Primary Nonfunction of Hepatic Allografts With Preexisting Fatty Infiltration1

Todo, Satoru; Demetris, Anthony J.; Makowka, Leonard; Teperman, Lewis; Podestá, Luis G.; Shaver, Timothy S.; Tzakis, Andreas G.; Starzl, Thomas E.

doi:10.1097/00007890-198905000-00034

Cited by 341 publications

(216 citation statements)

References 2 publications

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“…[21][22][23] In experimental situations, both genetic-based models and high-fat-diet-induced model proved that preexisting steatosis caused significant impairment of liver regeneration after PH. 12,24,25 In addition, the augmented hepatic steatosis after PH coexisted with the defective liver regeneration after PH in mice.…”

Section: Discussionmentioning

confidence: 99%

“…13 However, It is well established that excessive lipid accumulation in liver exhibits profound impairment of liver regeneration after PH. 12,[21][22][23][24][25] Adiponectin functions as a hormone to stimulate lipid catabolism. 26 It reduces lipid accumulation by inhibiting hepatic lipogenesis and stimulating fatty acid oxidation.…”

Section: The Effect Of Adiponectin Deficiency On Liver Mass Restoratimentioning

confidence: 99%

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Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Shu

Zhang

Wang

et al. 2009

Laboratory Investigation

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Liver regeneration is a very complex and well-orchestrated process associated with signaling cascades involving cytokines, growth factors, and metabolic pathways. Adiponectin is an adipocytokine secreted by mature adipocytes, and its receptors are widely distributed in many tissues, including the liver. Adiponectin has direct actions in the liver with prominent roles to improve hepatic insulin sensitivity, increase fatty acid oxidation, and decrease inflammation. To test the hypothesis that adiponectin is required for normal progress of liver regeneration, 2/3 partial hepatectomy (PH) was performed on wild-type and adiponectin-null mice. Compared to wild-type mice, adiponectin-null mice displayed decreased liver mass regrowth, impeded hepatocyte proliferation, and increased hepatic lipid accumulation. Gene expression analysis revealed that adiponectin regulated the gene transcription related to lipid metabolism. Furthermore, the suppressed hepatocyte proliferation was accompanied with reduced signal transducer and activator of transcription protein 3 (STAT3) activity and enhanced suppressor of cytokine signaling 3 (Socs3) transcription. In conclusion, adiponectin-null mice exhibit impaired liver regeneration and increased hepatic steatosis. Increased expression of Socs3 and subsequently reduced activation of STAT3 in adiponectin-null mice may contribute to the alteration of the liver regeneration capability and hepatic lipid metabolism after PH. The liver has a central role in metabolic homeostasis, as it is responsible for the metabolism, synthesis, storage, and redistribution of nutrients, carbohydrates, fats, and vitamins. Paradoxically, it is also the main detoxifying organ of the body, which is frequently challenged by chemical, traumatic, or infectious injuries. Consequently, the liver has evolved a unique ability to regenerate in respond to liver mass loss because of injuries. 1,2 Liver regeneration, which is driven by the replication of existing hepatocytes, is a process of compensatory hyperplasia rather than a differentiation process of stem cells. 3 One of the most effective models for studying liver regeneration after hepatocellular loss is partial hepatectomy (PH) in rodents. This technique, which was first described by Higgins and Anderson and performed in rats, 4 can be modified to be safely and reproducibly performed in mice. 5 After PH, resection of about 2/3 of liver mass results in quiescent hepatocytes rapidly re-entering the cell cycle. This highly regulated process is primed by different cytokines and growth factors that activate the downstream kinases and transcription factors. As a result, the hepatocytes initiate the transcription of more than 100 early genes, accumulate triglyceride and cholesterol to supply the energy and materials required for restore the liver mass. After one or two rounds of replication of hepatocytes, the original liver mass is restored within 5-7 days. Thus, liver regeneration constitutes a unique model to study signal transduction, lipid metabolism, and cell cycl...

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Section: Discussionmentioning

confidence: 99%

Section: The Effect Of Adiponectin Deficiency On Liver Mass Restoratimentioning

confidence: 99%

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Shu

Zhang

Wang

et al. 2009

Laboratory Investigation

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“…Transplanted steatotic livers exhibit increased rates of primary nonfunction and initial poor graft function (2)(3)(4). The current consensus is that donors with greater than 60% fat content should not be used, while mild to moderately steatotic grafts can perform as well as nonsteatotic grafts as long as there are no other risk factors with the donor or recipient.…”

Section: Introductionmentioning

confidence: 99%

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

Berthiaume

Barbe

Mokuno

et al. 2009

Journal of Surgical Research

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“…[5][6][7][8][9] Nuclear factor-kappa B (NF-B), crucial for the priming phase of liver regeneration, has been shown to be involved in both of these processes, promoting hepatocyte proliferation and also inhibiting apoptosis of liver cells. [10][11][12][13][14][15] To study the effects of dietary-induced obesity on liver regeneration, we subjected mice fed a high-fat diet (HFD) to PHx.…”

mentioning

confidence: 99%

A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-κB inhibitor, IκBα

et al. 2005

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Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in welldeveloped Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (I B␣) expression, which inhibited nuclear factor-kappa B (NF-B) activation and induction of its target genes, cyclin D1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through I B␣ overexpression and subsequent NF-B inhibition.

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Primary Nonfunction of Hepatic Allografts With Preexisting Fatty Infiltration1

Cited by 341 publications

References 2 publications

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Steatosis Reversibly Increases Hepatocyte Sensitivity to Hypoxia-Reoxygenation Injury

A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-κB inhibitor, IκBα

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