Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

Anderson, Steven P.; Yoon, Lawrence; Richard, Erika B.; Dunn, Corrie; Cattley, Russell C.; Corton, J. Christopher

doi:10.1053/jhep.2002.35276

Cited by 134 publications

(106 citation statements)

References 45 publications

(52 reference statements)

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“…13,[28][29][30][31][32][33] In contrast, solely a mild hepatic inflammation and no evidence of enhanced cell death or the development of insulin resistance was found in our model. Neither glucose nor insulin levels were altered and no relevant differences indicating development of diabetes in our model was observed in the diabetes assay.…”

Section: Discussioncontrasting

confidence: 60%

Steatosis does not impair liver regeneration after partial hepatectomy

Sydor

Schlattjan

et al. 2013

Laboratory Investigation

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Hepatic steatosis is a key feature of non-alcoholic fatty liver disease (NAFLD). While storage of lipid droplet-bound triglycerides in simple steatosis is physiologically inert, non-alcoholic steatohepatitis (NASH) is associated with hepatocyte damage and apoptosis. Mitochondrial oxidation of free fatty acids (FFA), derived from lipid droplets and hepatocellular uptake, is a rapid and effective way of energy supply for proliferating cells and FFA esterification provides substrates for lipid synthesis and cell proliferation. Thus, we investigated whether simple steatosis induced by western diet (WD) improves liver regeneration after partial hepatectomy (PHx). WD feeding for 6 weeks caused simple steatosis with hepatic lipid droplet and triglyceride accumulation accompanied by induction of fatty acid transport proteins (FATP), death receptors (DR), pro-and anti-apoptotic genes, hepatocyte growth factor (Hgf ) as well as increased serum leptin levels in a mouse model. After PHx, liver cell proliferation was higher in WD-fed mice and associated with FATP and Hgf induction. In addition, Erk1/2 (extracellular-related MAP kinase 1/2) dephosphorylation observed in standard diet (SD) mice was reduced in WD animals. PHx in steatotic livers did not affect hepatocyte apoptosis, despite DR upregulation. WD-induced steatosis enhances liver cell proliferation, which is accompanied by increased Hgf and leptin signaling as well as Erk1/2 phosphorylation. Induction of mild steatosis may therefore be beneficial for surgical outcome of hepatectomies.

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Section: Discussioncontrasting

confidence: 60%

Steatosis does not impair liver regeneration after partial hepatectomy

Sydor

Schlattjan

et al. 2013

Laboratory Investigation

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“…12,24,25 In addition, the augmented hepatic steatosis after PH coexisted with the defective liver regeneration after PH in mice. 10,34 This phenomenon was observed in adiponectin-null mice as well. These evidences suggest that excessive fat in hepatocytes may harm the normal process of liver regeneration.…”

Section: Discussionmentioning

confidence: 66%

“…8,9 Disruption of PPARamediated lipid signaling pathway delays the initiation of liver regeneration. 10 Activation of AMPK stimulates b-oxidation to influence the lipid metabolism in hepatocytes. 11 The first discovered adipocytokine, leptin, has been proved to be crucial during liver regeneration, 12,13 but whether adiponectin is required during liver regeneration is still unknown.…”

mentioning

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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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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“…4 and Table 4). It has been shown that peroxisomal proliferators, which activate PPAR-␣ signaling in the rodent liver, are mitogenic and that PPAR-␣-null mice have impaired liver regeneration (2). This suggests a positive role for PPAR-␣ in the regulation of hepatocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

Baumgardner¹,

Shankar²,

Korourian³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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To assess the relative contributions of undernutrition and ethanol (EtOH) exposure to alcohol-induced hepatotoxicity, female Sprague-Dawley rats were intragastrically infused liquid diets containing 187 or 154 kcal·kg−3/4·day−1 with or without 11 g·kg−1·day−1 EtOH. EtOH clearance was impaired in the 154 kcal·kg−3/4·day−1 EtOH group ( P ≤ 0.05). A combination of undernutrition and EtOH also increased the induction of hepatic cytochrome P-450 (CYP)2E1 and CYP4A1 mRNA, apoprotein, and activities ( P ≤ 0.05). This was accompanied by increased oxidative stress ( P ≤ 0.05). The severity of liver steatosis, macrophage infiltration, and focal necrosis was comparable in both EtOH groups. Alanine aminotransferase levels were elevated ( P ≤ 0.05) but did not significantly differ between the two EtOH groups. TUNEL analysis also demonstrated a comparable increase in apoptosis in the two EtOH groups ( P ≤ 0.05). The development of alcohol-induced liver pathology was accompanied by little change in fatty acid (FA) synthesis or degradation at 187 kcal·kg−3/4·day−1 but at 154 kcal·kg−3/4·day−1 was accompanied by decreased expression of FA synthesis genes and increased expression of peroxisome proliferator-activated receptor-α (PPAR-α)-regulated FA degradation pathways ( P ≤ 0.05). In addition, 154 kcal·kg−3/4·day−1 EtOH group livers exhibited greater hepatocyte proliferation ( P ≤ 0.05). We conclude that undernutrition does not exacerbate alcoholic steatohepatitis despite additional oxidative stress produced by an increased induction of CYP2E1 and CYP4A1. However, enhanced ethanol-induced cellular proliferation, perhaps as a result of enhanced PPAR-α signaling, may contribute to an increased risk of hepatocellular carcinoma in undernourished alcoholics.

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Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

Cited by 134 publications

References 45 publications

Steatosis does not impair liver regeneration after partial hepatectomy

Steatosis does not impair liver regeneration after partial hepatectomy

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Undernutrition enhances alcohol-induced hepatocyte proliferation in the liver of rats fed via total enteral nutrition

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