Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis

Ribback, Silvia; Calvisi, Diego F.; Cigliano, Antonio; Sailer, Verena; Peters, Michele; Rausch, Jenny; Heidecke, Claus–Dieter; Birth, M.; Dombrowski, Frank

doi:10.1016/j.jhep.2013.01.013

Cited by 27 publications

(40 citation statements)

References 40 publications

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“…For instance, overexpression of FASN occurs in liver preneoplastic lesions from rat models of chemically- and hormonally-induced hepatocarcinogenesis [6]. Similarly, sustained lipogenesis and FASN upregulation characterize human liver clear cell foci, whose preneoplastic nature has been hypothesized [7]. Also, levels of FASN and other lipogenic proteins as well as polymorphisms in lipogenic genes are associated with poor outcome in HCC patients [8–12].…”

Section: Introductionmentioning

confidence: 99%

Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans

Pilo

et al. 2016

Journal of Hepatology

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Background & Aims Cumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver. Methods FASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA. Results Overexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice. Conclusions FASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.

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Section: Introductionmentioning

confidence: 99%

Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans

Pilo

et al. 2016

Journal of Hepatology

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124

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“…Our results highlight the transcription of key oncogenes involved in cell proliferation ( fos ) and apoptosis ( jun D). These results suggest a possible balance between cell proliferation induced by hyperinsulinemia, and apoptosis induced by lipotoxicity and ER stress [39, 47, 55]. However, since we did not observe any hepatocyte proliferation at the histological level, and given the measurement of proliferative cell nuclear antigen ( PCNA ) (data not shown), our results indicate that the pro-apoptotic branch of the MAPK pathway predominated in BaP-treated Xenopus .…”

Section: Discussionmentioning

confidence: 69%

“…Previous studies have described changes in the liver in response to insulin including glycolysis induction and MAPK–ERK signaling pathway leading to cell proliferation [55]. However, the MAPK signaling pathway is classically defined as a key regulator of the cellular balance between apoptosis and proliferation [56].…”

Section: Discussionmentioning

confidence: 99%

Impaired liver function in Xenopus tropicalis exposed to benzo[a]pyrene: transcriptomic and metabolic evidence

et al. 2014

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BackgroundDespite numerous studies suggesting that amphibians are highly sensitive to cumulative anthropogenic stresses, the role pollutants play in the decline of amphibian populations remains unclear. Amongst the most common aquatic contaminants, polycyclic aromatic hydrocarbons (PAHs) have been shown to induce several adverse effects on amphibian species in the larval stages. Conversely, adults exposed to high concentrations of the ubiquitous PAH, benzo[a]pyrene (BaP), tolerate the compound thanks to their highly efficient hepatic detoxification mechanisms. Due to this apparent lack of toxic effect on adults, no studies have examined in depth the potential toxicological impact of PAH on the physiology of adult amphibian livers. This study sheds light on the hepatic responses of Xenopus tropicalis when exposed to high environmentally relevant concentrations of BaP, by combining a high throughput transcriptomic approach (mRNA deep sequencing) and a characterization of cellular and physiological modifications to the amphibian liver.ResultsTranscriptomic changes observed in BaP-exposed Xenopus were further characterized using a time-dependent enrichment analysis, which revealed the pollutant-dependent gene regulation of important biochemical pathways, such as cholesterol biosynthesis, insulin signaling, adipocytokines signaling, glycolysis/gluconeogenesis and MAPK signaling. These results were substantiated at the physiological level with the detection of a pronounced metabolic disorder resulting in a possible insulin resistance-like syndrome phenotype. Hepatotoxicity induced by lipid and cholesterol metabolism impairments was clearly identified in BaP-exposed individuals.ConclusionsOur data suggested that BaP may disrupt overall liver physiology, and carbohydrate and cholesterol metabolism in particular, even after short-term exposure. These results are further discussed in terms of how this deregulation of liver physiology can lead to general metabolic impairment in amphibians chronically exposed to contaminants, thereby illustrating the role xenobiotics might play in the global decline in amphibian populations.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-666) contains supplementary material, which is available to authorized users.

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“…[11] GSF were also detected in a significant number of human non-cirrhotic livers (88 of 236; 33.6%). [15] A combination of enzymatic and molecular biological approaches has shown the striking similarities in metabolic changes in human and rat GSF, including the activation of the AKT/mammalian target of rapamycin (mTOR) and Ras/MAPK signaling cascades. [15] Studies in more than 150 human explants showed the evidence for a characteristic sequence of cellular changes, from pre-neoplastic glycogenotic FAH via various intermediate stages [mixed cell foci (MCF)] to glycogen-poor malignant phenotypes, similar to that in animal models.…”

Section: Discussionmentioning

confidence: 99%

“…[15] A combination of enzymatic and molecular biological approaches has shown the striking similarities in metabolic changes in human and rat GSF, including the activation of the AKT/mammalian target of rapamycin (mTOR) and Ras/MAPK signaling cascades. [15] Studies in more than 150 human explants showed the evidence for a characteristic sequence of cellular changes, from pre-neoplastic glycogenotic FAH via various intermediate stages [mixed cell foci (MCF)] to glycogen-poor malignant phenotypes, similar to that in animal models. [9,11] These phenotypic cellular changes are due to a metabolic switch from gluconeogenesis toward the pentose phosphate pathway and the Warburg type of glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular carcinoma and type 2 diabetes mellitus: two cases highlighting changes in tumor glycogen content

Takegoshi¹,

Okada²,

Nomoto³

et al. 2015

Hepatoma Res

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This article reports two patients with hepatocellular carcinoma (HCC) and type 2 diabetes mellitus (T2DM), who showed marked changes in hepatocellular glycogen content. Periodic acid-Schiff (PAS)-positive and diastase-PAS-negative (glycogen-storing) hepatocytes were detected in both background liver parenchyma and in HCC tissues. In HCC tissues, the number of glycogen-storing cells resembling hepatocytes was considerably reduced and unevenly distributed as compared with hepatocytes in background liver. To be known, changes in hepatocellular glycogen content in T2DM patients have not been previously described. It is hypothesized that the reduction in glycogen content in both patients was likely associated with the emergence of Warburg type of glycolysis.

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Molecular and metabolic changes in human liver clear cell foci resemble the alterations occurring in rat hepatocarcinogenesis

Cited by 27 publications

References 40 publications

Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans

Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans

Impaired liver function in Xenopus tropicalis exposed to benzo[a]pyrene: transcriptomic and metabolic evidence

Hepatocellular carcinoma and type 2 diabetes mellitus: two cases highlighting changes in tumor glycogen content

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