Welcome all seeking refuge from low carb dogma!

“To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact”
~ Charles Darwin (it's evolutionary baybeee!)

Monday, August 22, 2011

Intracellular Fatty Acid Metabolism ~ Background Discussion

Before some of the recent commotion around here, a blog post entitled Let's Play Concentration caught the eye of Paul Jaminet over at Perfect Health.  His commentary then inspired me to write Glucose and NEFA: From Dysfunctional Metabolism to Toxicity.  

In the comments section Paul and I got into a discussion about free fatty acid (NEFA) clearance from circulation.  It seems that this is a subject of a lot of uncertainty.  Indeed when I first started looking into this stuff, way back when, I kept coming across statements like that insulin was required for fatty acids to be taken up by fat cells (three guesses where that traced to and the first two don't count ...).  My inner geek was prompted to look back into this.   This topic is of interest to me as my regular readers are well aware of my near-obsession with NEFA.  {grin}

I got to thinking that we know an awful lot about circulating NEFA levels and fatty acid turnover in adipose tissue.  We also know an awful lot about how fatty acids are ultimately metabolized to produce energy, the biochemistry of which is essentially undisputed.  Additionally, the effects of glucose availability on lipid oxidation and vice versa are quite well understood, although the intricacies of this regulation have not been fully elucidated.  But there's a gap -- a huge one --  in this whole process that we rarely see discussed:
  • How are NEFA transported into cells?  How is this regulated?
  • How are fatty acids stored in cells?  How are they subsequently mobilized?   How is this regulated?
  • How are fatty acids transported into mitochondria to be metabolized?  How is this regulated?
This series will be a, hopefully lay-person friendly, review of the current state of the answers to the questions above from recent peer review literature.  

In writing Glucose and NEFA: From Dysfunctional Metabolism to Toxicity, I really got to thinking a lot about these missing steps and I was reminded of a previous article I blogged on here, as well as Paul's fascinating take on same.  First the links:
In the spirit of Paul's post, just as our bodies continually cycle both glucose (glycogen) and fatty acids on a whole body basis between stores to regulate circulating levels, so, too, we have analogous phenomena occurring inside our cells.  The transport of glucose and fatty acids into the cells is akin to dietary intake for the whole body.  Once inside is what I want to shine a light on!

It was perhaps somewhat coincidental that a journal quite recently highlighted the topic of lipid droplets that I've been meaning to get to on this blog ever since.  Lipid droplets (LD) are actually organelles, much like mitochondria are organelles.  Organelles are structures in the cells with specialized functions.  Lipid droplets were thought for a long time to be passive depots for triglyceride storage within the cells -- much like adipose tissue was once viewed.  But it is now understood that these "lipid droplets" are more than just inert "droplets" after all, and are intricately involved in regulating fatty acid metabolism within the cells themselves.  Lipid droplets are to cells what adipocytes/fat is to the whole body.  The cytosol - intracellular fluid - is to cells what blood/lymph are to the whole body.  And it's a looser analogy, but the mitochondria are to the cell, somewhat like the peripheral cells to the whole body.  Let's do this another way and just look at fatty acids:

Whole body:     
FA stored as triglycerides in adipocytes  NEFA in circulation NEFA uptake into cells

Individual cell:
FA stored in lipid droplets   NEFA in cytosol  NEFA uptake to mitochondria  ß-oxidation

The NEFA that are taken up by the cell have two fates:  oxidation in mitochondria or storage in LD, much like dietary fats have two fates: uptake/use for energy by cells or storage in adipose tissue.  We spend a lot of time talking about the fairly well characterized blue arrows above.  Of course hormones regulate these steps.  But no mistake is so common as equating the forward direction of the release from fat cells with that last step of actually "burning" the fat for fuel.  The green arrow is somewhat discussed in terms of the competition between glucose and fatty acids as a source of the acetyl CoA that is the primary "fuel" for the rest of the mitochondrial "engine".  I'm going to add to this discussion the contribution of regulated fatty acid transport across the mitochondrial membrane.  But first, this series is going to address those pink arrows.  First discussing the role of transport and it's regulation (or rather somewhat lack thereof) on the nutritional state of the cell.  But probably most importantly the role of LD in sequestering fatty acids into the more inert triglyceride form.  

