College of Agriculture & Natural Resources

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    NPC1L1 knockout protects against colitis-associated tumorigenesis in mice
    (Springer Nature, 2015-03-27) He, Jianming; Shin, Hyunsu; Wei, Xing; Kadegowda, Anil Kumar G; Chen, Rui; Xie, Sandy Krystal
    Colorectal cancer is strongly associated with lipid metabolism. NPC1L1, a sterol transporter, plays a key role in modulating lipid homeostasis in vivo. Its inhibitor, ezetimibe, began to be used clinically to lower cholesterol and this caused the great debate on its role in causing carcinogenesis. Here we explored the role of NPC1L1 in colorectal tumorigenesis. Wild-type mice and NPC1L1−/− (NPC1L1 knockout) mice were treated with azoxymethane (AOM)-dextran sodium sulfate (DSS) to induce colitis-associated colorectal tumorigenesis. Mice were sacrificed 10, 15, 18 or 20 weeks after AOM treatment, respectively. Colorectal tumors were counted and analyzed. Plasma lipid concentrations were measured using enzymatic reagent kit. Protein expression level was assayed by western blot. NPC1L1−/− mice significantly had fewer tumors than wild-type. The ratio of malignant/tumor in NPC1L1−/− mice was significantly lower than in wild-type 20 weeks after AOM-DSS treatment. NPC1L1 was highly expressed in the small intestine of wild-type mice but its expression was undetectable in colorectal mucous membranes or tumors in either group. NPC1L1 knockout decreased plasma total cholesterol and phospholipid. NPC1L1−/− mice had significant lower intestinal inflammation scores and expressed inflammatory markers p-c-Jun, p-ERK and Caspase-1 p20 lower than wild-type. NPC1L1 knockout also reduced lymphadenectasis what may be caused by inflammation. NPC1L1 knockout in mice decreased β-catenin in tumors and regulated TGF-β and p-gp in adjacent colons or tumors. There was not detectable change of p53 by NPC1L1 knockout. Our results provide the first evidence that NPC1L1 knockout protects against colitis-associated tumorigenesis. NPC1L1 knockout decreasing plasma lipid, especially cholesterol, to reduce inflammation and decreasing β-catenin, p-c-Jun and p-ERK may be involved in the mechanism.
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    CHARACTERIZATION OF LIVER X RECEPTORS IN PROSTATE CANCER CHOLESTEROL METABOLISM AND PULMONARY IMMUNE RESPONSE
    (2011) Trasino, Steven E.; Lei, David K; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Liver x receptors (LXRs) are central regulators cholesterol homeostasis and the innate immune response. As modulators of inflammation and cholesterol metabolism LXRs might diminish dyslipidemia and inflammation related pathologies caused by high fat (HF) diets or obesity. There is also data demonstrating that LXRs can protect against progression of prostate cancer (PCa), but little is known about the cholesterol modulating effects of LXRs in transformed cells. The goal of this project is to characterize the cholesterol modulating properties of LXRs in two models of PCa and the anti-inflammatory properties of LXRs in swine bronchial alveolar macrophages (AMs). This project will also examine whether the anti-inflammatory and lipid lowering properties of the dietary probiotic bacteria Lactobacillus casei (L. casei), can interact with the LXR axis in AMs. Studies in two PCa cell lines, LNCaP and PC-3, revealed that LXR ligands regulate the LXR responsive genes, ABCA1 and ABCG1 through the LXR&beta isoform and not LXR&alpha in PC-3 cells, but only ABCG1 in LNCaP. LXR- ABCA1 mediated reverse cholesterol transport (RCT) resulted in a decrease in plasma membrane lipid raft cholesterol domains in PC-3 cells, suggesting a potential anti-cancer axis for LXR activation. Studies in LNCaP and PC-3 cells also demonstrated that soy isoflavones can activate transcriptional activation of ABCA1 and ABCG1 in LNCaP and PC-3 cells through the LXR&beta isoform, but did not lead to an increase in RCT. Metabolic and anti-inflammatory studies of LXR in AM from Ossabaw pigs fed either a control (C) diet, HF, HF plus L casei (HFPB) or L. casei alone (CPB) diet revealed that AM from HF fed pigs had significantly higher concentrations of cholesteryl-esters (CE) compared with AM from control (C) diet fed pigs. Ex-vivo activation of LXR with the LXR ligand T0901317 opposed LPS mediated upregulation of IL-1&beta , IL-6, IL-8 and IL-10 mRNA levels in AM from HF, HFPB and CPB fed pigs. Finally, it was observed that LPS stimulation lead to significant inhibition of LXR transcription of LXR&alpha, ABCA1, ABCG1, cholesterol 25 hydroxylase (CH25H) and PPAR&gamma in AM. This effect was abrogated by L. casei for ABCA1, CH25H and PPAR&gamma mRNA expression