Sequential Changes of Energy Charge, Lipoperoxide Level, and DNA Synthesis Rate of the Liver Following Biliary Obstruction in Rats

Komura, Masayoshi; Chijiiwa, Kazuo; Naito, Tokio; Kameoka, Nobuhisa; Yamashita, Hiroyuki; Yamaguchi, Koji; Kuroki, Shin-Ichiro; Tanaka, Masao

doi:10.1006/jsre.1996.0154

Cited by 18 publications

(11 citation statements)

References 10 publications

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“…The energetic deficiency should activate mitochondrial biogenesis through PGC-1␣, NRF-1, and GABP-␣/NRF2 (2,18,28,30). PGC-1␣ is a key regulator of cellular energy metabolism with crucial roles in the control of mitochondrial biogenesis and antioxidants (30).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions

Arduini

Serviddio

Escobar

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Arduini A, Serviddio G, Escobar J, Tormos AM, Bellanti F, Viña J, Monsalve M, Sastre J. Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions. Am J Physiol Gastrointest Liver Physiol 301: G119 -G127, 2011. First published March 17, 2011 doi:10.1152/ajpgi.00253.2010.-Chronic cholestasis is characterized by mitochondrial dysfunction, associated with loss of mitochondrial membrane potential, decreased activities of respiratory chain complexes, and ATP production. Our aim was to determine the molecular mechanisms that link long-term cholestasis to mitochondrial dysfunction. We studied a model of chronic cholestasis induced by bile duct ligation in rats. Key sensors and regulators of the energetic state and mitochondrial biogenesis, mitochondrial DNA (mtDNA)-to-nuclear DNA (nDNA) ratio (mtDNA/nDNA) relative copy number, mtDNA deletions, and indexes of apoptosis (BAX, BCL-2, and cleaved caspase 3) and cell proliferation (PCNA) were evaluated. Our results show that long-term cholestasis is associated with absence of activation of key sensors of the energetic state, evidenced by decreased SIRT1 and pyruvate dehydrogenase kinase levels and lack of AMPK activation. Key mitochondrial biogenesis regulators (PGC-1␣ and GABP-␣) decreased and NRF-1 was not transcriptionally active. Mitochondrial transcription factor A (TFAM) protein levels increased transiently in liver mitochondria at 2 wk after bile duct ligation, but they dramatically decreased at 4 wk. Reduced TFAM levels at this stage were mirrored by a marked decrease (65%) in mtDNA/nDNA relative copy number. The blockade of mitochondrial biogenesis should not be ascribed to activation of apoptosis or inhibition of cell proliferation. Impaired mitochondrial turnover and loss of the DNA stabilizing effect of TFAM are likely the causative event involved in the genetic instability evidenced by accumulation of mtDNA deletions. In conclusion, the lack of stimulation of mitochondrial biogenesis leads to mtDNA severe depletion and deletions in long-term cholestasis. Hence, long-term cholestasis should be considered a secondary mitochondrial hepatopathy.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions

Arduini

Serviddio

Escobar

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We have previously shown that the hepatic DNA synthesis rate was elevated on the seventh day after biliary obstruction versus sham-operated rats. 20 At the time of hepatectomy, the hepatic DNA synthesis rate in the OJ-Hx group was significantly higher than in the ED-Hx and ID-Hx groups. Serum liver function tests showed that both biliary drainage procedures were effective.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Incorporation of [3H] thymidine into DNA was calculated as disintegrations per minute per microgram DNA.…”

Section: Hepatic Dna Synthesis Ratementioning

confidence: 99%

Preoperative Internal Biliary Drainage Is Superior to External Biliary Drainage in Liver Regeneration and Function After Hepatectomy in Obstructive Jaundiced Rats

et al. 1999

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ObjectiveTo examine the differences in regeneration rates and functions of the liver at the time of and after hepatectomy in obstructive jaundiced rats with preoperative external and internal biliary drainage. Summary Background DataThe significance of biliary drainage before surgery is controversial in patients with obstructive jaundice. MethodsAfter biliary obstruction for 7 days, rats were randomly divided into three groups: obstructive jaundice and hepatectomy (OJHx), external biliary drainage and hepatectomy (ED-Hx), and internal biliary drainage and hepatectomy (ID-Hx). The OJ-Hx group underwent hepatectomy without biliary drainage; the other two groups underwent hepatectomy after biliary drainage for 7 days. At the time of hepatectomy, all rats were provided with internal biliary drainage. On days 0, 1, 2, 3, and 7 after hepatectomy, the DNA synthesis rate and the concentrations of adenine nucleotides and malondialdehyde in the liver were determined as markers of the hepatic regeneration rate, energy status, and lipoperoxide concentration, respectively. Portal endotoxin concentrations were measured and serum hyaluronic acid concentrations were determined as an indicator of hepatic endothelial function. ResultsThe relative liver weight was significantly higher in the ID-Hx group than in the OJ-Hx group on days 1, 3, and 7 after hepatectomy and than in the ED-Hx group on days 1 and 2. The rate of hepatic DNA synthesis was significantly higher in the ID-Hx group than in the OJ-Hx and ED-Hx groups on day 1. The rate was similar in the ED-Hx and ID-Hx groups on day 2 but was significantly higher than in the OJ-Hx group. The hepatic malondialdehyde concentration was significantly higher on day 1 in the ED-Hx group than in the other two groups. It was lowest in the ID-Hx group throughout the study. Both biliary drainage procedures lowered the portal endotoxin concentration and serum hyaluronic acid concentration at the time of hepatectomy. The serum hyaluronic acid concentration was lowest in the ID-Hx group. Hepatic adenine triphosphate concentrations and energy charge levels were similar among the three groups. ConclusionAlthough both external and internal biliary drainage before hepatectomy improved serum liver function tests, portal endotoxin concentration, and serum hyaluronic acid concentration at the time of surgery, preoperative internal biliary drainage was superior to external drainage, as evidenced by the better liver regeneration and function after hepatectomy.

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“…The effect of obstructive jaundice on liver regeneration after hepatectomy has been debated, while the decreased functional reserve of the jaundiced liver has been noted (10,11). Recent studies have indicated that hepatic basal expressions of HGF and TGF-␣ are enhanced in rats with obstructive jaundice (12,13) but that the regeneration activity of the jaundiced liver is suppressed even though biliary obstruction is released at the time of hepatectomy (14,15).…”

mentioning

confidence: 97%

Lower Activity of CCAAT/Enhancer-Binding Protein and Expression of Cyclin E, but Not Cyclin D1, Activating Protein-1 and p21WAF1, after Partial Hepatectomy in Obstructive Jaundice

Nakano

Chijiiwa

Tanaka

2001

Biochemical and Biophysical Research Communications

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Sequential Changes of Energy Charge, Lipoperoxide Level, and DNA Synthesis Rate of the Liver Following Biliary Obstruction in Rats

Cited by 18 publications

References 10 publications

Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions

Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions

Preoperative Internal Biliary Drainage Is Superior to External Biliary Drainage in Liver Regeneration and Function After Hepatectomy in Obstructive Jaundiced Rats

Lower Activity of CCAAT/Enhancer-Binding Protein and Expression of Cyclin E, but Not Cyclin D1, Activating Protein-1 and p21WAF1, after Partial Hepatectomy in Obstructive Jaundice

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