Deleterious Effects of Elevated NEFA - I: Monocytes and Vascular Adhesion

Elevated Concentrations of Nonesterified Fatty Acids Increase Monocyte Expression of CD11b and Adhesion to Endothelial Cells

First, a layperson friendly description of Monocytes:

Monocytes are a type of leukocyte or white blood cell which play a role in immune system function. Depending on a patient's level of health, monocytes make up between one and three percent of the total white blood cells in the body. They can be counted as part of a blood test, and changes in their levels can indicate changes in a patient's health. As a general rule, a low monocyte count is a good sign, and a high count indicates that a problem is present...

... Levels of monocytes in the blood tend to rise when someone has an infection, because more of these cells are needed to fight it. Monocytes can also increase in response to stress and other factors. A high monocyte count may be referred to as monocytosis, and it is typically addressed by determining why the count is so high, and addressing the problem. For example, if monocytes are elevated because of an inflammation caused by a viral infection, the patient would be given medication to kill the virus and bring down the inflammation.

My Study Summary:  The investigators incubated human monocytes with NEFA (physiological FA composition) and measured adhesion and the expression of a protein associated with adhesion.  NEFA increased adhesion in a dose and time related manner.  In other words, the more NEFA in the incubation medium and the longer the incubation, the greater the increase in adhesion (although it did peak at 48 hrs then fall off at 72 hrs).  NEFA also increased CD11b, a protein termed an integrin involved in the adhesion of monocytes to endothelial cells (vessel walls).

From the Discussion:

Monocytes from subjects with diabetes have been demonstrated to bind to endothelial cells in greater numbers than monocytes isolated from subjects without diabetes.¹⁵ ....However, there is increasing evidence that elevated levels of NEFA may have numerous proinflammatory effects on vascular cells in subjects with insulin resistance and diabetes. The goals of this study were to test whether elevated levels of NEFA could contribute to the enhanced adhesion of monocytes to endothelial cells and to ascertain the mechanism by which NEFA may achieve this effect.

We first demonstrated that exposure of monocytes to a physiological mixture of NEFA for 48 hours led to maximum monocyte adhesion; adhesion increased in a concentration-related fashion. This is the first report to our knowledge of increased monocyte adhesion resulting from prolonged exposure to a physiological mixture of fatty acids. Although NEFA-treated monocytes showed increased adhesion to unstimulated endothelial cells, pretreatment of endothelial cells with LPS greatly enhanced monocyte binding as has been previously reported.¹⁷This indicates that one consequence of prolonged exposure of monocytes to NEFA may be to prime these cells to bind to activated endothelial cells. This may be particularly relevant for the development of atherosclerosis where monocyte accumulation is enhanced at sites of vascular inflammation, where upregulation of a variety of adhesion molecules occurs. Monocyte firm adhesion usually requires interaction of integrins ^... Our studies indicate that NEFA stimulates the expression of both message and protein for CD11b [one such integrin]...

Our studies also demonstrate that NEFA-induced generation of ROS may mediate monocyte adhesion to endothelial cells. This was demonstrated by several lines of evidence. First, maximum stimulation of ROS by NEFA occurred after the same duration of exposure and at the same concentration as that of monocyte adhesion (Figure 1). Second, addition of glutathione or BHT, 2 structurally different antioxidants, prevented both production of monocyte ROS and monocyte adhesion (Table). Moreover, depletion of GSH with diethyl maleate before addition of NEFA further increased ROS generation and monocyte adhesion. Third, inhibitors of NADPH oxidase (a major producer of ROS in monocytes), but not those of nitric oxide synthase, xanthine oxidase or the mitochondrial electron transport pathway were shown to be effective inhibitors of monocyte adhesion. These latter experiments also demonstrate that NADPH oxidase appears to be an important and specific source of NEFA induced ROS in monocytes. Our results are consistent with those of previous studies that have indicated that inhibitors of NADPH oxidase, but not various mitochondrial complex inhibitors, inhibit ROS release from THP-1 cells induced by high glucose conditions, and that inhibitors of PKC, a recognized stimulator of NADPH oxidase, also reduced ROS generation and monocyte adherence.¹⁸ ...

Although levels of NEFA are increased in individuals with diabetes, similar degrees of elevation are frequently present in individuals with insulin resistance and might be expected to increase adhesiveness of monocytes in individuals with insulin resistance as well as in those with diabetes. Consistent with this notion, insulin resistance, as measured by a direct measure of insulin mediated glucose uptake, was a significant predictor of monocyte adhesion to endothelial cells.¹⁹ Although adipose tissue is a major source of serum NEFA, triglyceride-rich lipoproteins may also provide free fatty acids directly to the artery wall. Insulin resistance and type 2 diabetes are associated with increased levels of just such lipoproteins, resulting primarily from increased hepatic secretion of triglyceride-rich very-low-density lipoprotein and exaggerated postprandial hyperlipidemia.²⁰ ...

In summary, these studies demonstrate that elevated levels of NEFA, as frequently occurs in conditions of obesity, insulin resistance and type 2 diabetes, may contribute to increasedmonocyte expression of CD11b and enhance their adhesion to activated endothelial cells. These data provide another example of elevated levels of free fatty acids inducing inflammation and support the concept that modalities that will diminish levels of NEFA or inhibit their intracellular signaling may contribute to reduced atherogenesis in these individuals.

There's a LOT of info in this discussion -- I excised some of it to focus on the direct NEFA response.  If a low carb diet results in chronically elevated NEFA this does not seem to be a healthy outcome.  If, however, the impact is more acute, perhaps this is not sufficient to "prime" the monocytes.  However since the carb-restricted state is metabolically analogous to the fasted state, I fear this is more chronic than acute.

Therefore in deciding the proper macronutrient composition of a "healthy diet", NEFA levels, IMHO, should not be overlooked.