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16 Feb 2004 14:17:37 -0000

How Carbohydrates Make Fats

press-release

 

The Institute of Science in Society

Science Society Sustainability

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General Enquiries sam

Website/Mailing List press-release

ISIS Director m.w.ho

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This series was first published in Science and Society 21. Subscribe to Science

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1.. The Obesity Epidemic http://www.i-sis.org.uk/ObesityEpidemic.php

2.. How to Survive 40 Days Starvation http://www.i-sis.org.uk/HTSFDS.php

3.. How carbohydrates make fats http://www.i-sis.org.uk/HCMF.php

 

ISIS Press Release 12/02/04

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How Carbohydrates Make Fats

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Dr. Mae-Wan Ho traces the tangled paths of how diet affects metabolism affects

gene transcription affects metabolism.

 

Sources for this report are available in the ISIS members site.

http://www.i-sis.org.uk/full/HCMFFull.php

It has long been known that a high-carbohydrate diet stimulates the synthesis of

fatty acids and induces the transcription and expression not only of all the

enzymes needed to make fatty acids, but also the enzymes breaking down glucose

into the necessary building blocks for making all kinds of fat.

 

It appears that two distinct transcription factors are involved in providing the

signals for making fats. Transcription factors bind to promoters of genes to

boost transcription and hence gene expression. One transcription factor,

SREBP-1c (Sterol Response Element Binding Protein), is stimulated by insulin,

and binds to the SRE (Sterol Response Element) in the promoter region of genes

encoding key enzymes that make cholesterol.

 

A second element, the carbohydrate response element, ChoRE, is involved in the

transcription of fat-making enzymes after stimulation by high glucose in the

absence of insulin. ChoRE sits in the promoters of enzymes involved in making

other fats.

 

Two years ago, the research team headed by Kosaku Uyeda in the Dallas Veterans

Affairs Medical Centre and Department of biochemistry, University of Texas in

the United States, purified the protein that binds to the ChoRE in the promoter

of the gene encoding liver pyruvate kinase from the livers of 800 rats that had

been fasted and then refed a high-carbohydrate diet. This ChoRE binding protein

(ChREBP) contains amino-acids in certain positions of the polypeptide chain that

can be phosphorylated (accepting a phosphate group) by protein kinase A. Adding

a phosphate group to serine in position 196 inhibits the protein from entering

the nucleus, and adding a phosphate group to the threonine in position 666

inhibits its binding to the liver pyruvate kinase promoter site, both of which

prevent transcription of the genes involved.

 

It has been known for a long time that cholesterol in the diet suppresses

cholesterol synthesis in the body, mediated through feedback inhibition of SREBP

production.

 

Feeding fat also inhibits carbohydrate metabolism, and the chain of biochemical

events have been worked out by Uyeda's group. Fatty acids are activated by ATP

(adenosine triphosphate, the major energy intermediate in biochemical reactions)

in a reaction that produces AMP (adenosine monophosphate). Thus, an increase in

fatty acids boosts the level of AMP. AMP stimulates a protein kinase to

phosphorylate ChREBP thereby inhibiting it from binding to its promoter site,

preventing gene transcription.

 

Feeding high carbohydrate diet has the opposite effect on ChREBP, in that it

activates the protein to enter the nucleus and to bind to its promoter site,

thus enhancing transcription. Uyeda's group has published new findings on how

this is achieved, via the sugar phosphate, xylulose 5-phosphate, an obscure

terminal player in the hexose monophosphate shunt, a side branch from the main

glycolytic pathway that breaks down glucose.

 

The enzyme phosphofructokinase (PFK) sits at the intersection of the glycolytic

pathway and the hexose monophosate shunt. Its activity is controlled in liver by

the concentration of the metabolic molecule fructose-2,6-diphosphate, which

stimulates PFK to proceed along the glycolytic pathway that eventually supplies

all the building blocks for making fats.

 

Fructose-2,6 diphosphate is produced and destroyed by the same enzyme that

catalyses both the forward and reverse reactions. The kinase activity, which

makes fructose-2,6-diphosphate from fructose-6-phosphate by adding a phosphate

group, is inhibited, while the phosphatase activity, which removes phosphate to

regenerate fructose-6-phosphate, is activated by a cyclic-AMP dependent protein

kinase that donates a phosphate group to the enzyme itself.

 

(Phosphate groups coming on and off small molecules and especially so, big

molecules like enzymes and transcription factors, is the most common way to

change their activities, as biochemists have been finding out for some decades

now.)

 

A high-carbohydrate diet stimulates the kinase activity of this enzyme via a

specific protein phosphatase (PP2A) that removes a phosphate group from the

enzyme. PP2A itself is activated by, yes, xylulose-5-phosphate.

 

In the latest report from Uyeda's group, PP2A and others in the same family,

turn out to be agents that also activates ChREBP (by removing phosphate from

it), so that it can enter the nucleus and bind to its promoter sites. Though

their action on ChREBP, PP2A and family members are involved in promoting the

transcription of a host of genes that make fats out of carbohydrates.

 

This must be one of the most heroic and sustained feats of scientific sleuth in

our time. The group has hunted down all the culprits responsible for integrating

the major metabolic pathways and gene transcription, showing how changing one's

diet appropriately can make metabolic sense. It is definitely not all in the

genes.

 

Genes don't determine our fate. Metabolic intervention can do wonders, for genes

are at least as much the servants as masters of experience.

 

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This article can be found on the I-SIS website at

http://www.i-sis.org.uk/HCMF.php

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General Enquiries sam

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ISIS Director m.w.ho

 

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