Identification of dicarboxylate carrier Slc25a10 as malate transporter in de novo fatty acid synthesis.
Mitochondrial solute carrier family 25 member 10 (Slc25a10) transports dicarboxylates such as malate or succinate across the mitochondrial inner membrane. Although fatty acid synthesis in adipose tissue or the liver is initiated by citrate transport in exchange for malate across the mitochondrial membrane, the transporter responsible for supplying malate during citrate transport has not been identified. In the present study, we clarified the role of Slc25a10 in supplying malate for citrate transport and examined the effect of Slc25a10 suppression on the lipogenic pathway and lipid accumulation. We have reported an Slc25a10 increase in white adipose tissue in obese mouse models and a decrease in a fasted mouse model using expression profiles. Next, we examined the effect of Slc25a10 suppression by small interfering RNA on citrate transport in the lipogenic cell lines HepG2 and 3T3-L1. We observed that inhibition of malate transport by Slc25a10 suppression significantly reduced the citrate transport from the mitochondria to the cytosol. We also found that suppression of Slc25a10 down-regulated the lipogenic pathway, indicated by decreases in ACC1 expression and malonyl-CoA level. Furthermore, suppression of Slc25a10 decreased triglyceride lipid accumulation in adipose-differentiated 3T3-L1 cells. These results suggested that Slc25a10 plays an important role in supplying malate for citrate transport required for fatty acid synthesis and indicated that inhibition of Slc25a10 might effectively reduce lipid accumulation in adipose tissues.
Mizuarai
Shinji
S
Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., Ibaraki, Japan.
Miki
Satomi
S
Araki
Hiromitsu
H
Takahashi
Kazuhiko
K
Kotani
Hidehito
H
D041721:3T3-L1 Cells; D000085:Acetates / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D001692:Biological Transport; D015153:Blotting, Western; D002264:Carboxylic Acids / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002951:Citrates / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D029382:Dicarboxylic Acid Transporters / Q000737:chemistry / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism; D008293:Malates / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection
D000085:Acetates; D001391:Azo Compounds; D002264:Carboxylic Acids; D002951:Citrates; D029382:Dicarboxylic Acid Transporters; D005227:Fatty Acids; D008293:Malates; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C504725:Slc25a10 protein, mouse; D008316:Malonyl Coenzyme A; C011049:oil red O