Those NEFA are Pesky Things!

NEFA = Non-Esterified Fatty Acids aka Free Fatty Acids (FFA)
(By the way, I've just always preferred the NEFA acronym because in my head it sounds out more nicely than "ef ef ay" -- and for whatever reason, I sound it out "knee fah", though a reader once wondered about "neh fay".  I don't know there's a correct pronunciation for acronyms like this!)
On a hypothetical Metabolic SAT test NEFA are to lipids what glucose is to carbohydrates and amino acids are to proteins.  These are the forms of the three macronutrient classes that are absorbed/transported into and out of cells and circulation and the forms that enter into the energy-producing pathways.  By contrast, lipids are stored as triglycerides (aka triacyl glycerols, TAG), while carbs are stored in rather more limited quantities as glycogen, and there exists essentially no true storage depot for protein in excess of "tissue maintenance" needs.

Excess protein becomes toxic as it must be stripped of it's nitrogen moiety prior to oxidation in metabolic pathways.  Buildup of the product of this (urea) can occur if one overwhelms kidney excretion capacity leading to a number of deleterious effects.  Still, unless one is trying to subsist on skinless chicken breast or rabbit flesh for their sole nutritional source in weight maintenance, it is unlikely to be toxic or lead to damage.  (Once compromised, however, protein excesses can be an issue for kidneys, etc.) .  In the LC-aware (by that I mean low carbers/advocates and those associated with lifestyles embracing LC), we are all cognizant of the toxic effects of hyperglycemia = glucose excess.  I consider it unfortunate that there is not at least equal awareness and attention paid to toxic levels of the lipids though.  Lipotoxicity is not a controversial concept in the realm of metabolic research, however it goes almost totally ignored in low carb circles.   I think this stems from the reactionary response to the misplaced Keys-ian dietary lipophobia -- if low fat is wrong-headed, only the 180 degree opposite must be right!  A lot of research on lipotoxicity is couched in the not-so-pleasant context of gluttony and sloth and how high-fat diets promote it.  Indeed it is simply chronic energy excess to adiposity past some individual threshold that is the ultimate culprit.  (In the case of the liver, excessive fructose or alcohol seem to cause hepatic lipotoxicity even in absence of whole-body caloric excess).

At the risk of tooting my own horn, I like to think that as a blogger my greatest achievement has been to heighten awareness of the role of NEFA in metabolism and disease.   Obesity, metabolic syndrome and diabetes all share one thing in common:  hyperNEFAemia (if you don't pronounce the "A", hyper-knee-fee-mia rolls nicely off the tongue!).    Each time I pursue a different road, a new hypothesis, whatever, it seems they always eventually lead back to NEFA.  The precipitating factor producing hyperNEFAemia being adipocyte dysfunction.  Whether it's adipocyte-IR leading to insufficient suppression of HSL by insulin resulting in excessive NEFA release, or dysfunction on the uptake side of NEFA hydrolyzed from dietary chylomicrons (almost assuredly a dysfunction in the ASP pathway), all roads seem to lead back to those pesky NEFA.  

