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Cholesterol-lowering Decreased mTOR Complex 2 Signaling and Enhanced Antitumor Immunity

ABSTRACT: In an exploratory human study, RNAseq was performed to quantify immune cells present in prostate cancer. Two patients were examined, and both showed increased CD8+ lymphocytes and M1 macrophages scores following cholesterol-lowering intervention with the combination of ezetimibe and simvastatin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159529 | GEO | 2021/01/01

REPOSITORIES: GEO

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Cholesterol-lowering Decreased mTOR Complex 2 Signaling and Enhanced Antitumor Immunity

Project description:Cholesterol-lowering Decreased mTOR Complex 2 Signaling and Enhanced Antitumor Immunity

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Cholesterol-Lowering Intervention Decreases mTOR Complex 2 Signaling and Enhances Antitumor Immunity.

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Simvastatin treated Lymphoblastoid Cell lines from Cholesterol and Pharmacogenomics (CAP) Trial

Project description:Statins reduce cardiovascular disease risk by lowering plasma low density lipoprotein (LDL)-cholesterol. To identify novel pathways that modulate statin response, we assessed the influence of simvastatin exposure on expression quantitative trait locus (eQTL) associations across the genome in 480 lymphoblastoid cell lines (LCLs). Cell lines were derived blood samples collected ant entry visit from participants in the Cholesterol and Pharmacogenomics (CAP) trial, who underwent a 6 week 40mg/day simvastatin trial. We identified 4590 cis-eQTLS that were independent of treatment status (FDR=1%) and six cis-eQTLS for which there was evidence of an interaction with treatment (FDR=20%). Genotypes and Phenotypes derived from these indivudals are available through dbGaP (Accession Number). eQTL results are available at: http://eqtl.uchicago.edu/cgi=bin/gbrowse/eqtl/ Dataset consists of 960 expression beadarrays (Illumina HumanRef-8v3) representing paired samples derived from 24-hour exposures of 480 lymphoblastoid cell lines (LCLs) to 2 micromolar simvastatin acid or control buffer.

2012-06-30 | E-GEOD-36868 | biostudies-arrayexpress

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Simvastatin treated Lymphoblastoid Cell lines from Cholesterol and Pharmacogenomics (CAP) Trial

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Cooperation between ASTER-dependent nonvesicular transport and NPC1L1 facilitates dietary cholesterol uptake

Project description:Intestinal cholesterol absorption is an important determinant of systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe, is a critical player in dietary cholesterol uptake. But how cholesterol moves within the cell downstream of NPC1L1 is unknown. Here we show that the nonvesicular sterol transporters Aster-B and -C cooperate with NPC1L1 to deliver dietary cholesterol from the gut lumen to the enterocyte ER for chylomicron packaging. Aster proteins are recruited to the enterocyte plasma membrane (PM) in response to NPC1L1-dependent cholesterol accumulation. Mice lacking Asters in intestine have impaired cholesterol absorption, and reduced plasma cholesterol. NanoSIMS imaging and tracer studies reveal delayed lipid trafficking into chylomicrons in Aster-deficient enterocytes. Interestingly, in addition to potently blocking NPC1L1, ezetimibe is also a low-affinity inhibitor of Aster-B and -C but not -A, and the structure of the Aster-C-ezetimibe complex reveals the basis for this selectivity. Our findings support a model in which NPC1L1 enriches dietary cholesterol at the apical PM, and ASTERs subsequently traffic this cholesterol to the ER. The findings identify the enterocyte Aster pathway as potential target for treatment of hypercholesterolemia. Alessandra Ferrari, PhD

2023-12-21 | GSE206780 | GEO

Transintestinal cholesterol transport is important in mice and humans and controls ezetimibe induced fecal neutral sterol excretion

Project description:Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of these pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4-weeks treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile-derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a fourfold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

2016-11-04 | GSE77236 | GEO

Cholesterol and Pharmacogenetics (CAP) Study

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Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR.

Project description: Not available

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IL-1β inhibition partially negates the beneficial effects of diet-induced lipid lowering

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2024-05-06 | GSE264253 | GEO

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