Sinusoidal Flow Block after Warm Ischemia in Rats with Diet-Induced Fatty Liver

Hakamada, Kenichi; Sasaki, Mutsuo; Takahashi, Kazuhiro; Umehara, Yutaka; Konn, Mitsuru

doi:10.1006/jsre.1997.5077

Cited by 70 publications

(76 citation statements)

References 24 publications

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“…First, steatotic livers have impaired sinusoidal blood flow. 12,25 For example, Ohara et al 25 showed that the sinusoidal space is decreased by 53% in steatotic livers, causing significant microcirculatory disturbance. Second, steatotic livers show significant changes in the cell metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…These patients typically have an uneventful immediate postoperative course and develop hepatic failure between postoperative days 3 and 7. Although there is accumulating evidence in various animal models that steatotic livers have decreased tolerance to normothermic or cold ischemic injury, [10][11][12] no data are currently available on the regenerative ability of the fatty liver. The delayed occurrence of liver failure in patients undergoing resection suggests that dysfunction in the regenerative response may represent an important mechanism of injury.…”

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confidence: 99%

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Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

2000

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Hepatic resection or transplantation in patients with fatty liver is associated with increased morbidity and mortality. The regenerative capacity of fatty livers after major tissue loss is unknown. Interleukin 6 (IL-6) is a potent inducer of hepatic regeneration in normal and ischemic livers. Therefore, we studied hepatic regeneration at day 1, day 2, and day 4 in a model of 70% hepatectomy in obese and lean Zucker rats, and obese Zucker rats pretreated with recombinant interleukin 6 (rIL-6). Hepatic steatosis is a common clinical problem resulting from a variety of etiologies such as obesity, diabetes mellitus, alcohol intoxication, and other metabolic disorders. Mild steatosis, typically defined as fatty infiltration in fewer than 30% of the hepatocytes, is present in a third of the western population. Moderate (30% to 60% fatty hepatocytes) to severe (Ͼ60% fatty hepatocytes) hepatic steatosis is found in 6% to 11% of autopsies after accidental deaths. 1,2 Fatty infiltration of the liver is associated with an increased incidence of complications and mortality after liver resection 3 and transplantation. [4][5][6] For example, the mortality of liver resection in patients with moderate to severe steatosis exceeds 10%, 3 whereas this figure is below 2% for nonfatty livers in most centers. 7,8 Livers with more than 30% steatosis are often not used for transplantation due to an increased risk of primary nonfunction. 5,6,9 This represents a significant waste of organs, which further increases the already serious shortage of donor organs available for transplantation.The mechanisms of liver failure after resection of steatotic livers remain elusive. These patients typically have an uneventful immediate postoperative course and develop hepatic failure between postoperative days 3 and 7. Although there is accumulating evidence in various animal models that steatotic livers have decreased tolerance to normothermic or cold ischemic injury, [10][11][12] no data are currently available on the regenerative ability of the fatty liver. The delayed occurrence of liver failure in patients undergoing resection suggests that dysfunction in the regenerative response may represent an important mechanism of injury.To study the regenerative capacity of steatotic livers we chose a model of 70% liver resection in obese Zucker rats. Zucker rats are well characterized animals consistently exhibiting fatty deposition in all hepatocytes. Homozygous Zucker rats lack the cerebral leptin receptor and develop an obese phenotype due to markedly increased food intake and decreased energy expenditure at the age of 8 weeks. This model best simulates hepatic steatosis associated with obesity, the most common etiology of steatotic liver in western countries. Furthermore, the Zucker rat model is not associated with inflammatory changes within the liver in contrast to other models of fatty liver using ethanol ingestion or a cholinedeficient diet. 11,13 Four different markers of regeneration were evaluated in this study: proliferating cell nuclear anti...

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Section: Discussionmentioning

confidence: 99%

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Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

2000

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“…19 Triglycerides represent the main component of the lipids accumulated in the cytoplasmatic vacuoles. 20 Control rats were kept on a standard chow diet containing adequate levels of choline. All procedures involving rats were conducted according to the guidelines for the care and use of laboratory animals approved by our institutions.…”

Section: Animals and Protocolmentioning

confidence: 99%

Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status

et al. 2001

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Hepatic steatosis is associated with mitochondrial oxidative alterations. This study aimed to characterize in a choline-deficient model of rat fatty liver whether this oxidative imbalance is related to an impairment of the capacity of ATP synthesis both under fed conditions and after starvation, which may sensitize mitochondria to oxidative injury. Mitochondria were isolated from normal and fatty livers of fed or 18-hour fasted rats. Oxidative injury was evaluated by measuring the mitochondrial content of thiobarbituric reactive substances, protein carbonyls, glutathione, and protein sulfhydryls. The mitochondrial F 0 F 1 -ATP synthase content, tissue ATP concentration, and liver histology were also determined. Compared with normal liver, under fed conditions, fatty livers showed a greater mitochondrial content of oxidized lipids and proteins together with a low concentration of sulfhydryls and glutathione. The mitochondrial catalytic ␤-F 1 subunit of the F 0 F 1 -ATP synthase was about 35% lower in fatty livers. Hepatic ATP was also significantly reduced in fatty liver. Starvation exacerbated mitochondrial oxidative injury in both groups but to a greater extent in fatty livers. In the steatotic group, fasting induced a significant decrease of the ATP levels, which was accompanied by a 70% fall of the catalytic ␤-F 1 subunit. These data indicate that the mitochondrial oxidative alterations in fatty livers are associated with an important reduction of the F 0 F 1 -ATP synthase. These changes, which are greatly exacerbated after starvation, may account for the reduced synthesis of the hepatic ATP observed in the presence of fatty infiltration. (HEPATOLOGY 2001;33:808-815.)Hepatic steatosis without concomitant inflammation or fibrosis, is usually considered a benign condition. However, fatty degeneration increases the sensitivity of the liver to several types of injury, such as those due to ischemia-reperfusion 1 or drug toxicity. 2 Fatty infiltration is associated with a number of intracellular disorders, which can be either a cause or a consequence of lipid accumulation. 3 Among them, mitochondrial abnormalities related to an increased generation of reactive oxygen species have been described in human steatosis of various etiology (alcoholic 4 and nonalcoholic steatohepatitis, 5 iron, 6 or copper 7 overload) and in several experimental models of fatty liver, including alcohol administration 8 and drug toxicity. 2,9 Mitochondrial oxidative injury has been also described in conditions of chronic administration of commonly used drugs, such as valproate 10 or amiodarone, 11 the hepatic metabolites of which are known to interfere with mitochondrial respiration and fatty acid metabolism, thus producing fatty degeneration.Oxidative metabolism in mitochondria represent the main source of energy for the cells. Alterations of specific mitochondrial functions may, therefore, lead to an impaired production of ATP and a reduced uptake of substrates for mitochondrial metabolism 12 and eventually limit resistance and survival o...

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“…Hepatic steatosis is known to impose an additional risk of primary graft dysfunction [1]. Fat accumulation within hepatocytes increases cell volume resulting in a decreased sinusoidal space and impaired microcirculatory blood flow [2]. Nevertheless, the molecular underlying mechanisms the susceptibility of fatty livers to ischemia/reperfusion (I/R) injury remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury

Llacuna

Fernández

Montfort

et al. 2011

Journal of Hepatology

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Sinusoidal Flow Block after Warm Ischemia in Rats with Diet-Induced Fatty Liver

Cited by 70 publications

References 24 publications

Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia–reperfusion injury

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