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Review
. 2016 Mar:78:17-23.
doi: 10.1016/j.vph.2015.06.012. Epub 2015 Jun 30.

Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates

Harry C Blair  1 , Jorge Sepulveda  2 , Dionysios J Papachristou  3
Affiliations
Review

Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates

Harry C Blair et al. Vascul Pharmacol. 2016 Mar.

Abstract

Macrophages recycle components of dead cells, including cell membranes. When quantities of lipids from cell membranes of dead cells exceed processing capacity, phospholipid and cholesterol debris accumulate as atheromas. Plasma lipid profiles, particularly HDL and LDL cholesterol, are important tools to monitor atherosclerosis risk. Membrane lipids are exported, as triglycerides or phospholipids, or as cholesterol or cholesterol esters, via lipoproteins for disposal, for re-use in cell membranes, or for fat storage. Alternative assays evaluate other aspects of lipid pathology. A key process underlying atherosclerosis is backup of macrophage fatty acid catabolism. This can be quantified by accumulation of acylcarnitine intermediates in extracellular fluid, a direct assay of adequacy of β-oxidation to deal with membrane fatty acid recycling. Further, membranes of somatic cells, such as red blood cells (RBC), incorporate fatty acids that reflect dietary intake. Changes in RBC lipid composition occur within days of ingesting modified fats. Since diets with high saturated fat content or artificial trans-fatty acids promote atherosclerosis, RBC lipid content shifts occur with atherosclerosis, and can show cellular adaptation to pathologically stiff membranes by increased long-chain doubly unsaturated fatty acid production. Additional metabolic changes with atherosclerosis of potential utility include inflammatory cytokine production, modified macrophage signaling pathways, and altered lipid-handling enzymes. Even after atherosclerotic lesions appear, approaches to minimize macrophage overload by reducing rate of fat metabolism are promising. These include preventive measures, and drugs including statins and the newer PCSK9 inhibitors. New cell-based biochemical and cytokine assays provide data to prevent or monitor atherosclerosis progression.

Keywords: Atherogenesis; Carnitine; Cholesterol synthesis; Coenzyme A; Fcγ; HDL; LDL; PCSK9; Statin.

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Figures

Figure 1
Figure 1
Percent of deaths from ischemic heart disease from 1865–1950 from a long series of autopsies at St Bart’s Hospital, London. Shown are deaths in the over age 40 population attributed to ischemic heart disease or dissecting aortic aneurysms, divided by the numbers of autopsies in the over 40 age groups in the time intervals shown. Data are from Table 2 in Finlayson [3], and are used by permission. Data for 1940–45 are assumed all to be over age 40; this is not specified for these years.
Figure 2
Figure 2. Degradation of unsaturated fatty acids, and structures of common fatty acids
A. Fatty acids unsaturated at odd-numbered bonds require enoyl Co-A isomerase for oxidation. The β-oxidation of unsaturated fatty acids at with unsaturation at odd carbons from the terminal carboxy is complex. Double bonds at odd numbered position are of phase with trans-2,3 CoA reductase. This is adjusted by enoyl CoA reductases (two isoforms) that move the double bond from 3,4 to 2,3-trans. Fatty acids with cis double bonds at even positions are degraded similarly but by cis-2,3 CoA reductase (not illustrated). The enoyl CoA reductases are mitochondrial NADPH-requiring enzymes. Either cis- or trans-unsaturation that is out of phase with the trans-2,3-CoA reductase reduces the efficiency of β-oxidation. The effect varies widely with the position and type of unsaturation. Oleate at 30 μM suppresses β-oxidation measurably; elaidate at the same concentration has a strong inhibitory effect. Inefficient processing of C18:1 Δ9 trans by enoyl CoA lead to accumulation of extracellular trans-C12 and trans C-14 carnitine adducts; CoA is the mitochondrial carrier; carnitine is the cytoplasmic fatty acid carrier. B. Key fatty acid types. Animal fat is about 50% saturated. Of this, of this about a quarter is C18:0, stearate, the bottom drawing. There is typically twice as much C16:0, palmitate, as stearate. Unsaturated cis fatty acids melting points lower than saturated fatty acids of the same length. These increase membrane flexibility. Oleate, C18:1 ⊗9 cis, is shown in the top diagram. The cis bond is in red. Oleate is a liquid and the most abundant monounsaturated fatty acid in mammalian cell membranes. The occurrence of trans double bonds creates stiff structures that have much higher melting points; elaidate, the middle diagram, is a hard wax. The trans bond is in red. This is the major trans-fatty acid in partially hydrogenated oils.
Figure 3
Figure 3. Foam cells in vitro and accumulation of acylcarnitines in the supernatant
Human macrophages in vitro were maintained in MEM with 10% fetal bovine serum (left) or with the same serum saturated with soy oil or partially hydrogenated soy oil (middle and right). At 10 days supernatants were collected as dried spots for MS/MS determination of acylcarnitine fatty acids as described [8]. The bottom row shows phase photographs of oil red O stained cells; note that in control cells lipid (red) occurs in dust-like vacuoles (red, carets) although the cells are physaliferous, or prominently vacuolated, (arrows). In the lipid saturated cells the large vacuoles contain lipid (arrows). This is pronounced in the partially hydrogenated oil saturated serum, where also reduced cell numbers reflect increased cell death (not shown). The graph at top shows that there is a slight, but significant, increase in C12-carnitine in the soy oil treated cells, and a much larger increase in C12-carnitine in the partially hydrogenated soy oil treated cells (right). To what extent this reflects release due to cell death is unknown. Since carnitine is required as a carrier for the free fatty acids entering the cells, this is a potential gate-keeper to restrict overload and death of “foam cells” hypothesized to lead to a vicious cycle of phagocytosis and toxicity causing growth of atheromata. Modified from [8]; used with permission.
Figure 4
Figure 4. Unsaturated fatty acids in RBC occur with development of atherosclerotic disease
Fatty acid extraction and analysis by gas chromatography and mass spectroscopy shows clearly that red blood cells accumulate C18:2 in a manner reflecting development of cardiovascular disease. N=10–18, mean ± SEM. The data are from [27] and are used with permission.
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