Non-esteriﬁed fatty acid metabolism and postprandial lipaemia
Yet another gem from ... who else? ... Keith Frayn!
Non-esteriﬁed fatty acids (NEFA, or free fatty acids) are an important metabolic fuel. Both the concentration of NEFA and their ﬂux through the circulation vary widely from hour to hour, reﬂecting nutritional state and physical activity. Inappropriately elevated plasma NEFA concentrations may have a number of adverse effects on both carbohydrate and lipid metabolism.
As my regular readers know well, this is a focus of my research.
These adverse effects are likely to be most marked in the postprandial period, when NEFA release from adipose tissue is usually suppressed. Although the regulation of NEFA release in the postabsorptive state is well understood in molecular terms, the predominant pathway for release of NEFA in the postprandial state is the action of lipoprotein lipase (LPL) in adipose tissue capillaries on chylomicron-triacylglycerol (TG). Fatty acids released by LPL may either be sequestered in the adipocytes by esteriﬁcation, or released as NEFA into the plasma. The regulation of this branch-point, which may be of crucial signiﬁcance for postprandial metabolism, is not well understood. Factors stimulating tissue retention of fatty acids include insulin and acylation stimulating protein.
This summary is why studies like this one, that I've blogged on previously, do concern me. If you've achieved insulin-deficient nirvana through extreme carbohydrate restriction, you release NEFA in addition to those that escape from the adipose tissue. The NEFA levels nearly tripled four hours after the high fat low carb meal and appear to still be rising for the lean subjects, and they are significantly elevated above normal for the obese (almost 4X those of lean levels).
There is considerable indirect evidence that impaired regulation of this step occurs in insulin resistance and other conditions collectively recognised by an elevated concentration of apolipoprotein B (hyper-apo B). Inappropriate release of NEFA in the postprandial period is likely both to reduce the sensitivity of glucose metabolism to insulin and to accentuate postprandial lipaemia. Further study of the regulation of this pathway is much needed
Below is a side-by-side screen shot of NEFA for all tissues and Adipose Tissue metabolism:
Fatty acid movement across the adipose tissue capillary wall is bi-directional, unlike the situation in any other tissue (Fig. 3). In the fasting state, fatty acids are predominantly generated within the adipocyte by the action of HSL on stored TG, and ﬂow in a net sense out into the capillaries and thus into the systemic circulation for delivery to other tissues such as skeletal muscle and liver. In the fed state, however, adipocyte fat stores must be replenished. This occurs by the action of lipoprotein lipase (LPL) in the adipose tissue capillaries upon circulating TG in the TG-rich lipoprotein particles, very-low-density lipoproteins (VLDL) and chylomicrons. In the postprandial period chylomicron-TG is the preferred and major substrate for adipose tissue LPL, competing with VLDL-TG to the extent that clearance of the latter in adipose tissue is markedly reduced [9–11]. The fatty acids released by LPL may ﬂow into the adipocyte for esteriﬁcation and storage as TG. Thus, the net transcapillary ﬂux of fatty acids in the fed state must be inwards from capillaries to cell.
The implications of the emphasized statement above are at least something to be considered. Low carbers are usually very proud of their low fasting triglycerides. But what of 24-hour exposure when eating a high fat diet so that one's blood runs replete with chylos?
Even in normal, healthy subjects adipose tissue ‘capture’ of LPL-derived fatty acids never seems to be complete in the postprandial period. A proportion always ‘escape’ into the venous plasma. ... Thus, an important metabolic branch point may be identiﬁed in adipose tissue in the postprandial period. This is ‘downstream’ from LPL and determines the fate of fatty acids released by the action of LPL: entrapment in adipose tissue or release into the plasma. We and others have argued fully elsewhere [18–21] that efﬁcient ‘trapping’ of fatty acids in adipose tissue in the postprandial period is a determinant of a ‘healthy’ lipoprotein phenotype, and that impaired trapping may lead to a multitude of adverse consequences, amongst which will be the generation of the features of hyper apo B  or the atherogenic lipoprotein phenotype.
As I've been trying to convey, putting fat where it belongs is a *good thing*. If we can't properly trap fat eating VLC, that's NOT.
The rate of fatty acid uptake and esteriﬁcation is undoubtedly highly controlled. It has been known since early work with adipose tissue in vitro that this pathway is stimulated by insulin , and this is also clearly seen in vivo [35,36]. It has often been assumed that the action of insulin is to increase glucose uptake and hence the supply of glycerol 3-phosphate necessary for fatty acid esteriﬁcation, but measurements in vivo suggest that the stimulation of fatty acid uptake by adipose tissue by insulin is not accompanied by increased glucose uptake: rather, an increased proportion of glucose is directed into glycerol 3-phosphate synthesis . This implies that insulin stimulates directly either fatty acid transport or one or more of the enzymes of fatty acid esteriﬁcation. Whilst insulin is undoubtedly important in the postprandial regulation of fatty acid movement in adipose tissue, in recent years another regulator of this pathway has been described, acylation stimulating protein (ASP) [37,38]. ASP is a more potent stimulus to fatty acid uptake and esteriﬁcation in adipocytes than is insulin. ASP is the product of the interaction of components of the alternate complement pathway secreted by adipocytes themselves, and is identical to the peptide otherwise known as C3a-desarg . Its production is markedly stimulated by the presence of chylomicrons . Thus, ASP can be seen as a key part of a system of ‘microenvironmental regulation’  in adipose tissue...
...In respect of glucose metabolism, elevated NEFA concentrations will impair glucose uptake in skeletal and potentially cardiac muscle by mechanisms which are part of the glucose-fatty acid cycle [43,44]. The net effect will be a diminution of sensitivity of glucose metabolism to insulin. This will be reinforced by the marked stimulatory effect of NEFA on hepatic glucose output, usually suppressed during the postprandial period . In addition elevated NEFA concentrations may reduce hepatic insulin clearance , thus leading to systemic hyperinsulinaemia and subsequent downregulation of insulin-sensitive processes. Inappropriate NEFA release in the postprandial period can therefore be seen as a cause of insulin resistance and potentially risk of type 2 diabetes, and elevated NEFA concentrations are indeed a risk marker for that condition .
It's amazing the things one discovers following the work of researchers forward ... or in this case sideways. Please do go read this in its entirety for yourselves. I've probably not done it justice even with extended excerpts.