I've discussed frequently here how, aesthetics aside, we want excess fat to be stored in its proper place:  the adipocytes designed for just this purpose.  That insulin regulates this and promotes this is not in question.  And most importantly, metabolic derangement associated with obesity is almost assuredly due a breakdown in this protective role of insulin:  failure of insulin to suppress NEFA release appropriately and/or impaired NEFA uptake.  In obesity this breakdown occurs in over-stuffed fat cells, and leads to the elevated circulating NEFA that set the ball rolling.  

I propose we have a similar breakdown at the cellular level:   Excess NEFA delivered to the cells are stored in LD which is protective of the cell.  Overnutrition of the cell, due to an inability to refuse the excessive delivery from circulation, leads to lipid droplets of size and/or number that no longer function properly in this regard.  This leads to excessive NEFA in the cytosol.  It is plausible that this forces the mitochondria to utilize fatty acids throwing glucose metabolism out of whack.  Actually, that's not my proposal, it is the general knowledge and thinking of those researchers working in this area.  I hope that by sharing some of this information I've come across, and highlighting the "workings" at the cellular level, we can put one of the biggest myths in the arena of low carb to rest for once and for all:  

My goal:  R.I.P. The Myth of the Starving Cells.

This is a bit of a preview of something to come here.  I'm unsure if it will end up being a couple of posts, or develop into a research-review style premium content series.  I guess that will depend on the interest folks take in the initial offerings and the amount of time involved.  Sorry to be a tease there, but I really just don't know.


Ned Kock said...

While I don't agree with the conclusions 100%, I think you present arguments in a very compelling way CS. It is great to have different views argued like that, it gets us closer to the truth. That's the reason for what I said about you in my interview with Jimmy:

When people are looking for the truth they have to develop a thick skin, and be willing to look at the same data from different angles.

Jeremy said...

Let me be one of the first to say that I definitely appreciate the continued education in fat metabolism and dysfunction.

Here is my question: in an iso- or hypo-caloric state, even in an obese IR individual, what's the danger of having elevated NEFA's? I understand the correlations shown by the studies, and I understand the causal pathways that lead to suppression of glycolysis and non-oxidative glucose disposal in peripheral (non-adipose) tissues. However, in the absence of elevated blood glucose levels (e.g., on a VLC diet, but otherwise as well), I don't understand the concern.

I keep going back to your post "From Dysfunctional Metabolism to Toxicity" (superb btw), and I just get a bit lost at the bottom when you disagree with Paul that it's not just glucolipotoxicity that is the danger, but elevated NEFA's overall. I haven't read the ketogenic-diabetic rat study you reference, but it seems to me that since rats (and accompanying studies) are pretty much always hypercaloric, it wouldn't necessarily tell us much about an iso- or hypo-caloric state, even for one predisposed to diabetes.

Thanks, and again, love the continued education in metabolism!

Evelyn aka CarbSane said...

Hi Ned! I had intended to thank you for the mention ... I had a little chuckle though as I could swear that was the sound of Jimmy's teeth gnashing in the background! I don't remember what came up at the time, and by the time I got around to it, it seemed so hopelessly delayed as to seem self-serving. Anyway, I enjoyed your interview!

Hi Jeremy! Long time no see :-) Thanks for reading and you're welcome for anything I can add here.

OK let me give the glucotoxicity v. lipotoxicity v. glucolipotoxicity thing a Cliff Notes summary. Since chronic hyperglycemia is an endgame manifestation, the effects cannot be extrapolated to short term glucose spikes. And actually it is impossible to look at GT without the confounding LT. What I'm trying to say is that there may not even be such a thing as pure glucotoxicity b/c we already have some degree of lipotoxicity as it seems a necessary precursor to hyperglycemia. What I tried to do in that post was distinguish between a "phase 1" LT if you will where excess NEFA interfere with function in various ways, and a "phase 2" -- that appears to be GLT -- where glucose and fatty acids act in concert and actually kill off cells. Make sense?

Here's the keto study

Evelyn aka CarbSane said...

BTW Jeremy, so long as NEFA delivered is NEFA oxidized, there seems to be no problem. Trained athletes have lipid stores in skeletal muscle exceeding those of obese women. Their regular use of the fatty acids => high turnover = no apparent problem.

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