PMID- 34292642
OWN - NLM
STAT- MEDLINE
DCOM- 20220114
LR  - 20240226
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 74
IP  - 6
DP  - 2021 Dec
TI  - Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular 
      Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis.
PG  - 3037-3055
LID - 10.1002/hep.32064 [doi]
AB  - BACKGROUND AND AIMS: Insulin receptor (IR) transduces cell surface signal through 
      phosphoinositide 3-kinase (PI3K)-AKT pathways or translocates to the nucleus and 
      binds to the promoters to regulate genes associated with insulin actions, 
      including de novo lipogenesis (DNL). Chronic activation of IR signaling drives 
      malignant transformation, but the underlying mechanisms remain poorly defined. 
      Down-regulation of fructose-1,6-bisphosphate aldolase (ALDO) B in hepatocellular 
      carcinoma (HCC) is correlated with poor prognosis. We aim to study whether and 
      how ALDOB is involved in IR signaling in HCC. APPROACH AND RESULTS: Global or 
      liver-specific ALDOB knockout (L-ALDOB(-/-) ) mice were used in 
      N-diethylnitrosamine (DEN)-induced HCC models, whereas restoration of ALDOB 
      expression was achieved in L-ALDOB(-/-) mice by adeno-associated virus (AAV). 
      (13) C(6) -glucose was employed in metabolic flux analysis to track the de novo 
      fatty acid synthesis from glucose, and nontargeted lipidomics and targeted fatty 
      acid analysis using mass spectrometry were performed. We found that ALDOB 
      physically interacts with IR and attenuates IR signaling through down-regulating 
      PI3K-AKT pathways and suppressing IR nuclear translocation. ALDOB depletion or 
      disruption of IR/ALDOB interaction in ALDOB mutants promotes DNL and 
      tumorigenesis, which is significantly attenuated with ALDOB restoration in 
      L-ALDOB(-/-) mice. Notably, attenuated IR/ALDOB interaction in ALDOB-R46A mutant 
      exhibits more significant tumorigenesis than releasing ALDOB/AKT interaction in 
      ALDOB-R43A, whereas knockdown IR sufficiently diminishes tumor-promoting effects 
      in both mutants. Furthermore, inhibiting phosphorylated AKT or fatty acid 
      synthase significantly attenuates HCC in L-ALDOB(-/-) mice. Consistently, ALDOB 
      down-regulation is correlated with up-regulation of IR signaling and DNL in human 
      HCC tumor tissues. CONCLUSIONS: Our study reports a mechanism by which loss of 
      ALDOB activates IR signaling primarily through releasing IR/ALDOB interaction to 
      promote DNL and HCC, highlighting a potential therapeutic strategy in HCC.
CI  - (c) 2021 by the American Association for the Study of Liver Diseases.
FAU - Liu, Guijun
AU  - Liu G
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Wang, Ningning
AU  - Wang N
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Zhang, Cunzhen
AU  - Zhang C
AD  - Department of Hepatic Surgery I (Ward l), Shanghai Eastern Hepatobiliary Surgery 
      Hospital, Shanghai, China.
FAU - Li, Min
AU  - Li M
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - He, Xuxiao
AU  - He X
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Yin, Chunzhao
AU  - Yin C
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
FAU - Tu, Qiaochu
AU  - Tu Q
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
FAU - Shen, Xia
AU  - Shen X
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
FAU - Zhang, Lili
AU  - Zhang L
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Lv, Jingwen
AU  - Lv J
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Wang, Yongqiang
AU  - Wang Y
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Jiang, Huimin
AU  - Jiang H
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Chen, Shiting
AU  - Chen S
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Li, Nan
AU  - Li N
AD  - Department of Hepatic Surgery I (Ward l), Shanghai Eastern Hepatobiliary Surgery 
      Hospital, Shanghai, China.
FAU - Tao, Yongzhen
AU  - Tao Y
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
FAU - Yin, Huiyong
AU  - Yin H
AUID- ORCID: 0000-0001-7049-1560
AD  - CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute 
      of Nutrition and Health (SINH), University of the Chinese Academy of Sciences 
      (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
AD  - Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210826
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Fatty Acids)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 4.1.2.13 (Fructose-Bisphosphate Aldolase)
SB  - IM
MH  - Animals
MH  - Carcinogenesis/chemically induced/*genetics/pathology
MH  - Cell Line, Tumor
MH  - Diethylnitrosamine/administration & dosage
MH  - Down-Regulation
MH  - Fatty Acids/biosynthesis
MH  - Fructose-Bisphosphate Aldolase/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Lipidomics
MH  - Lipogenesis/*genetics
MH  - Liver/metabolism/pathology
MH  - Liver Neoplasms, Experimental/chemically induced/*genetics/metabolism/pathology
MH  - Male
MH  - Mice, Knockout
MH  - Phosphorylation
MH  - Receptor, Insulin/*metabolism
MH  - Mice
EDAT- 2021/07/23 06:00
MHDA- 2022/01/15 06:00
CRDT- 2021/07/22 12:40
PHST- 2021/06/11 00:00 [revised]
PHST- 2021/01/29 00:00 [received]
PHST- 2021/06/28 00:00 [accepted]
PHST- 2021/07/23 06:00 [pubmed]
PHST- 2022/01/15 06:00 [medline]
PHST- 2021/07/22 12:40 [entrez]
AID - 10.1002/hep.32064 [doi]
PST - ppublish
SO  - Hepatology. 2021 Dec;74(6):3037-3055. doi: 10.1002/hep.32064. Epub 2021 Aug 26.