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:

• My blog posts:  Fat Futile Cycling ~ From Carb Excess??!! , More lay-person friendly version
• The journal article: Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity  Dulloo, et.al. 2004
• Paul Jaminet's blog:  How Does a Cell Avoid Obesity?

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.