And so it was yesterday when I was off trolling other blogs where I dare not post (sarcasm), and reading the comments, that I came across a comment by Jack Kruse, Neurosurgeon!   Apparently there's this whole pair of dimes shift revolutionizing the biological world revolving around ROS.  He writes:
Mainline scientific theories may have long lifespans but are inevitably overturned as accumulating evidence renders them obsolete and brings alternative theories to the fore. This happened in physics in 1905 with the advent of the theory or relativity and it happened 150 yrs ago in biology when many diseases became explainable not in the established terms of “spontaneous generation” but instead in terms of germs and then viruses. It has now happened in molecular biology with ROS and antioxidants.
When such a major change in paradigm happens there is usually a period of significant and often bitter controversy between scientists seeking to hold on to the theories of the older paradigm and those espousing the newer one. I think your comment reflects that. This is followed gradually by changes in basic thinking patterns and a subsequent long period of fertile discovery. This is what I am trying to convey a bit here.
Here are few links off my current hard drive at home. My master list is at my office and I don't have access to it. ... [last link]
For whatever reason, I happened to go look at just the last link:
Diabetes mellitus type-2 (DMT-2) is a hyperglycemic syndrome with several characteristic features. It continues to rise unabatedly in all pockets of the world, parallels with affluence and can be controlled but not cured. It has a definite involvement of genetic component but environmental factors play overwhelmingly dominant role in etiopathogenesis. Insulin resistance (IR) and obesity are singular instigators of DMT-2. The various events cause critical defects in insulin signaling cascade followed by beta-cell dysfunction. Over a period of time, numerous other metabolic aberrations develop, resulting in diabetic complications which could be both vascular (cardiovascular complications, nephropathy, neuropathy, retinopathy and embryopathy) or a-vascular (cataract and glaucoma etc). It has been proposed that all these abnormal events are initiated or activated by a common mechanism of superoxide anion, which is accompanied with generation of a variety of reactive oxygen species (ROS), reactive nitrogen specie (RNS) and resultant heightened oxidative stress (OS). Provoked OS causes IR and altered gene expressions.  Hyperglycemia induces OS through multiple routes : a)stimulated polyol pathway where in ≤ 30% glucose can be diverted to sorbitol and fructose, b)increased transcription of genes for proinflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1) c) activation of protein kinase-C (PKC) leading to several molecular changes d)increased synthesis of Advanced Glycation End Products (AGEs) e)changes in a receptor far AGEs and f) autooxidation of glucose with formation of ketoimines and AGEs. All these processes are accompanied with alteration in redox status, ROS, RNS and OS which trigger DMT-2 and its complications. Initial hurriedly planned and executed experimental and clinical studies showed promising results of antioxidant therapies, but recent studies indicate that excess intake/supplement may have adverse outcomes including increased mortality. It is advocated that antioxidants should be given only if preexisting deficiency is present. Selection of antioxidant is another important aspect. Lastly but most importantly the impact of OS is not obligatory but facultative. As such only those diabetic patients will be benefited by antioxidant therapies that have impelling punch of prooxidants.     {Disclaimer:  Acronyms not mine!!}
Now, clearly the development of ROS and related molecules and their impact on mitochondrial, cell and overall organism health is not some novel concept.   But what I found rather more interesting was Figure 15 on p. 335 of the article.

Yep!  Those NEFA sure are pesky suckers.  I would also point out that this example of a "paradigm shifting" citation from someone who accuses me of being steeped in dogma (conventional, I presume) is rife with that same dogma.  For example:  
... Simple obesity is due to excess energy intake than expended....
... The etiology of simple obesity is multifunctional andmultimechanistic.  The fundamental defect in this condition is lopsided energy management by body:  more calories consumed than expended.  Besides genetic inclination, the definite social, behavioral and environmental courses are increased consumptions of high energy foods particularly fast foods, increased frequency of food intake, indiscriminate selection of foods, especially refined foods, excess of trans fat and higher glycemic load carbohydrates.  The social aspects influencing the caloric intake are overzealous advertising of sweetened beverages and foods.  All these factors in concert tend to alter metabolism and appetite due to aforesaid reasons resulting in the tilted activities and excess energy intake, the body thus starts gaining weight.  This gain is practically confined to accumulation of fat in adipocytes which are centre of adiposity from where aberrant signals originate to initiate various abnormal biochemical outcomes.  The struggle begins between physiological and non physiological forces and diseases set in when physiological processes are overwhelmed.  The positive energy balance adversely affects almost all cells of the body but major affected ones are adipocytes, hepatocytes and beta-cells of Langerhans in pancreas.  Obviously, these abnormalities make obese persons very prone to DMT-2 ....
Perhaps ... just perhaps ... this "dogma" of over-nutrition is not so misguided after all.   And also perhaps, it is time to look more closely on the impact of diet on circulating NEFA levels (in the context of weight maintenance) with the same skepticism and, dare I say, fear, as blood glucose levels and hyperglycemia are viewed.  Does this mean a low fat diet is not such a bad prescription after all?  Perhaps.  Or perhaps whatever diet finds you in caloric balance at some level of adipose tissue mass below some individual  threshold allowing for storage where it's supposed to be -- in the fat cells -- where it doesn't muck up your mitochondria, is that nutritional nirvana to be sought after.


re "Jack Kruse, Neurosurgeon!" Now with Kungfu grip!
CarbSane said…

What levee are you on?
Kindke said…
Those pesky NEFA!!!!

