Thursday, May 18, 2017

Fructose and metabolic syndrome: Uric acid

Some weeks ago a friend sent me a full text copy of the Naked Mole Rats (NMR) paper

Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat

which demonstrated that they (NMRs) appear to generate and use fructose as a coping stratagem for dealing with hypoxia or even anoxia. This is fascinating and leads back to research in the late 1980s, mostly looking at anoxia in liver or liver cells. I'm guessing that this liver work was funded to look at ways of improving the condition of transplant grafts. Fructose is significantly better than glucose for supporting anoxic liver cells, possibly something you might expect, possibly not. Perhaps in another post.

Anyway. So I've been looking at why fructose is different to glucose and to do this you end up asking rather difficult questions about the upper sections of both glycolysis and fructolysis.

Fructose enters the fructolytic pathway by being phosphorylated very rapidly to fructose-1-phosphate. Given a large enough supply of fructose this phosphorylation can deplete the ATP supply in a cell, most obviously in hepatocytes which bear the brunt of metabolising fructose. This takes place before aldolase generates the trioses which probably (or don't, in the case of fructose) control insulin signalling through mtG3Pdh and the glycerophosphate shuttle.

If this initial ATP depletion by fructokinase is profound it is perfectly possible to take two "waste" ADP molecules and transfer a phosphate from one to the other. This generates one ATP and one AMP. The ATP is useful to the cell and the excess AMP is degraded to uric acid.

This is all basic biochemistry.

In the Protons series I have worked on the (incorrect) basis that fructose should drive the glycerophosphate shuttle hard enough to generate RET (reverse electron transport) and so signal insulin resistance. The degree of insulin resistance should neatly reduce insulin mediated glucose supply by an appropriate amount to offset the fructose and so maintain a stable flux of ATP generation from the combined fructose and glucose. That's not quite how it appears to work. Even before the aldolase step in fructolysis, the body is starting to prepare the process of insulin resistance. This paper is not unique but shows general principles:

Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver

The title of the paper is sneaky, it doesn't give away the answer! Nor does the abstract. If you don't want to read the paper, the missing link is NOX4.

NADPH oxidase 4 (NOX4), if exposed to uric acid (present here from fructolysis induced AMP degradation), translocates to the mitochondria and starts to generate enough hydrogen peroxide* to down regulate aconitase, abort the TCA and divert citrate out of the mitochondria through the citrate/malate shuttle for DNL. This will not just affect fructose metabolism, acetyl-CoA from glucose, entering the TCA as citrate, will also be diverted to DNL.

*The NOX family appear to be the only enzymes with no function other than to produce ROS, mostly superoxide. NOX4 is unique in that it always produces hydrogen peroxide. There is uncertainty if the "E loop" of the enzyme converts superoxide to hydrogen peroxide directly or if this is a docking site for superoxide dismutase, which does the conversion as an accessory module to NOX4.

I think it is a reasonable assumption that the hydrogen peroxide generated by NOX4 will be what signals the insulin resistance induced by fructose, rather than RET via mtG3Pdh. Quite why fructose doesn't drive the glycerophosphate shuttle is a difficult question to answer. Obviously the aldolase products of fructose-1-P (fructolysis) differ from those of fructose-1-6-bisphosphate (glycolysis) but these pathways are very difficult to get at experimentally and I've not found any papers looking at what controls why dihydroxyacetone phosphate from fructolysis doesn't drive mtG3Pdh, but that appears to be the case. There are hints that some activation of the glycerophosphate shuttle does occur but NOX4 seems to be the main player. It might relate to the consumption of NADH in the conversion of glyceradehyde to glycerol and so reducing the need to decrease it using the glycerophosphate shuttle. Hard to be sure.

So. Uric acid is the evil molecular link between fructose and metabolic syndrome via NOX4. And yes, yes, you can block metabolic syndrome using allopurinol to reduce uric acid production in rats but you have to give them a sh*tload of it. After that NOX4 might be considered evil or hydrogen peroxide is evil or aconitase is evil when it's on strike. Lots of drug targets available for molecular cleansing.

My own concept is that there is the necessity to developing insulin resistance when fructose is available so as to limit glucose ingress to offset the ATP from that fructose ingress. If that is done by NOX4, so be it. The facility to deal with fructose by the generation of hydrogen peroxide is not random, it's not some accidental mistake perpetrated by evolution on hapless humans who munched on a few Crab apples or found a little honey. It is an appropriate evolutionarily response to a relatively common occurrence. The fact that uric acid mediated insulin resistance is common to alcohol metabolism as well as to fructose metabolism suggests that this mechanism is a general approach to dealing with a calorie input which takes priority over metabolising glucose.

Developing a drug along the lines of allopurinol to block uric acid production, or an inhibitor of NOX4, or a hydrogen peroxide scavenger to avoid insulin resistance is simply trying to block a perfectly adaptive response to a reasonable dose of fructose.

All that's needed to avoid a pathological response to fructose is to avoid ingesting a pathological dose of the stuff. There is actually quite a lot of evidence to suggest that physiological levels of uric acid production might be beneficial...



cavenewt said...

"All that's needed to avoid a pathological response to fructose is to avoid ingesting a pathological dose of the stuff."

Silly, where's the profit in that?

altavista said...

