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Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation
- Source :
- Cells, Vol 11, Iss 24, p 3988 (2022)
- Publication Year :
- 2022
- Publisher :
- MDPI AG, 2022.
-
Abstract
- 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 α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα 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 AMPKα 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.
- Subjects :
- LMNA
AMPK
lipid metabolism
hepatocellular carcinoma
Cytology
QH573-671
Subjects
Details
- Language :
- English
- ISSN :
- 11243988 and 20734409
- Volume :
- 11
- Issue :
- 24
- Database :
- Directory of Open Access Journals
- Journal :
- Cells
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.05801fd6ea9148708326964e746d9e4d
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/cells11243988