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

DeAngelis, Robert A.; Markiewski, Maciej M.; Taub, Rebecca; Lambris, John D.

doi:10.1002/hep.20879

Cited by 127 publications

(94 citation statements)

References 43 publications

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“…The effects of chronic exposure to a highfat diet on liver regeneration in mice subjected to partial hepatectomy has been recently studied (DeAngelis et al 2005). Besides obesity and steatosis, there was a significant impaired liver regeneration in comparison to mice fed standard diet.…”

Section: Discussionmentioning

confidence: 99%

“…The liver maintains a functional cell mass consisting of several specialized cell types, of which the hepatocytes form the major part (Zimmermann 2004). However, animals submitted to a highfat diet and the subsequent development of steatosis predisposes to hepatic injury (Zhang et al 1999, Rao et al 2001, Picard et al 2002, DeAngelis et al 2005. Earlier studies evaluated hepatic regeneration in murine experimental schistosomiasis.…”

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confidence: 99%

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Hepatic stereology of schistosomiasis mansoni infected-mice fed a high-fat diet

Neves

Alencar

Águila

et al. 2006

Mem. Inst. Oswaldo Cruz

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High-fat diets induce weight gain and fatty liver in wild-type mice. Schistosomiasis mansoni infection also promotes hepatic injury. This study was designed to quantify hepatic alterations in schistosomiasis mansoni infected mice fed a high-fat diet (IHFC) or standard chow (ISC), uninfected mice fed a high-fat diet (HFC) or standard chow (SC). Mice were sacrificed during early infection (9 weeks from exposure). The following hepatic biometry and the stereology parameters were determined: volume density (hepatocytes [h], sinusoids [s], steatosis [st] and hepatic fibrosis [hf]); numerical density (hepatocyte nuclei -Nv[h]); absolute number of total hepatocyte N[h], normal hepatocyte N[nh], and binucleated hepatocyte N[bh], percentage of normal hepatocyte P[nh] and binucleated hepatocyte P[bh]. IHFC and HFC groups exhibited TC, HDL-C, LDL-C, and body mass significantly greater (p < 0.05) than control group. No significant differences were found regards liver volume (p = 0.07). Significant differences were observed regards P[nh] (p = 0.0045), P[bh] (p = 0.0045), Nv[h] (p = 0.0006), N[h] (p = 0.0125), N[bh] (p = 0.0164) and N[nh] (p = 0.0078). IHFC mice group presented 29% of binucleated hepatocytes compared to HFC group (19%), ISC group (17%) and SC (6%

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hepatic stereology of schistosomiasis mansoni infected-mice fed a high-fat diet

Neves

Alencar

Águila

et al. 2006

Mem. Inst. Oswaldo Cruz

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“…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%

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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“…22,23 Suppression of fat accumulation in the liver after PH impairs LR in mice. 24 On the other hand, excessive liver steatosis, such as in leptin-and leptinreceptor-deficient mice [25][26][27] or high fat diet-fed mice, 28 also derails LR post PH. At the molecular level, ob/ob and high fat diet-fed mice show decreased expression of cyclin D1, and heightened p21 protein levels, 29 which recapitulates the molecular signature we identified in HET mice.…”

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confidence: 99%

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

et al. 2015

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (440%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of 41000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver proregenerative therapies. Humans and mice restore their liver mass within 2 weeks of surgical, viral or toxic parenchymal loss via compensatory regrowth, referred to as liver regeneration (LR). 1,2 Adequate LR is contingent upon maintaining a minimum healthy residual liver mass without which hepatocyte proliferation is stunned, resulting in hepatic failure. In liver transplantation (mainly living donor liver transplantation), 'small-for-size' syndrome illustrates this outcome. 3 Incremental 78% and 87% hepatectomy in mice reproduces this syndrome, causing 50% and 100% lethality, respectively. 4 Despite considerable knowledge characterizing the molecular basis of LR, better understanding of this process's shortcomings in the face of extensive resection and/or damage is required for uncovering therapie...

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

Cited by 127 publications

References 43 publications

Hepatic stereology of schistosomiasis mansoni infected-mice fed a high-fat diet

Hepatic stereology of schistosomiasis mansoni infected-mice fed a high-fat diet

Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

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