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| 1 | Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver显示文摘Obesity is a major risk factor for cancers including hepatocellular carcinoma(HCC)that develops from a background of non-alcoholic fatty liver disease(NAFLD).Hypercholesterolemia is a common comorbidity of obesity.Although cholesterol biosynthesis mainly occurs in the liver,its role in HCC development of obese people remains obscure.Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models,we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T(NKT)cell-mediated antitumor immunosurveillance.Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients.Notably,cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development.Moreover,suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin(mTOR)inhibitor vistusertib preceded tumor regression,which was abolished by NKT inactivation but not CD8^(+)T cell depletion.Mechanistically,sterol regulatory element-binding protein 2(SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells,which were supported by findings in people with obesity,NAFLD and NAFLD-HCC.This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment,providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic. | Wenshu Tang Jingying Zhou Weiqin Yang Yu Feng Haoran Wu Myth T.S.Mok Lingyun Zhang Zhixian Liang Xiaoyu Liu Zhewen Xiong Xuezhen Zeng Jing Wang Jiahuan Lu Jingqing Li Hanyong Sun Xiaoyu Tian Philip Chun Yeung Yong Hou Heung Man Lee Candice C.H.Lam Howard H.W.Leung Anthony W.H.Chan Ka Fai To John Wong Paul B.S.Lai Kelvin K.C.Ng Simon K.H.Wong Vincent W.S.Wong Alice P.S.Kong Joseph J.Y.Sung Alfred S.L.Cheng | 2022 | Cellular & Molecular Immunology2022，19，7： | 3 |
| 2 | The influence of polymeric properties on ehitosan/siRNA nanoparticle formulation and gene silencing显示文摘 | Liu X Howard KA Dong M | 2007 | Biomaterials2007，28，6： | 1 |
| 3 | RNA interference in vitro and in vivo using a novel chitosan/siRNA nanoparticle system 显示文摘 | Howard KA Rahbek UL Eiu X | 2006 | Mol Ther2006，14，4： | 1 |
| 4 | Chitosan/siRNA nanoparticle-mediated TNF-alpha knockdown in peritoneal macrophages for anti-inflammatory treatment in a murine arthritis model显示文摘 | Howard KA Paludan SR Behlke MA | 2009 | Mol Ther2009，7，1： | 1 |
| 5 | The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing显示文摘 | Liu X Howard KA Dong M | 2007 | Biomaterials2007，28，6： | 1 |
| 6 | Influence of hydrophilicity of cationic polymers on the biophysical properties of electrolyte complexes formed by self-assembly with DNA 显示文摘 | Howard KA Dash PR Read ML | 2000 | Biochim Biophys Acta2000，1475，3： | 1 |
| 7 | RNA interference in vitro and in vivo using a chitosan/siRNA nanoparticle system 显示文摘 | HOWARD KA RAHBEK UL LIU X | 2006 | Mol Ther2006，14，4： | 1 |
| 8 | Tissue-specific regulation of aromatase promoter II by the orphan nuclear receptor LRH-1 in breast adipose stromal fibroblasts显示文摘 | Chand AL Herridge KA Howard TL | 2011 | Steroids2011，76，8： | 1 |
| 9 | Developmental age influences the effect of epidural dexmedetomidine on inflammatory hyperalgesia in the rat pups 显示文摘 | Walker SM Howard RF Keay KA | 2005 | Anesthesiology2005，102，： | 1 |
| 10 | Developmental age influences the effect of epidural dexmedetomidine on inflafmmatory hyperalgesia in rat pups 显示文摘 | Walker SM Howard RF Keay KA | 2005 | Anesthesiology2005，102，6： | 1 |
| 11 | To whom do adolescents turn for help? Differences between disturbed and nondisturbed adolescents 显示文摘 | Offer D Howard KI Schonert KA | 1991 | J Am Acad Child Adolesc Psychiatry1991，30，4： | 1 |
| 12 | Protection against bubonic and pneumonic plague with a single dose microencapsulated sub-unit vaccine显示文摘 | Elvin SJ Eyles JE Howard KA | 2006 | Vaccine2006，24，20： | 1 |
| 13 | RNAi using a chitosan/siRNA nanoparticle system: in vitro and in vivo applications 显示文摘 | Andersen MO Howard KA Kjems J | 2009 | Methods Mol Biol2009，555，1： | 1 |
| 14 | Developmental age influences the effect of epidural dexmedetomidine on inflammatory hyperal- gesia in rat pups 显示文摘 | Walker SM Howard RF Keay KA | 2005 | Anesthesiolory2005，102，6： | 1 |
| 15 | 中年美国印第安人身体镉负荷与血压升高的关系显示文摘镉(Cd)是一种环境污染物,已知其与人群心血管病相关,但是镉与高血压的关系研究结果不一致。研究人员对美国印第安人(身体镉负荷高于美国全国人口平均水平)尿镉浓度(总身体负荷测定指标)与血压的关系进行分析。使用电感耦合等离子体质谱法测定尿镉浓度,并依照尿肌酐浓度进行调整。结果: | 刘莉 叶鹏 Franceschini N Fry RC Balakrishnan P Navas-Acien A Oliver-Williams C Howard AG Cole SA Haack K Lange EM Howard BV Best LG Francesconi KA Goessler W Umans JG Tellez-Plaza M | 2017 | 中华高血压杂志2017，25，2： | 1 |
| 16 | The influence of polymeric properties on chitosan/siRNA nanoparticle formulation and gene silencing显示文摘 | Liu X Howard KA Dong M | | 0，，： | 1 |
| 17 | Delivery of siRNA from lyophilized polymeric surfaces显示文摘 | Andersen MΦ Howard KA Paludan SR | | 0，，： | 1 |
| 18 | Polycation-based nan- oparticles for RNAi-mediated cancer treatment 显示文摘 | Ballarfn-Gonz01ez B Ebbesen MF Howard KA | 2014 | Cancer Letters2014，352，1： | 1 |
| 19 | Influence of hydrophilicity of cationic polymers on the biophysical properties of polyelectrolyte complexes formed by self-assembly with DNA 显示文摘 | Howard KA Dash PR Read ML | 2000 | Biochimica et Biophysica Acta2000，1475，3： | 1 |
| 20 | Comparison of swab and sponge methodologies for identification of Acinetobacter baumannii from the hospital environment显示文摘 | Thom KA Howard T Sembajwe S | 2012 | J Clin Microbiol2012，50，： | 1 |
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