Why o why didnt evolution evolve us to run purely on carbs!!! Then everything would be fine!!
@ evelyn bwahahahahaha................ :)
cwaiand said…
i think evolution did intend for us to run primarily on is the fuel of choice for brain and muscular function.
Lerner said…
I agree 100% about the 180 degrees. It's a non sequitur and a dangerous gamble to go from "Keyes was wrong" to "I can eat limitless fat with zero harm".

and at risk of sounding like a repeating parrot, there is the Homburg Cream and Sugar Study:

which says: postprandial TAG is highly associated with CVD in normoglycemics

Wait! Hahaaa! I just did a websearch and inadvertently came across this: "CarbSane Explains Why She Is A Taunter Of Gary Taubes"

I can't stop laughing from the title and I'm going to
listen to it now...
CarbSane said…
LOL ... Please excuse the nervous laughter. Hard to believe that was taped almost a year ago! My how things change. Betcha I won't be asked on his new podcast for head-to-head contrarian viewpoints! He's wiped the comments on that clean.
Lerner said…
David vs Goliath
Frodo vs Sauron
Evelyn vs Gary what's-his-name


Btw, as people have been reading study after study, would anybody out there like to actually be in one?

The VITAL study is recruiting-> using vit D and fish oil vs incidence of CVD, stroke and cancer. From the prestigious Brigham and Women's Hospital, men > 50, women > 55, no prior related disease.


Now for something actually on topic: whatever happened to the concept of "labile protein stores" ?
Quarrel said…
Nonono, it's an odd numbered day, CHO = bad, FFA = good!

(along with bonus Hepatic de novo lipogenesis from CHO dig!)

Exhibit A:

CarbSane said…

which says: postprandial TAG is highly associated with CVD in normoglycemics

PP TAG clearance is a big issue. The inefficient clearance of TAG fatty acids seems to precede the IR of adipose tissue/excessive lipolysis. And guess what fasting hormone level correlates with this and can serve as a biomarker? Forget pesky, let's try exASPerating!

Q!! Only high glycemic carbs ... phew!!
Anonymous said…
I am outraged by the ridiculous history Kruse is espousing. 150 years ago? I am quite certain that "spontaneous generation" was debunked centuries before 1861!!! And germs were discovered upon the development of sufficiently powerful microscopes. (Since semen was one of the first substances examined, the "homunculus" theory of reproduction was skewered at the same moment.)

And physics... don't get me started. For one thing, he can't spell; for another thing, he doesn't have a clue what he's going on about. I could spend all day ranting. To be fair here, Einstein did take the same data everyone else was aware of, and, because he was young (and bored), looked at it a slightly different way. Most non-scientists have this mistaken apprehension that special relativity just leapt--spontaneously generated, as it were--out of Einstein's wooly gray head. (Pretty sure his hair wasn't grey when he wrote his most important papers. Also hadn't been forced, as a Jew, to flee Europe yet, but whatevs.)

Evelyn, your "pair of dimes" quip was hilarious--and spot on!
Sanjeev said…
> have this mistaken apprehension that special relativity just leapt

Only 2 people I believe have been documented to have come anywhere near AE - Poincaré and Lorentz.

> "spontaneous generation" was debunked centuries before 1861

The first major inroads started around the late 1670s, and accelerated after Van Leeuwenhoek popularized the microscope & built much better ones than had been available to that time.
Sanjeev said…
your point is taken though, the historical facts are being cast in a light that serves the rhetorical purpose; from my memory of the science and philosophy of the time, relativity didn't overturn anything that wasn't ready to be discarded - more of a synthesis than an upsetting of the apple cart, or the goring of anyone else's sacred cows. It was accepted without much of a fight, unlike for example, Pons & Fleischmann's announcement, or the experience of last year's Nobel Laureate for the quasicrystal work.

it answered questions that most in the field were familiar with and acknowledged needed answering.
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Steve said…
Carb Sane, what do you make of this? The vegans had higher NEFA levels but better insulin sensitivity.
carbsane said…
The difference in NEFA is not statistically significant. This is also fasting and NEFA in the postprandial state are likely more important. The lower IMCL indicates less "excess" NEFA delivered to the cell. This is an older post and really needs some fleshing out in terms of the whole of the science. Somehow it got on an SEO thing or something!
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