Inhibition of insulin and T3-induced fatty acid synthase by hexanoate.
Fatty acid synthase (FAS) is responsible for the de novo synthesis of palmitate and stearate. This enzyme is activated by insulin and T(3), and inhibited by fatty acids. In this study, we show that insulin and T(3) have an inducing effect on FAS enzymatic activity, which is synergetic when both hormones are present. Octanoate and hexanoate specifically inhibit this hormonal effect. A similar inhibitory effect is observed at the level of protein expression. Transient transfections in HepG2 cells revealed that hexanoate inhibits, at least in part, FAS at a transcriptional level targeting the T(3) response element (TRE) on the FAS promoter. The effect of C6 on FAS expression cannot be attributed to a modification of insulin receptor activation or to a decrease in T(3) entry in the cells. Using bromo-hexanoate, we determined that hexanoate needs to undergo a transformation in order to have an effect. When incubating cells with triglyceride-hexanoate or carnitine-hexanoate, no effect on the enzymatic activity induced by insulin and T(3) is observed. A similar result was obtained when cells were incubated with betulinic acid, an inhibitor of the diacylglycerol acyltransferase. However, the incubation of cells with Triacsin C, a general inhibitor of acyl-CoA synthetases, completely reversed the inhibitory effect of hexanoate. Our results suggest that in hepatic cells, hexanoate needs to be activated into a CoA derivative in order to inhibit the insulin and T(3)-induced FAS expression. This effect is partially transcriptional, targeting the TRE on the FAS promoter.
Akpa
Murielle M
MM
Département des Sciences Biologiques, Centre de Recherche BioMed, Université du Québec à Montréal, C.P. 8888, Succursale Centre-ville, Montréal, H3C 3P8, Canada.
Point
Floriane
F
Sawadogo
Sabine
S
Radenne
Anne
A
Mounier
Catherine
C
D000818:Animals; D002208:Caproates / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D002208:Caproates; D005227:Fatty Acids; D006727:Hormone Antagonists; D007328:Insulin; D007329:Insulin Antagonists; D014284:Triiodothyronine; C037652:hexanoic acid; D064429:Fatty Acid Synthases
Biochim Biophys Acta. 2005 Oct 15;1737(1):36-43
16226916
J Biol Chem. 1992 Jul 25;267(21):14918-27
1634532
J Nutr. 2002 Mar;132(3):329-32
11880549
Proc Nutr Soc. 1991 Aug;50(2):115-22
1749785
J Lipid Res. 2002 May;43(5):691-8
11971939
Mol Cell Biochem. 1984 Sep;64(1):63-8
6208476
Endocrinology. 1997 Sep;138(9):4030-3
9275096
Biochemistry. 1989 May 30;28(11):4523-30
2669958
Arch Biochem Biophys. 1978 Sep;190(1):332-44
30416
Prostaglandins Leukot Essent Fatty Acids. 2006 Sep;75(3):149-59
16829065
Am J Physiol Endocrinol Metab. 2008 Oct;295(4):E884-94
18682535
Biochemistry. 1970 Jan 20;9(2):239-45
5412661
Anal Biochem. 1976 May 7;72:248-54
942051
Am J Clin Nutr. 1987 Feb;45(2):399-405
3812339
Mol Cell Biol. 1987 Feb;7(2):725-37
3821727
J Dairy Sci. 2002 Feb;85(2):295-350
11913692
IUBMB Life. 2004 Oct;56(10):595-600
15814457
Diabetes. 1992 May;41(5):641-7
1568535
J Biol Chem. 1986 Sep 25;261(27):12555-61
3528158
Genes Dev. 1993 Jul;7(7B):1423-35
8392479
Biochim Biophys Acta. 1958 Nov;30(2):376-83
13607455
J Dairy Res. 2004 Nov;71(4):398-404
15605705
J Biol Chem. 1985 Jan 25;260(2):1326-37
3968064
J Biol Chem. 1986 Nov 15;261(32):15179-82
3533937
Prog Lipid Res. 1997 Mar;36(1):43-53
9373620
J Biol Chem. 1972 Nov 10;247(21):6946-52
5082134
J Nutr. 1996 Nov;126(11):2720-9
8914941
Physiol Rev. 2001 Jul;81(3):1097-142
11427693
J Biol Chem. 1998 Jun 19;273(25):15373-81
9624119
Eur J Biochem. 1972 Apr 24;26(4):553-9
5025931
Am J Clin Nutr. 1982 Nov;36(5):950-62
6814231
J Lipid Res. 1970 Sep;11(5):458-65
5501480
J Med Invest. 2007 Aug;54(3-4):385-8
17878693
Eur J Biochem. 1992 Apr 15;205(2):433-42
1349281
Prog Lipid Res. 1996 Sep;35(3):227-41
9082451
Am J Physiol. 1960 Jul;199:71-6
13814616
Proc Natl Acad Sci U S A. 1975 May;72(5):1940-4
1098047
Diabetes. 1999 Dec;48(12):2255-69
10580412
J Biol Chem. 1989 Jan 5;264(1):574-7
2535847
J Biol Chem. 2008 Jun 13;283(24):16514-24
18390901
Lipids. 1987 Jun;22(6):417-20
3112486
J Biol Chem. 1973 Jun 25;248(12):4318-26
4145797
Annu Rev Nutr. 1994;14:83-98
7946534
Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1105-8
1736293
Neuroscience. 2007 May 25;146(3):1073-81
17434686
J Nutr Biochem. 2009 Jul;20(7):537-43
18789670
J Biol Chem. 1986 Mar 25;261(9):4190-7
3005324
J Biol Chem. 1990 Oct 25;265(30):18442-6
2170411
DNA Cell Biol. 2005 Jan;24(1):54-61
15684720
Ann N Y Acad Sci. 2002 Jun;967:52-65
12079835
J Lipid Res. 2003 Feb;44(2):356-68
12576518
Biochem J. 1990 Mar 15;266(3):793-7
2327966
Obes Res. 2003 Jun;11(6):734-44
12805394
J Nutr. 1990 Dec;120(12):1727-9
2175783
J Nutr. 2005 Jul;135(7):1636-41
15987842
Life Sci. 1998;62(14):1203-15
9570335