PMID- 35595819
OWN - NLM
STAT- MEDLINE
DCOM- 20220701
LR  - 20230703
IS  - 2042-0226 (Electronic)
IS  - 1672-7681 (Print)
IS  - 1672-7681 (Linking)
VI  - 19
IP  - 7
DP  - 2022 Jul
TI  - Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance 
      through natural killer T cell dysfunction in obese liver.
PG  - 834-847
LID - 10.1038/s41423-022-00872-3 [doi]
AB  - 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.
CI  - (c) 2022. The Author(s), under exclusive licence to CSI and USTC.
FAU - Tang, Wenshu
AU  - Tang W
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Zhou, Jingying
AU  - Zhou J
AUID- ORCID: 0000-0002-9740-6159
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China. zhoujy@cuhk.edu.hk.
FAU - Yang, Weiqin
AU  - Yang W
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Feng, Yu
AU  - Feng Y
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Wu, Haoran
AU  - Wu H
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Mok, Myth T S
AU  - Mok MTS
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Zhang, Lingyun
AU  - Zhang L
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Liang, Zhixian
AU  - Liang Z
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Liu, Xiaoyu
AU  - Liu X
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Xiong, Zhewen
AU  - Xiong Z
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Zeng, Xuezhen
AU  - Zeng X
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Wang, Jing
AU  - Wang J
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Lu, Jiahuan
AU  - Lu J
AD  - Department of Anatomical and Cellular Pathology, The Chinese University of Hong 
      Kong, Hong Kong SAR, 999077, China.
FAU - Li, Jingqing
AU  - Li J
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Sun, Hanyong
AU  - Sun H
AD  - Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao 
      Tong University, Shanghai, 200127, China.
FAU - Tian, Xiaoyu
AU  - Tian X
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China.
FAU - Yeung, Philip Chun
AU  - Yeung PC
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, 
      999077, China.
FAU - Hou, Yong
AU  - Hou Y
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 
      Hong Kong SAR, 999077, China.
FAU - Lee, Heung Man
AU  - Lee HM
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 
      Hong Kong SAR, 999077, China.
FAU - Lam, Candice C H
AU  - Lam CCH
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, 
      999077, China.
FAU - Leung, Howard H W
AU  - Leung HHW
AD  - Department of Anatomical and Cellular Pathology, The Chinese University of Hong 
      Kong, Hong Kong SAR, 999077, China.
FAU - Chan, Anthony W H
AU  - Chan AWH
AD  - Department of Anatomical and Cellular Pathology, The Chinese University of Hong 
      Kong, Hong Kong SAR, 999077, China.
FAU - To, Ka Fai
AU  - To KF
AUID- ORCID: 0000-0003-4919-3707
AD  - Department of Anatomical and Cellular Pathology, The Chinese University of Hong 
      Kong, Hong Kong SAR, 999077, China.
FAU - Wong, John
AU  - Wong J
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, 
      999077, China.
FAU - Lai, Paul B S
AU  - Lai PBS
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, 
      999077, China.
FAU - Ng, Kelvin K C
AU  - Ng KKC
AUID- ORCID: 0000-0002-3679-6368
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, 
      999077, China.
FAU - Wong, Simon K H
AU  - Wong SKH
AD  - Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, 
      999077, China.
FAU - Wong, Vincent W S
AU  - Wong VWS
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 
      Hong Kong SAR, 999077, China.
FAU - Kong, Alice P S
AU  - Kong APS
AUID- ORCID: 0000-0001-8927-6764
AD  - Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 
      Hong Kong SAR, 999077, China.
FAU - Sung, Joseph J Y
AU  - Sung JJY
AD  - State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, 
      Hong Kong SAR, 999077, China.
AD  - Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 
      639798, Singapore.
AD  - Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen 
      University, Guangzhou, 510080, China.
FAU - Cheng, Alfred S L
AU  - Cheng ASL
AD  - School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 
      SAR, 999077, China. alfredcheng@cuhk.edu.hk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220520
PL  - China
TA  - Cell Mol Immunol
JT  - Cellular & molecular immunology
JID - 101242872
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - *Carcinoma, Hepatocellular
MH  - Cholesterol/metabolism
MH  - Humans
MH  - Liver/pathology
MH  - *Liver Neoplasms
MH  - Mammals
MH  - Mice
MH  - Monitoring, Immunologic/adverse effects
MH  - *Natural Killer T-Cells
MH  - *Non-alcoholic Fatty Liver Disease/pathology
MH  - Obesity/pathology
MH  - Tumor Microenvironment
PMC - PMC9243114
OTO - NOTNLM
OT  - HCC
OT  - NAFLD
OT  - NKT cells
OT  - cholesterol
OT  - mTOR
COIS- JZ and ASLC received the funding support and drug (vistusertib) from AstraZeneca. 
      VWSW has consultancy in 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center 
      for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi 
      Pharmaceutical, Intercept, Inventiva, Merck, Novartis, Novo Nordisk, Perspectum 
      Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions and 
      Terns; has lectures in Abbott, AbbVie, Bristol-Myers Squibb, Echosens, Gilead 
      Sciences and Novo Nordisk; received research grants from Gilead Sciences; and 
      holds stock as co-founder of Illuminatio Medical Technology Limited. The other 
      authors declare no competing interests.
EDAT- 2022/05/21 06:00
MHDA- 2022/07/02 06:00
PMCR- 2023/07/01
CRDT- 2022/05/20 23:20
PHST- 2021/12/28 00:00 [received]
PHST- 2022/04/14 00:00 [accepted]
PHST- 2022/05/21 06:00 [pubmed]
PHST- 2022/07/02 06:00 [medline]
PHST- 2022/05/20 23:20 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - 10.1038/s41423-022-00872-3 [pii]
AID - 872 [pii]
AID - 10.1038/s41423-022-00872-3 [doi]
PST - ppublish
SO  - Cell Mol Immunol. 2022 Jul;19(7):834-847. doi: 10.1038/s41423-022-00872-3. Epub 
      2022 May 20.