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

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 preventative 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.

A pilot data analysis of a metabolomic HPLC-MS/MS study of patients with COPD

“…23 The significantly lower ratio of free carnitine/acylated carnitine (C0/AC) in COPD patients, despite the lack of distinct differences in the concentration of free carnitine, and the total and individual acylcarnitine levels, possibly indicates a predisposition to atherosclerosis as a result of inadequate β-oxidation of fatty acids, as well as of being at risk for carnitine deficiency. 24,25 Evidence suggests that impaired fatty acid oxidation has some effect on the development of type-2 diabetes. 26,27 The prevalence of diabetes in COPD patients is significant, and may be one of the factors which cause the progression and worsen the prognosis of COPD.…”

Investigation of novel metabolites potentially involved in the pathogenesis of coronary heart disease using a UHPLC-QTOF/MS-based metabolomics approach

“…Therefore, the accumulation of acylcarnitines, especially those of medium-chain species, has been attributed to incomplete fatty acid oxidation and energy metabolism in CHD 51 . Studies have also suggested the elevation of acylcarnitines as being a signature for inadequate β-oxidation in macrophage lipid metabolism 52 , which is a key process underlying atherosclerosis. Moreover, L-carnitine and acylcarnitines have been shown to contribute to the development of atherosclerosis by increasing the levels of the independent CHD risk factor trimethylamine N-oxide (TMAO) in experimental animals 53 .…”

Transport of fatty acids within plasma lipoproteins in lactating and non‐lactating cows fed on fish oil and hydrogenated palm oil

“…It has been demonstrated that alterations in the diet can affect the distribution and chemical composition of plasma lipoproteins in models such as in humans (Blair et al., ), and in animal models such as rabbits (Niimi et al., ), rats (Sawale et al., ), swine (Nichols et al., ) and chickens (Jensen et al., ). Also, it has been shown that the degree of saturation of dietary lipids can affect the chemical composition of plasma lipoproteins in steers (Scislowski et al., ,b) and dairy cows (Offer et al., ).…”