PMID- 36552752
OWN - NLM
STAT- MEDLINE
DCOM- 20230109
LR  - 20230115
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 24
DP  - 2022 Dec 9
TI  - Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis 
      via AMPKalpha Activation.
LID - 10.3390/cells11243988 [doi]
LID - 3988
AB  - The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid 
      metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). 
      We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem 
      cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro 
      experiments, we discovered a significant increase in phosphorylated lamin A/C 
      levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased 
      lipid synthesis in a liver cell line (7701 cells) and two hepatocellular 
      carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did 
      not survive after LMNA knockout (KO) or even KD. Evidently, the functions of 
      lamin A/C differ between the liver and adipose tissue. To date, the mechanism of 
      hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our 
      in-depth study aimed to identify the molecular connection between lamin A/C and 
      pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function 
      experiments were performed to investigate functional changes and the related 
      molecular pathways in 7701 cells. Adenosine 5' monophosphate-activated protein 
      kinase alpha (AMPKalpha) was activated when abnormalities in functional lamin A/C were 
      observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) 
      treatment. Active AMPKalpha directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) 
      and subsequently inhibited lipid synthesis but induced glycolysis in both HCC 
      cells and normal cells. According to the mass spectrometry analysis, lamin A/C 
      potentially regulated AMPKalpha activation through its chaperone proteins, ATPase or 
      ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions 
      significantly decreased the proliferation of the two HCC cell lines more 
      efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of 
      prelamin A.
FAU - Zhou, Ying
AU  - Zhou Y
AD  - Department of Biochemistry and Molecular Biology, Capital Medical University, 
      Beijing 100069, China.
FAU - Yang, Jia-Jie
AU  - Yang JJ
AD  - Department of Biochemistry and Molecular Biology, Capital Medical University, 
      Beijing 100069, China.
FAU - Cheng, Yuan
AU  - Cheng Y
AD  - Department of Physiology, Capital Medical University, Beijing 100069, China.
FAU - Feng, Ge-Xuan
AU  - Feng GX
AD  - Department of Biochemistry and Molecular Biology, Capital Medical University, 
      Beijing 100069, China.
FAU - Yang, Rong-Hui
AU  - Yang RH
AUID- ORCID: 0000-0002-9765-9666
AD  - Department of Biochemistry and Molecular Biology, Capital Medical University, 
      Beijing 100069, China.
FAU - Yuan, Yuan
AU  - Yuan Y
AD  - Department of Pathology, Capital Medical University, Beijing 100069, China.
FAU - Wang, Li-Yong
AU  - Wang LY
AD  - The Central Laboratory for Molecular Biology, Capital Medical University, Beijing 
      100069, China.
FAU - Wang, Miao
AU  - Wang M
AD  - Department of Pathology, Beijing Friendship Hospital, The Second Clinical Medical 
      College of Capital Medical University, Beijing 100050, China.
FAU - Kong, Lu
AU  - Kong L
AUID- ORCID: 0000-0002-4998-1327
AD  - Department of Biochemistry and Molecular Biology, Capital Medical University, 
      Beijing 100069, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221209
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 2.7.11.1 (AMPK alpha1 subunit, mouse)
RN  - 0 (lamin C)
RN  - 0 (Lamin Type A)
RN  - 0 (Lipids)
RN  - IOW153004F (lonafarnib)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *AMP-Activated Protein Kinases/genetics/metabolism
MH  - *Carcinoma, Hepatocellular/drug therapy/genetics/metabolism
MH  - Homeostasis
MH  - *Lamin Type A/genetics/metabolism
MH  - Lipids/physiology
MH  - *Liver Neoplasms/drug therapy/genetics/metabolism
PMC - PMC9777081
OTO - NOTNLM
OT  - AMPK
OT  - LMNA
OT  - hepatocellular carcinoma
OT  - lipid metabolism
COIS- The authors have no conflicts of interest to declare.
EDAT- 2022/12/24 06:00
MHDA- 2022/12/27 06:00
PMCR- 2022/12/09
CRDT- 2022/12/23 01:17
PHST- 2022/08/21 00:00 [received]
PHST- 2022/12/06 00:00 [revised]
PHST- 2022/12/06 00:00 [accepted]
PHST- 2022/12/23 01:17 [entrez]
PHST- 2022/12/24 06:00 [pubmed]
PHST- 2022/12/27 06:00 [medline]
PHST- 2022/12/09 00:00 [pmc-release]
AID - cells11243988 [pii]
AID - cells-11-03988 [pii]
AID - 10.3390/cells11243988 [doi]
PST - epublish
SO  - Cells. 2022 Dec 9;11(24):3988. doi: 10.3390/cells11243988.