Hepatic long-chain acyl-CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways.
Long-chain acyl-CoA synthetases (ACSLs) and fatty acid transport proteins (FATPs) activate fatty acids (FAs) to acyl-CoAs prior to their downstream metabolism. Of numerous ACSL and FATP isoforms, ACSL5 is expressed predominantly in tissues with high rates of triacylglycerol (TAG) synthesis, suggesting it may have an anabolic role in lipid metabolism. To characterize the role of ACSL5 in hepatic energy metabolism, we used small interference RNA (siRNA) to knock down ACSL5 in rat primary hepatocytes. Compared with cells transfected with control siRNA, suppression of ACSL5 expression significantly decreased FA-induced lipid droplet formation. These findings were further extended with metabolic labeling studies showing that ACSL5 knockdown resulted in decreased [1-(14)C]oleic acid or acetic acid incorporation into intracellular TAG, phospholipids, and cholesterol esters without altering FA uptake or lipogenic gene expression. ACSL5 knockdown also decreased hepatic TAG secretion proportionate to the observed decrease in neutral lipid synthesis. ACSL5 knockdown did not alter lipid turnover or mediate the effects of insulin on lipid metabolism. Hepatocytes treated with ACSL5 siRNA had increased rates of FA oxidation without changing PPAR-α activity and target gene expression. These results suggest that ACSL5 activates and channels FAs toward anabolic pathways and, therefore, is an important branch point in hepatic FA metabolism.
Bu
So Young
SY
Department of Food Science and Nutrition, University of Minnesota, St Paul, MN, USA.
Mashek
Douglas G
DG
D000818:Animals; D001692:Biological Transport; D003066:Coenzyme A Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004951:Esterification / Q000235:genetics; D005227:Fatty Acids / Q000096:biosynthesis* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D005227:Fatty Acids; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D003066:Coenzyme A Ligases; C508147:Acsl5 protein, rat
Obesity (Silver Spring). 2007 May;15(5):1068-75
17495181
J Biol Chem. 2007 Aug 3;282(31):22678-88
17526931
J Biol Chem. 2003 Sep 19;278(38):35931-9
12853447
J Lipid Res. 2004 Mar;45(3):592-601
14999041
Curr Opin Lipidol. 2006 Jun;17(3):274-8
16680032
J Clin Invest. 2001 Apr;107(7):813-22
11285300
Cell Metab. 2007 Jul;6(1):69-78
17618857
J Biol Chem. 2006 Dec 1;281(48):37246-55
17028193
J Biol Chem. 2001 Jul 6;276(27):24667-73
11319222
J Biol Chem. 2004 Jun 4;279(23):23882-91
15051725
Hepatology. 2005 Aug;42(2):362-71
16001399
Can J Biochem Physiol. 1959 Aug;37(8):911-7
13671378
J Biol Chem. 2008 Jan 11;283(2):849-54
18003621
Cell Metab. 2006 Sep;4(3):199-210
16950137
J Biol Chem. 2008 Jan 25;283(4):1773-7
18024425
J Lipid Res. 2004 Jul;45(7):1279-88
15102885
J Biol Chem. 2009 Feb 20;284(8):5352-61
19049983
J Lipid Res. 2009 Aug;50(8):1621-9
19304987
Arch Biochem Biophys. 2002 Aug 15;404(2):263-70
12147264
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12027-32
14512514
Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2480-97
16428347
J Lipid Res. 2006 Nov;47(11):2562-74
16929033
Future Lipidol. 2007 Aug;2(4):465-476
20354580
J Biol Chem. 1957 May;226(1):497-509
13428781
J Biol Chem. 2002 Jul 26;277(30):27029-35
12016216
J Biol Chem. 2001 Jul 6;276(27):24674-9
11319232
Am J Physiol Endocrinol Metab. 2002 Jan;282(1):E46-51
11739082
J Lipid Res. 2007 Mar;48(3):609-20
17164224
J Physiol. 2009 Dec 15;587(Pt 24):5939-50
19858228
J Biol Chem. 2009 Oct 9;284(41):27816-27826
19648649
J Biol Chem. 2006 Jan 13;281(2):945-50
16263710
Am J Physiol Endocrinol Metab. 2005 May;288(5):E835-44
15598672
Biochim Biophys Acta. 2008 Jun-Jul;1781(6-7):352-8
18522808
Biochimie. 2005 Dec;87(12):1149-55
16198472
J Biol Chem. 2009 Oct 30;284(44):30474-83
19737935
Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E67-75
19366875
J Biochem. 1998 Sep;124(3):679-85
9722683
J Biol Chem. 2005 Jul 8;280(27):25629-36
15878874
FASEB J. 2002 Feb;16(2):155-68
11818363
J Biol Chem. 2001 Dec 28;276(52):49066-76
11551957
J Lipid Res. 2006 Sep;47(9):2004-10
16772660
Cell Metab. 2005 May;1(5):309-22
16054078