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Increased mitochondrial fission drives the reprogramming of fatty acid metabolism in hepatocellular carcinoma cells through suppression of Sirtuin 1

Authors :
Dan Wu
Yi Yang
Yiran Hou
Zifeng Zhao
Ning Liang
Peng Yuan
Tao Yang
Jinliang Xing
Jibin Li
Source :
Cancer Communications, Vol 42, Iss 1, Pp 37-55 (2022)
Publication Year :
2022
Publisher :
Wiley, 2022.

Abstract

Abstract Background Mitochondria are dynamic organelles that constantly change their morphology through fission and fusion processes. Recently, abnormally increased mitochondrial fission has been observed in several types of cancer. However, the functional roles of increased mitochondrial fission in lipid metabolism reprogramming in cancer cells remain unclear. This study aimed to explore the role of increased mitochondrial fission in lipid metabolism in hepatocellular carcinoma (HCC) cells. Methods Lipid metabolism was determined by evaluating the changes in the expressions of core lipid metabolic enzymes and intracellular lipid content. The rate of fatty acid oxidation was evaluated by [3H]‐labelled oleic acid. The mitochondrial morphology in HCC cells was evaluated by fluorescent staining. The expression of protein was determined by real‐time PCR, iimmunohistochemistry and Western blotting. Results Activation of mitochondrial fission significantly promoted de novo fatty acid synthesis in HCC cells through upregulating the expression of lipogenic genes fatty acid synthase (FASN), acetyl‐CoA carboxylase1 (ACC1), and elongation of very long chain fatty acid protein 6 (ELOVL6), while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A (CPT1A) and acyl‐CoA oxidase 1 (ACOX1). Consistently, suppressed mitochondrial fission exhibited the opposite effects. Moreover, in vitro and in vivo studies revealed that mitochondrial fission‐induced lipid metabolism reprogramming significantly promoted the proliferation and metastasis of HCC cells. Mechanistically, mitochondrial fission increased the acetylation level of sterol regulatory element‐binding protein 1 (SREBP1) and peroxisome proliferator‐activated receptor coactivator 1 alpha (PGC‐1α) by suppressing nicotinamide adenine dinucleotide (NAD+)/Sirtuin 1 (SIRT1) signaling. The elevated SREBP1 then upregulated the expression of FASN, ACC1 and ELOVL6 in HCC cells, while PGC‐1α/PPARα suppressed the expression of CPT1A and ACOX1. Conclusions Increased mitochondrial fission plays a crucial role in the reprogramming of lipid metabolism in HCC cells, which provides strong evidence for the use of this process as a drug target in the treatment of this malignancy.

Details

Language :
English
ISSN :
25233548
Volume :
42
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cancer Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.21221f0b7fc14ee0b28d946c8bef6bac
Document Type :
article
Full Text :
https://doi.org/10.1002/cac2.12247