Zhou, Y.; Yang, J.; Cheng, Y.; Feng, G.; Yang, R.; Yuan, Y.; Wang, L.; Kong, L. Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation. Preprints2022, 2022070253. https://doi.org/10.20944/preprints202207.0253.v1
APA Style
Zhou, Y., Yang, J., Cheng, Y., Feng, G., Yang, R., Yuan, Y., Wang, L., & Kong, L. (2022). Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation. Preprints. https://doi.org/10.20944/preprints202207.0253.v1
Chicago/Turabian Style
Zhou, Y., Li-yong Wang and Lu Kong. 2022 "Abnormal in LMNA Triggers a Shift in Intracellular Metabolic Homeostasis Via AMPK Activation" Preprints. https://doi.org/10.20944/preprints202207.0253.v1
Abstract
Laminopathies are a spectrum of diseases caused by LMNA mutations. In familial partial lipodystrophy of Dunnigan (FPLD), LMNA plays role in the differentiation and development of adipocytes and lipid metabolism. Changes in LMNA predict not only the differentiation of adipose-derived mesenchymal stem cells (AD-MSCs) but also the transformation of cancer cells. Hence, our in-depth study aimed to identify the molecular connection between disordered lipid metabolism and hepatic carcinogenesis. We first discovered significant positive correlations between pLMNA and two key rate-limiting enzymes in de novo fatty acid synthesis, acetyl-CoA-carboxylase 1 (ACC1) and fatty acid synthase (FASN), in the liver tissue but not in adipose tissue of obese model rats. Moreover, LMNA knockdown (KD) in rat AD-MSCs prevented the differentiation and maturation of adipocytes. To clarify the mechanistic relationship with lipogenesis, gain- and loss-of-function experiments in which functional changes and the related molecular pathways were investigated in a normal hepatocyte line (7701 cells). Adenosine 5'-monophosphate activated protein kinase α (AMPKα) was found to be activated by abnormalities in the LMNA structure under conditions of LMNA deletion, farnesyltransferase inhibitor (FTI) treatment and LMNA mutations associated with clinical FPLD pathogenic phenotype. Active AMPKα could directly phosphorylate ACC1 and thus inhibit lipid synthesis but induced glycolysis in both HCC cells and normal cells. The HCC cells could not survive with LMNA knockout (KO) or even KD. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of HepG2 and MHCC cells by inhibiting glycolysis and the maturation of prelamin A.
Keywords
LMNA; AMPK; lipid metabolism; cancer
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
