Wednesday, February 14, 2018

TRAK2 and HDL. Do we care?

George posted the link to this editorial in the comments of a post some considerable time ago (so it seems now). So this is another old post which has been lying around on the hard drive... Anyway the link is:

Making sense of a seemingly odd connection

It gives an overview and extension of the ideas included in a paper in the same edition of the European Heart Journal

TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis

Both papers are steeped, very deeply, in the Lipid Hypothesis. As such, the chances of them doing anything useful for anyone at all are vanishingly small. Because TRAK2 reduces HDL formation and knocking it down increases HDL, the obvious conclusion is:

"TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies"

Another target to raise HDL... Sigh, here we go again.

You have to understand that, in the 1950s, the Lipid Hypothesis was bollocks. At no point has anything ever been found to alter that situation. As such I find it very hard to worry about ApoB counts, ApoB sizes, oxidised LDL etc etc etc. including low HDL. Manipulating these numbers by sugar avoidance and saturated fat inclusion will do good. Manipulating them with drugs will bomb. We all still giggle over torcetrapib, anacetrapib, any-other-etrapib and their astronomical, yet useless, levels of HDL.

However, there is that one simple intervention which raises HDL in an effective and totally non toxic manner.

That is saturated fat. Monounsaturated fat is neutral and omega six PUFA lowers HDL. The editorial points out, very perceptively, that not only is 27-hydroxycholesterol a key messenger in HDL formation, but that HDL can be viewed as an export mechanism for free radicals.

Saturated fat raises HDL. Saturated fat drives FADH2 facilcitated RET through complex I in the mitochondria. This process is, undoubtedly, beneficial. Is it the RET which drives the HDL formation? Whether the rise in HDL itself is of benefit or whether the benefits accrue solely from the RET, generated by palmitic acid, which facilitated its formation is an interesting area to speculate in.

MUFA are less effective at RET and HDL generation than saturates. PUFA are useless at both RET and (subsequent?) HDL formation.

HDL, as a vehicle for ROS modified sterols, might be good for you per se. Raising HDL without the ROS/oxidised sterols will be useless. Forget TRAK2.

Just my two penneth.



cavenewt said...

The editorial states "Mitochondria are a major source of reactive oxygen species." (Never mind that I fixated on this sentence because it was about the only thing I could understand.)

I'm only surprised that they didn't suggest pharmaceutically suppressing mitogenesis as a way of reducing ROS.

Peter said...

One day, maybe...

Anonymous said...

G'day Peter. It seems inhibiting evolutionary tools can be lucrative business. Not CETP, of course,(I find that one amusing too), but the precedent left by inhibiting HMG-CoA Reductase and the developing cashcow of PCSK9 inhibitors is a potential pot of gold that many labcoats find it easy to sell their souls for. ApoE e4 is always being toyed with and inhibiting the tide is probably worth a crack. Inhibiting stupidity perhaps, although that might be killing the golden goose.

Speaking of birds, I recently figured out why one of my chooks lays green eggs. That the rest of my family don't find this interesting is a tad disappointing. Especially considering I had no idea the eggs were green until they pointed it out to my genetically flawed eyes.

Your chooks move with you to your new place?

Have a good one.

Peter said...

Oh yes, they're laying a total of three or four eggs a day now, better than mid winter (one a day???). We really need more ex-batts but the accommodation for integrating them is all in use for other chickens.....

OK, why does your chicken lay green eggs????????


cavenewt said...


"inhibiting evolutionary tools can be lucrative business". Phrase of the day!

cavenewt said...

I thought egg color was up to the breed of the bird. I had an Americauna mix that laid green eggs.

Peter said...

cave, yup, our Cream Legbars lay green/blue, Vourvarks white and others brown +/- speckles.... But maybe you can push feed-wise....

Anonymous said...

I figured it was the result of blue and brown layers getting busy. The lady who dropped off half a dozen Australorps this morning was confident it was Americauna mix.


Peter said...

Google google google. Nice colour!

Passthecream said...

Peter, thanks for digging out those fructose facts. It seems quite important to me. Extremely!

Chips, I stumbled over a different HMGCoA reductase inhibition strategy the other day, an easy DIY for the intrepid/foolish bio-hacker. Pigface* is a common plant** near where I live:

In this thesis they discovered that a concentrated extract of the leaf juice is full of HMG. Swallow that and apparently you overload the enzyme ==> the damage of statins without all that messy doctor business.


* Autocorrect turns pigface into 'upgrade'

** plants - best avoided.

Passthecream said...

Whoops, meant to add this to the next item on fructose. Please mentally transpose.

raphi said...

when applying to PhDs a few months back I had to pretend i was excited about this group's forays into "ABCA1 gene expression for cholesterol efflux"

i hate applications

Peter said...

raphi, hahahahaha!

Puddleg said...

Just to clear something up for newbies - SFA is protective


If you stack it up in the blood by eating it when your insulin is high (e.g. in a cake) and you are making even more from carb-driven DNL, the unused TGs will run down the CETP banana tunnel to HDL, there will still be no call from the muscles to use them from HDL, so HDL will have to shuttle them back to the liver.

This will depress HDL, and it will depress you too. Hence TG/HDL - more than HDL- is a word to the wise.