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

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 can-cer.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 hepa-tocellular 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[PH]-labelled oleic acid.The mito-chondrial morphology in HCC cells was evaluated by fluorescent staining.The expression of protein was determined by real-time PCR,imnmunohistochemistry 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 carboxylasel(ACCI),and elonga-tion of very long chain fatty acid protein 6(ELOVL6),while suppressed fatty acid oxidation by downregulating carnitine palmitoyl transferase 1A(CPTIA)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,mito-chondrial fission increased the acetylation level of sterol regulatory element-binding protein 1(SREBPI)and peroxisome proliferator-activated receptor coaC-tivator 1 alpha(PGC-1a)by suppressing nicotinamide adenine dinucleotide(NAD+)/Sirtuin 1(SIRTI)signaling.The elevated SREBP1 then upregulated the expression of FASN,ACC1 and ELOVL6 in HCC cells,while PGC-1c/PPARa sup-pressed the expression of CPTIA and ACOXL Conclusions:Increased mitochondrial fission plays a crucial role in the repro-gramming 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.