ZIA BC 005562 (ZIA) | |||
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Title | Xenobiotic receptors | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Gonzalez, Frank | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,240,094 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (75.0%) |
Breast (15.0%) Colon/Rectum (25.0%) Liver Cancer (50.0%) |
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Research Type | |||
Endogenous Factors in the Origin and Cause of Cancer Dietary Interventions to Reduce Cancer Risk and Nutritional Science in Cancer Prevention |
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Abstract | |||
Metabolic diseases include obesity type 2 diabetes mellitus (insulin resistance) and non-alcoholic fatty liver disease (NAFLD). These disorders are associated with increased risk for cardiovascular diseases such as atherosclerosis and non-alcoholic steatohepatitis (NASH), and cancer. There is a marked increase in cancer risk of over 35% depending on the cancer type, associated with obesity, and insulin resistance. NAFLD and NASH are associated with markedly increased risk for liver cancer. A chronic imbalance between energy intake and energy expenditure causes obesity for which there is no safe and effective drug therapy. Accumulating reports indicate that hypoxia-inducible factors (HIFs), members of the basic helix-hoop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor family, exert a pivotal role during the pathogenesis of NAFLD. HIF is a heterodimer of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit (HIF1beta or ARNT). Under normoxic conditions, HIFalpha (HIF1alpha and HIF2alpha) is rapidly hydroxylated and degraded by several prolyl hydroxylase domain enzymes (PHD) followed by conjugation with the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex. Conversely, the HIF proteins are stabilized during hypoxia due to inhibition of PHD activity induced by low O2. Hepatocyte-specific disruption of PHD2 and PHD3 or VHL, which lead to overexpression of both HIF1alpha and HIF2alpha, was demonstrated to promote hepatic steatosis. Hepatic HIF2alpha but not HIF1alpha was further identified as a major regulator of hepatic lipid metabolism through the up-regulation of genes involved in fatty acid synthesis (Srebp1c (official symbol: Srebf1) and Fasn) and fatty acid uptake (Cd36) and the down-regulation of genes involved in regulating fatty acid beta-oxidation (Ppara and Acox1). Most studies on the relationship between HIF and NAFLD focused on evaluating the effects of liver HIF. However, liver HIF2alpha activation was recently observed to ameliorate hyperglycemia through the insulin-dependent pathway with increased insulin receptor substrate-2 (Irs2), or the insulin-independent pathway with the repression of glucagon action. These studies imply that pharmacological inhibition of liver HIF2alpha might not be suitable to exploit for NAFLD therapy, due to the increased risk of increased hepatic glucose production and type 2 diabetes. Several novel targets in the intestine were recently implicated in the development of NAFLD. While both HIF1alpha and HIF2alpha are expressed in the intestinal epithelial cells, the role of the intestine HIFalpha on the pathogenesis of NAFLD and other metabolic diseases is poorly understood. The intestine-specific knockout or activation of HIFalpha and metabolomics profiling analysis were adopted to clarify the role and dissect the precise mechanism of intestine HIFalpha in NAFLD development. This study revealed that intestine HIF2alpha but not HIF1alpha signaling is activated during obesity. Intestine-specific Hif2a (official symbol: Epas1) ablation substantially ameliorates high-fat diet (HFD)-induced obesity and hepatic steatosis in mice. Amelioration of the adverse metabolic phenotypes is correlated with alterations in ceramide metabolism. Neu3, encoding a key enzyme in the ceramide salvage pathway, was identified as a novel target gene of HIF2alpha. A HIF2alpha-NEU3-ceramide axis was found to influence NAFLD development. Notably, a specific HIF2alpha inhibitor PT2385, which is in clinical trials for the treatment of renal cancer, was found to prevent and reverse metabolic disorders through the inhibition of intestinal HIF2alpha. This work suggests that intestine HIF2alpha is a novel target for the treatment of NAFLD. Human intestine biopsies from individuals with or without obesity revealed a relationship between activated HIF2alpha but not HIF1alpha in higher body mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-spec |