On Jul 4, 1:13 am, MattLB <mat...@angelfire.com> wrote:
> it's not a negative feedback
> mechanism where increased AA inhibits the enzymes, it's a feed-forward
> mechanism where the precursors i.e. LA and LNA inhibit their own
> conversion to AA or EPA/DHA.
You are dead wrong, MattLB. Do you understand transcriptional gene
regulation?
J. Lipid Res., doi:10.1194/jlr.M200195-JLR200
Transcriptional regulation of rat and human delta-6 desaturase genes
by fatty acids and WY 14,643: Identification of a functional direct
repeat-1 cis-acting element in the human delta-6 desaturase gene
Arachidonic [20:4(n-6)] and docosahexenoic [22:6(n-3)] acids are
potent inhibitors of lipogenic gene expression and consequently reduce
the hepatic secretion and tissue accumulation of triglycerides. The
rate-limiting step in 20:4(n-6) and 22:6(n-3) synthesis is the
desaturation of 18:2(n-6) and 18:3(n-3) by delta-6 desaturase (D6ase).
In this report, we demonstrate that (n-6) and (n-3) polyunsaturated
fats (PUFA) suppressed the hepatic expression of rodent D6ase by
inhibiting the rate of D6ase gene transcription. In contrast,
consumption of the PPARa activator WY 14,643 significantly enhanced
the transcription of hepatic D6ase by more than 500%. Transfection-
reporter assays with HepG2 cells revealed that the PUFA response
region for the human D6ase gene involved the proximal promoter region
of –283/+1 human D6ase gene, while the WY 14,643 response element was
identified as an imperfect direct repeat (DR-1) located at –385/-373.
The WY 14,643 induction of the human D6ase promoter activity was
dependent upon the expression of PPARa. Electrophoretic mobility shift
assays revealed that nuclear proteins extracted from HepG2 cells
expressing PPARa specifically interacted with the –385/-373 DR-1
sequence of the human D6ase gene. The interaction was eliminated by
unlabelled PPARa-response element of the rat acyl-CoA oxidase gene,
and the protein/DNA complex was super-shifted by treatment with anti-
PPARa. The –385/-373 sequence also interacted with a mixture of in
vitro translated PPARa/RXRa but by themselves neither PPARa nor RXRa
could bind to the D6ase DR-1. These data indicate that the 5’-flanking
region of the human D6ase gene contains a DR-1 that functions in the
regulation of human D6ase gene transcription, and thereby plays a role
in the synthesis of 20- and 22-carbon polyenoic fatty acids.
Reproduction (2007) 133 467-477 DOI: 10.1530/REP-06-00294
Essential fatty acid deficiency induces fatty acid desaturase
expression in rat epididymis, but not in testis
On the molecular level, essential fatty acid deficiency (EFAD) has
been associated with induced fatty acid (FA) desaturase expression and
activity in several tissues. However, there seem to be exceptions. In
the present study, we examine the effects of EFAD in the male rat
genital tract, combining FA analysis, gene expression studies, and
morphological evaluation of epididymal spermatozoa. When feeding 21-
day-old Wistar rats, a fat-free diet for 6 weeks, an increase in
18:1n-9 and 20:3n-9 and a concomitant decrease in the 18:2n-6 and
20:4n-6 species are seen in testis, as well as in liver. However, with
regard to desaturase expression the rat testis seems to be
unresponsive to EFAD conditions, in contrast to other organs studied.
In the sexually mature testis none of the desaturases (SCD1, SCD2,
D5D, or D6D) are induced in response to lowered contents of
polyunsaturated FAs. This also applies to caput epididymis, while EFAD
sensitivity is regained in cauda epididymis, where the desaturases are
upregulated. The FA profile of epididymal spermatozoa is increasingly
affected by EFAD during the transport from testis to cauda epididymis.
Furthermore, a significant increase in the number of abnormal
spermatozoa is observed in cauda epididymis.
J Lipid Res. 2005 Nov;46(11):2432-40. Epub 2005 Aug 16.
Peroxisome proliferator-activated receptor alpha is required for
feedback regulation of highly unsaturated fatty acid synthesis.
Li Y, Nara TY, Nakamura MT.
Department of Food Science and Human Nutrition, University of Illinois
at Urbana-Champaign, Urbana, IL 61801, USA.
Delta6 desaturase (D6D), the rate-limiting enzyme for highly
unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty
acid-deficient diets. Sterol regulatory element-binding protein-1c
(SREBP-1c) in part mediates this induction. Paradoxically, D6D is also
induced by ligands of peroxisome proliferator-activated receptor alpha
(PPARalpha). Here, we report a novel physiological role of PPARalpha
in the induction of genes specific for HUFA synthesis by essential
fatty acid-deficient diets. D6D mRNA induction by essential fatty acid-
deficient diets in wild-type mice was diminished in PPARalpha-null
mice. This impaired D6D induction in PPARalpha-null mice was not
attributable to feedback suppression by tissue HUFAs because PPARalpha-
null mice had lower HUFAs in liver phospholipids than did wild-type
mice. Furthermore, PPARalpha-responsive genes were induced in wild-
type mice under essential fatty acid deficiency, suggesting the
generation of endogenous PPARalpha ligand(s). Contrary to genes for
HUFA synthesis, the induction of other lipogenic genes under essential
fatty acid deficiency was higher in PPARalpha-null mice than in wild-
type mice even though mature SREBP-1c protein did not differ between
the genotypes. The expression of PPARgamma was markedly increased in
PPARalpha-null mice and might have contributed to the induction of
genes for de novo lipogenesis. Our study suggests that PPARalpha,
together with SREBP-1c, senses HUFA status and confers pathway-
specific induction of HUFA synthesis by essential fatty acid-deficient
diets.
PMID: 16106047
Annu Rev Nutr. 2004;24:345-76.
Structure, function, and dietary regulation of delta6, delta5, and
delta9 desaturases.
Nakamura MT, Nara TY.
Department of Food Science and Human Nutrition, University of Illinois
at Urbana-Champaign, Urbana, Illinois 61801, USA.
Fatty acid desaturases introduce a double bond in a specific position
of long-chain fatty acids, and are conserved across kingdoms. Degree
of unsaturation of fatty acids affects physical properties of membrane
phospholipids and stored triglycerides. In addition, metabolites of
polyunsaturated fatty acids are used as signaling molecules in many
organisms. Three desaturases, Delta9, Delta6, and Delta5, are present
in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids.
Oleic acid, a main product of Delta9 desaturase, is the major fatty
acid in mammalian adipose triglycerides, and is also used for
phospholipid and cholesteryl ester synthesis. Delta-6 and Delta5
desaturases are required for the synthesis of highly unsaturated fatty
acids (HUFAs), which are mainly esterified into phospholipids and
contribute to maintaining membrane fluidity. While HUFAs may be
required for cold tolerance in plants and fish, the primary role of
HUFAs in mammals is cell signaling. Arachidonic acid is required as
substrates for eicosanoid synthesis, while docosahexaenoic acid is
required in visual and neuronal functions. Desaturases in mammals are
regulated at the transcriptional level. Reflecting overlapping
functions, three desaturases share a common mechanism of a feedback
regulation to maintain products in membrane phospholipids. At the same
time, regulation of Delta9 desaturase differs from Delta6 and Delta5
desaturases because its products are incorporated into more diverse
lipid groups. Combinations of multiple transcription factors achieve
this sophisticated differential regulation.
PMID: 15189125
MattLB
