute a putative effector mechanism, through which growth or inflammatory factors inhibiting cell proliferation could initiate LR termination. (HEPATOLOGY 2003;37:842-851.)

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Section: Discussionmentioning

confidence: 99%

Changes in mitochondrial adenine nucleotides and in permeability transition in two models of rat liver regeneration

et al. 2003

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“…The 20-dayold male rat pups (NB) known to exhibit extensive liver growth during this early development [14][15][16] were chosen for this study.…”

Section: Models Of Liver Tissue Repair or Liver Regenerationmentioning

confidence: 99%

“…[4][5][6][7][8] Monitoring the markers of liver regeneration in drug overdose victims has been proposed as a prognostic predictor. 5 Under a variety of circumstances in which liver regeneration is stimulated experimentally either by chemical injury (e.g., low dose of thioacetamide, APAP) [6][7][8][9][10] or by surgical resection (two-thirds partial hepatectomy), [11][12][13][14] the liver is known to exhibit resistance toward the higher doses of the hepatotoxicants. Liver cell division during postnatal development in newborns is known to impart resistance against toxicity.…”

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confidence: 99%

Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

et al. 2006

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Acute liver failure induced by hepatotoxic drugs results from rapid progression of injury. Substantial research has shown that timely liver regeneration can prevent progression of injury leading to a favorable prognosis. However, the mechanism by which compensatory regeneration prevents progression of injury is not known. We have recently reported that calpain released from necrotic hepatocytes mediates progression of liver injury even after the hepatotoxic drug is cleared from the body. By examining expression of calpastatin (CAST), an endogenous inhibitor of calpain in three liver cell division models known to be resistant to hepatotoxicity, we tested the hypothesis that increased CAST in the dividing hepatocytes affords resistance against progression of injury. Liver regeneration that follows CCl 4 -induced liver injury, 70% partial hepatectomy, and postnatal liver development were used. In all three models, CAST was upregulated in the dividing/newly divided hepatocytes and declined to normal levels with the cessation of cell proliferation. To test whether CAST overexpression confers resistance against hepatotoxicity, CAST was overexpressed in the livers of normal SW mice using adenovirus before challenging them with acetaminophen (APAP) overdose. These mice exhibited markedly attenuated progression of liver injury and 57% survival. Whereas APAP-bioactivating enzymes and covalent binding of the APAP-derived reactive metabolites remained unaffected, degradation of calpain specific target substrates such as fodrin was significantly reduced in these mice. In conclusion, CAST overexpression could be used as a therapeutic strategy to prevent progression of liver injury where liver regeneration is severely hampered. (HEPATOLOGY 2006;44:379-388.)

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“…Subsequent studies showed that HSS is a heat-stable, ethanol precipitable factor that is able to exert mitogenic effects on primed liver in an organ-specific, but species-non-specific manner [6]. Currently, the participation of HSS in animal models of acute liver injury induced by toxins, such as D-galactosamine [7][8][9], cadmium (Cd) [10][11][12][13], thioacetamide (TAA) [14][15][16][17][18], carbon tetrachloride (CCl 4 ) [19][20][21], and ethanol [22,23], has been investigated. In these studies, variations of HSS activity in the injured liver were noticed [13,15,17,20,22,23].…”

Section: Introductionmentioning

confidence: 99%

“…In these studies, variations of HSS activity in the injured liver were noticed [13,15,17,20,22,23]. Additionally, exogenous HSS administration ameliorated hepatic damage [8, 10-12, 14, 16, 18, 19, 22, 23], enhanced hepatic proliferative capacity post-toxininduced liver injury [7, 8, 11-13, 16, 18, 19, 22, 23], or improved survival of toxin-administered animals [7,9,18,21]. However, HSS activity has not been assessed in animal models of chronic liver injury as in the case of fibrosis and cirrhosis induction.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Hepatic Stimulator Substance in Experimentally Induced Fibrosis and Cirrhosis in the Rat

et al. 2008

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Liver fibrosis results from sustained wound healing response to chronic liver injury. Liver cirrhosis, the end stage of the fibrotic process, is characterized by disruption of the entire liver architecture and reduced hepatocyte regenerative ability. Hepatic stimulator substance (HSS) is a liver-specific growth factor triggering hepatocyte proliferation in vitro and in vivo. Previous studies have indicated the involvement of HSS in animal models of acute liver injury. The aim of the present study was to investigate the involvement of HSS in the process of fibrosis and cirrhosis induction. Liver fibrosis and cirrhosis were induced in rats by thioacetamide (TAA) administration (300 mg/l) in the drinking water for 3 months, and animals were killed at 0, 1, 2, and 3 months of treatment. TAA administration resulted in progressively increasing liver fibrosis, leading to the onset of cirrhosis at the end of the experimental time. HSS was continuously produced during the course of fibrosis and cirrhosis induction, peaking at the 2nd month of TAA treatment, coinciding with markers of hepatic proliferative capacity, as thymidine kinase activity and DNA biosynthesis. Significantly reduced HSS activity was noted in cirrhotic liver (3rd month). In this case, the exogenous HSS administration during the 3rd month of TAA treatment suppressed the onset of liver cirrhosis, stimulating the hepatic regenerative capacity. Our data indicate the active participation of HSS in the process of fibrosis and cirrhosis induction post-TAA treatment in rats, suggesting also the beneficial effect of HSS treatment against cirrhosis induction with future possible clinical implications.

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Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: Role of hepatic stimulator substance

Abstract: Regenerating rat liver exhibits resistance to CCl4-induced hepatotoxicity, and the protection afforded by the regenerating state can be attributed, at least in part, to HSS-induced increases in mitochondrial respiratory activity and plasma membrane fluidity.

Cited by 26 publications

References 31 publications

Changes in mitochondrial adenine nucleotides and in permeability transition in two models of rat liver regeneration

Changes in mitochondrial adenine nucleotides and in permeability transition in two models of rat liver regeneration

Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

Involvement of Hepatic Stimulator Substance in Experimentally Induced Fibrosis and Cirrhosis in the Rat

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