Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 01/2010; 140(2):197-208. DOI: 10.1016/j.cell.2009.12.052
Source: PubMed

ABSTRACT Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.

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Available from: Christoph Oesterreicher, Jul 22, 2014
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    • "Furthermore, the source of cytokines in kidney disease (Spoto et al., 2012) may not be the same as in obesity or metabolic disease where adipose tissues are believed to be a major source (Fruhbeck et al., 2001). In other inflammation/infection models, other tissues such as spleen and liver can be a major source of cytokines (Arsenijevic et al., 1998; Park et al., 2010). "
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    ABSTRACT: The role of mild kidney dysfunction in altering lipid metabolism and promoting inflammation was investigated in uninephrectomized rats (UniNX) compared to Sham-operated controls rats. The impact of UniNX was studied 1, 2, and 4 weeks after UniNX under mild food restriction at 90% of ad libitum intake to ensure the same caloric intake in both groups. UniNX resulted in the reduction of fat pad weight. UniNX was associated with increased circulating levels of beta-hydroxybutyrate and glycerol, as well as increased fat pad mRNA of hormone sensitive lipase and adipose triglyceride lipase, suggesting enhanced lipolysis. No decrease in fat pad lipogenesis as assessed by fatty acid synthase activity was observed. Circulating hormones known to regulate lipolysis such as leptin, T3, ghrelin, insulin, corticosterone, angiotensin 1, and angiotensin 2 were not different between the two groups. In contrast, a select group of circulating lipolytic cytokines, including interferon-gamma and granulocyte macrophage-colony stimulating factor, were increased after UniNX. These cytokine levels were elevated in the spleen, but decreased in the kidney, liver, and fat pads. This could be explained by anti-inflammatory factors SIRT1, a member of the sirtuins, and the farnesoid x receptor (FXR), which were decreased in the spleen but elevated in the kidney, liver, and fat pads (inguinal and epididymal). Our study suggests that UniNX induces adipose tissue lipolysis in response to increased levels of a subset of lipolytic cytokines of splenic origin.
    Frontiers in Physiology 07/2015; 6:195. DOI:10.3389/fphys.2015.00195 · 3.53 Impact Factor
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    • "The euthanized mice did not show evidence of tumor burden. Sample size sufficient to detect a 20% change in tumor number was estimated a priori, using a power analysis based on group means and standard deviations previously reported [35]. Dietary intervention was delayed until 4 weeks after treatment with the carcinogen, to distinguish tumor initiation by the carcinogen from promotion of lesion growth by the diets. "
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    ABSTRACT: Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.
    Journal of Hepatology 10/2014; 62(3). DOI:10.1016/j.jhep.2014.10.024 · 11.34 Impact Factor
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    • "For example, induction of inflammation by bacterial and viral infections increases cancer risk (Ferreri et al, 2009). Similarly, tobacco smoke and obesity are tumour-promoting factors by triggering chronic inflammatory signalling (Park et al, 2010; Takahashi et al, 2010). IL1b, a pro-inflammatory cytokine and an activator of IRAK signalling, plays a direct role in tumour cell growth, angiogenesis, invasion, drug resistance, and metastasis (Vidal-Vanaclocha et al, 2000; Carmi et al, 2013). "
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    ABSTRACT: Innate immune signalling has an essential role in inflammation, and the dysregulation of signalling components of this pathway is increasingly being recognised as an important mediator in cancer initiation and progression. In some malignancies, dysregulation of inflammatory toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signalling is typified by increased NF-κB activity, and it occurs through somatic mutations, chromosomal deletions, and/or transcriptional deregulation. Interleukin-1 receptor-associated kinase (IRAK) family members are mediators of TLR/IL1R superfamily signalling, and mounting evidence implicates these kinases as viable cancer targets. Although there have been previous efforts aimed at the development of IRAK kinase inhibitors, this is currently an area of renewed interest for cancer drug development.British Journal of Cancer advance online publication, 7 October 2014; doi:10.1038/bjc.2014.513
    British Journal of Cancer 10/2014; 112(2). DOI:10.1038/bjc.2014.513 · 4.84 Impact Factor
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