Free Fatty Acid Transport and Metabolism in Endothelial Cells: Localized Increases in Utilization and Effects of AMPK Activation

This article [Hamilton and Kamp, 1999: (http://diabetes.diabetesjournals.org/cgi/reprint/48/12/2255)(http://www.ncbi.nlm.nih.gov/pubmed/10580412?dopt=Abstract)] is really terrific, and the authors discuss all of the unanswered questions about the transport and oxidation of free fatty acids (FFAs) by endothelial cells and other cell types. The authors point out that FFAs may cross plasma membranes by the passive, flip-flop "mechanism" and not just by active transport. The authors also discuss the fact that localized increases in the generation of and utilization (oxidation) of FFAs, by endothelial cells and other cell types, can seriously confound attempts to view FFA metabolism in terms of strict rules. Dagher et al. (2001) [Dagher et al., 2001: (http://circres.ahajournals.org/cgi/content/full/88/12/1276?ijkey=6528ccf131742699838075ec892dca9444f4806b)(http://www.ncbi.nlm.nih.gov/pubmed/11420304?dopt=Abstract)] found that the activation (phosphorylation) of AMP-activated protein kinase (AMPK), by AICAR, in the presence of carnitine, increased the utilization of fatty acids as energy substrates substantially. Dagher et al. (2001) also found that some of the fatty acids were being generated from intracellular pools, a fact that could lead to erroneous conclusions in the context of research focusing exclusively on changes in plasma FFA. Hamilton and Kamp (1999) note that the estimates of the solubility of palmitate have varied 100,000-fold (p. 2257) (0.1 nM vs. 10,000 nM at pH 7.4), and the movements of FFAs in and out of membranes is extremely dynamic. AMPK activation is likely to occur in the context of insulin resistance, given that glucose availability is obviously a major factor that maintains the ATP/AMP ratio high and prevents AMPK activation in cells. But AMPK activation is regarded as a "good" or "desirable" strategy for increasing glucose transport. So insulin resistance impairs ATP production and can thereby activate AMPK and increase glucose transport, and some treatments for diabetes are thought to increase glucose transport mainly by providing an extra stimulus for AMPK activation (they augment AMPK activation). But what about the effect of AMPK activation on FFA metabolism? I'm not saying that fatty acids are very effective energy substrates, but the endless focus on AMPK activation as a supposedly-effective strategy for restoring glucose transport has never made sense to me. That's just my opinion. I've discussed the fact that the activation of the PGC-1alpha-mediated increase in mitochondrial proliferation ("mitochondrial biogenesis"), in response to AMPK activation, is unlikely, in my opinion, to be beneficial and is likely to be maladaptive. I would say that, in the majority of contexts in which I've seen mitochondrial proliferation discussed, in the context of mitochondrial disorders or other contexts, the mitochondrial proliferation has been viewed as being maladaptive and evidence of pathology. But Davidson and Duchen, 2007 [cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/01/mitochondrial-activity-in-endothelial.html)] note that mitochondria in endothelial cells have generally been viewed as being either "nonexistent" or unimportant. But the activities of the mitochondrial tricarboxylic acid cycle enzymes is an important factor that helps to maintain glycolysis, by indirectly maintaining the transport activities of, for example, the malate-aspartate shuttle, etc. In any case, there are some issues with research on fatty acid metabolism.