So on balance, if you were to choose between a dose of PUFA and one of fructose, at a social event, what's the less bad option?

Bob said...

Thanks for the Cliff Notes version of the "Uric Acid Induces Hepatic Steatosis" article. I doubt I would have picked up on the NOX4 significance (in fact, I'm damn sure I wouldn't have), but this line struck me as being Very Bad:

"Compared with controls, uric acid-treated HepG2 cells demonstrated mitochondria that were shorter and smaller (Fig. 5, A and B), suggesting mitochondrial fragmentation."

Further, I notice a Richard J Johnson is the reviewing author (I think that's correct). I also notice he is an author in one capacity or another on many of 56 articles which reference the "Uric Acid" article. Seems further he wrote a couple of books on sugar. Is he possibly the same J Johnson who left comments on Hyperlipid a few years ago?

Great post which strongly supports that the sugar critics are on the right track.

Unknown said...

Thanks for the write up, lol, I enjoyed the parts that weren't way over my head. If I may, I have struggled with gout or pseudo-gout for around 8 years. I'm obese but have lost 125 pounds via the Ketogenic diet while also incorporating intermittent fasting. This lifestyle change has made a tremendous impact on my health as I'm now off all prescriptions and rely solely on supplements and real foods. However, gout in my left big toe remains an issue. My doctor offered up allopurinol but I'd rather take care of it naturally and by addressing the root cause. I take a tart cherry capsule supplement and ingest several antioxidants a day.
Interestingly the last two flare ups have come as I've started extended fasting periods. I have read other articles stating the lack of causative factors between purines and uric acid build up.

My diet is extremely low in carbs, particularly fructose and I avoid high fructose corn syrup like the plague.

Curious if you have any suggestions or advice? Thanks in advance!

John Watson said...

Not sure why this was anonymous but I'm John Watson and look forward to your thoughts.

Boundless said...

re: Seems further he wrote a couple of books on sugar.

The Fat Switch, 2012, Mercola Press. It's about, no surprise, uric acid and fructose.

In my view it's not "the" fat switch, but it's a worthy contribution to understanding our modern metabolic mayhem.

Chris Jefferis said...

@John Watson

I heard dr Veech recommend taking Potassium Citrate to avoid Gout on an interview he did with Dave Asprey.

John Watson said...

I'll order some today, thanks!

Peter said...

Cavenewt, too true……

altavista, I don’t really know on this one… I don’t stress about the occasional dose of either. If you had to choose then maybe fructose has a shorter time course.

Bob, I’m no lover of sugar but I suspect it causes diseases of obesity without necessarily causing obesity per se. There are papers to suggest fructose acts directly on adipocytes to increase DNL but simultaneously increases palmitate output from said adipocytes. Metabolic syndrome w/o the obesity, if the balance of effects is normal sized adipocytes. Another post there some day. PUFA seem a much better candidate as the necessary factor to make adipocytes over sensitive to normal levels of insulin so giving obesity. Not sure about Richard Johnson, might be the person.

John, dropping your uric acid levels is one way to generate an acute flare of gout. It’s a standard side effect of allopurinol. Reduced uric acid starts crystal dissolution which releases crystals in to the joint from the synovium. The other factor is palmitate. This appears to activate certain subtypes of inflammasome which can trigger a flare without reducing uric acid levels (but you can't find the glucose concentration used in cell culture, as so often). Fasting might do this but you would expect the ketones to offset the effect. Interesting. Obviously elevated FFAs in the presence of hyperglycaemia (AKA metabolic syndrome) would certainly drive a flare but that’s not the situation on keto eating. I did a little reading about citrate (Chris) and gout but can’t recall what the conclusion was! One serious problem with gout is that crystal dissolution cause flares but acute rises in uric acid don’t, they just form the crystals which have to dissolve at some stage in the future. Causing a flare.

As an aside the elevation of uric acid via AMP might be triggered by ethanol as its metabolite, acetate, reacts with ATP to give acetate-AMP and PPi and generation of acetyl-CoA releases AMP for degradation. Fatty acids have the same activation step between FFA and acyl-CoA yielding AMP and PPi. The difference is that FFA supply is controlled and both alcohol and fructose are diet intake driven.


Marko Peteri said...

Hi Peter,

I've been a long term lurker and an avid reader; read all your posts from start to now with great interest. I didn't recall you ever mentioning about FGF's such as 19 and 21. So did a quick search with no results. Are you aware of these and their link to measures of metabolic health? Would love to hear your thoughts.

Here is a starting point:

Peter said...

Hi Marko,

Over the years I've read snippets about FGF21 (not picked up on 19). Pattern is usually along the lines of "FGF21 is good". Quick pubmed of "FGF21" and "ketogenic diet". Ketogenic diet is just like starvation without the tedious hunger and eventual death. I kind of never got beyond that level of enquiry!!!!

All the best, Peter

Peter said...

On time from Bill Lagakos


js290 said...

Taubes points out in The Case Against Sugar a few factors that decreases uric acid excretion:

1. insulin resistance/hyperinsulinemia
2. lactic acid from fructose metabolism

He also pointed out that a higher protein diet may actually help increase the excretion of uric acid.

Acutely high levels of uric acid doesn't sound like a problem as long as you can excrete it.

Simple actionable heuristic: more meat and no sugar.