Polyunsaturated Fatty Acid Regulation of Gene Transcription

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Polyunsaturated Fatty Acid Regulation of Gene Transcription:

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A Molecular Mechanism to Improve the Metabolic Syndrome1 ,2 Steven D. Clarke

Graduate Program of Nutrition and the Institute of Cell and Molecular Biology,

The University of Texas at Austin, Austin, Texas 78712

 

ABSTRACT INTRODUCTION

PUFA Induction of Lipid... PUFA Suppression of Lipogenesis:... Summary.

REFERENCES

 

This review addresses the hypothesis that polyunsaturated fatty acids (PUFA),

particularly those of the (n-3) family, play pivotal roles as " fuel

partitioners "

 

in that they direct fatty acids away from triglyceride storage and toward

oxidation,

 

and that they enhance glucose flux to glycogen.

 

In doing this, PUFA protects against the adverse symptoms of the metabolic

syndrome and

reduce the risk of heart disease.

 

PUFA exert their beneficial effects by up-regulating the expression of genes

encoding proteins involved in

 

fatty acid oxidation while simultaneously down-regulating genes encoding

proteins of lipid synthesis.

 

PUFA govern oxidative gene expression by activating the transcription factor

peroxisome proliferator-activated receptor .

 

PUFA suppress lipogenic gene expression by reducing the nuclear abundance and

DNA-binding affinity of transcription factors responsible for imparting insulin

and carbohydrate control to lipogenic and glycolytic genes.

 

In particular, PUFA suppress the nuclear abundance and expression of sterol

regulatory element binding protein-1 and reduce the DNA- binding activities of

nuclear factor Y, Sp1 and possibly hepatic nuclear factor-4.

 

Collectively, the studies discussed suggest that the fuel " repartitioning " and

gene expression actions of PUFA should be considered among criteria used in

defining the dietary needs of (n- 6) and (n-3) and in establishing the dietary

ratio of (n-6) to (n-3) needed for optimum health benefit.

 

 

ABSTRACT

 

 

Dietary (n-6) and (n-3) polyunsaturated fatty acids (PUFA)4

 

reduce triglyceride accumulation

 

in skeletal muscle and potentially in cardiomyocytes and cells (1 ,2) .

 

Lower tissue lipids are associated with improvements in the metabolic syndrome,

such as increased insulin sensitivity (1 ,3) .

 

PUFA elicit their effects by coordinately suppressing lipid synthesis in the

liver,

 

up-regulating fatty acid oxidation in liver and skeletal muscle

 

and increasing total body glycogen storage (3 4 5 6 7 . -6

 

Desaturation of 18:2(n-6) and 18:3(n-3) is required for this " repartitioning " of

metabolic fuel (9) , and on a carbon-for- carbon basis,

 

(n-3) fatty acids are more potent than (n-6) fatty acids. The repartitioning

activity of PUFA, particularly (n-3) PUFA, has been observed in humans as well

as various animal models (3 ,10 11 12 13) .

 

However, as little as 2-5 g of 18:3(n-3) or 20:5 and 22:6(n-3)

 

lower blood triglyceride concentrations

 

and reduce the risk of fatal ischemic heart disease (12 ,13) .

 

Some of the beneficial effects of PUFA are due to changes in membrane fatty acid

composition and subsequent alterations in hormonal signaling (1) .

 

However, fatty acids themselves exert a direct, membrane-independent influence

on molecular events that governs gene expression.

 

It is the regulation of gene expression by dietary fats that we believe has the

greatest impact on the development of insulin resistance and its related

pathophysiologies (i.e., the metabolic syndrome). More importantly,

determination of the cellular and molecular mechanisms regulated by PUFA may

identify novel sites for pharmacological intervention.

 

i

 

 

Summary. TOP ABSTRACT INTRODUCTION PUFA Induction of Lipid... PUFA Suppression

of Lipogenesis:... Summary. REFERENCES

 

 

For nearly 40 y, PUFA have been known to uniquely suppress lipid synthesis.

PUFA, particularly (n-3), accomplish this by coordinating an up-regulation of

lipid oxidation and a down-regulation of lipid synthesis.

 

In other words, PUFA function as metabolic fuel repartitioners. The outcome is

an improvement in the symptoms of the metabolic syndrome and a reduced risk of

heart disease.

 

PUFA control these metabolic pathways by governing the DNA-binding activity and

nuclear abundance of select transcription factors responsible for regulating the

expression of genes encoding key regulatory proteins of lipid and glucose

metabolism.

 

PUFA increase the fatty acid oxidative capacity of tissues through their ability

to function as ligand activators of PPAR and thereby induce the transcription of

several genes encoding proteins affiliated with fatty acid oxidation.

 

http://www.nutrition.org/cgi/content/full/131/4/1129

 

 

 

 

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<DietaryTipsForHBP >

Tuesday, June 21, 2005 10:08 PM

Polyunsaturated Fatty Acid Regulation

of Gene Transcription

 

 

>

> http://www.nutrition.org/cgi/content/full/131/4/1129

 

The URL at nutrition.org seems not to be working at the moment.

The full article, with many hotlinks to further info, can be viewed here:

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