Non-Esterified Fatty Acid in Plasma- MCQ of the Day

 Non-esterified fatty acids in the plasma
a) circulate in an unbound state
b) bind to lipoproteins and circulated
c) bind to albumin and circulated
d) bind to the fatty acid-binding protein and circulated

The objective of the above question is to discuss
- the function of non-esterified fatty acid and derivatives
- the metabolism of non-esterified fatty acids.
- the origin of non-esterified fatty acid in plasma
- the role of non-esterified fatty acids in diabetes

Answer and Explanation
Fatty acids play critical roles in the energy metabolism of mammals. The bulk of fatty acids are stored in adipose tissues as triglycerides and mobilized during the energy-deprived state to tissues such as skeletal muscle, heart to fulfill their energy requirements. In addition, they are building blocks for phospholipids and other complex lipids which are a component of the cell membrane, a precursor for biologically active substances such as leukotrienes, prostaglandins, etc., and; insulation for nerve tissues.

Triglycerides are a major dietary source of fatty acids which are absorbed in the small intestine. The absorbed triglycerides are incorporated into chylomicrons. Chylomicrons are the lipoproteins that are formed in intestinal cells and once triglycerides are loaded into it to form mature chylomicrons, they are transported via lymphatics to peripheral tissues. The triglycerides are predominantly taken up by adipose tissue.

The endothelial lipoprotein lipase hydrolyzes triglycerides into non-esterified fatty acids (NEFA) and glycerol, and facilitate uptake by adipose tissues. These NEFAs enters the adipose tissues re-esterified into adipose tissues. Minimum quantity of NEFAs escape into the bloodstream; reaches hepatocytes where they are taken up, re-esterified into triglycerides, incorporated into very low-density lipoproteins.

NEFAs exist in a low concentration in plasma and interstitial fluids. Because of the low solubility of non-esterified fatty acids in aqueous solutions, they require binding and transporting protein in extracellular fluids. The fatty acids are bound asymmetrically to hydrophobic pockets of the albumin. Plasma albumin possesses multiple binding sites NEFAs with moderate to high affinity for them. 
The amphipathic nature of fatty acids facilitates binding to albumin by both hydrophobic and electrostatic interactions. Albumin-FA interaction also facilitates the efficient uptake of fatty acids by target tissues such as cardiomyocytes.

Diabetes mellitus, NEFAs, and Albumin:
Increased NEFAs have been associated with insulin resistance and microvascular complications in diabetes. Increased blood glucose in diabetes mellitus has been shown to modify proteins such as hemoglobin and albumin. The non-enzymatic glycation of these proteins leads to altered function and the formation of advanced glycation end products that elicit an inflammatory response and microvascular derangements. 
Recently, a study was conducted to investigate whether the glycation or glycoxidation of albumin is relevant to NEFA related pathobiology. The investigator hypothesized that modification of albumin due to hyperglycemia potentially results in an impaired binding to NEFAs. As predicted, the modification of albumin invitro reduced binding to NEFAs to albumin. These changes were similar to those observed in diabetic individuals who have high NEFAs, and the binding affinity toward albumin is reduced. 
The result showed that hyperglycemia leads to glycation and oxidation of albumin, reduced binding affinity. These events lead promote platelets activation and aggregation. The impaired ability to sequester platelet-derived NEFAs namely arachidonic acid may account for these effects. 
Thus, increased NEFAs and increased glycation of albumin may provide a proatherogenic environment characterized by diabetes.

The correct answer is option C