The impact of dietary fatty acids on macrophage cholesterol homeostasis

January 1, 2014 Human Health and Nutrition Data 0 Comments

The impact of dietary fatty acids on macrophage cholesterol homeostasis

Year: 2014
Authors: da Silva Afonsoa, M. Castihoa, G. Lavradora, M.S. Passarellia, M. Nakandakarea, E.R Lottenbergb, S.A. Lottenberga, A.M.
Publication Name: J Nutr Biochem
Publication Details: Volume 25; Issue 2; Pages 95 to 103


The impact of dietary fatty acids in atherosclerosis development may be partially attributed to their effect on macrophage cholesterol homeostasis. This process is the result of interplay between cholesterol uptake and efflux, which are permeated by inflammation and oxidative stress. Although saturated fatty acids (SAFAs) do not influence cholesterol efflux, they trigger endoplasmic reticulum stress, which culminates in increased lectin like oxidized LDL (oxLDL) receptor (LOX1) expression and, consequently, oxLDL uptake, leading to apoptosis. Unsaturated fatty acids prevent most SAFAs minus mediated deleterious effects and are generally associated with reduced cholesterol efflux, although α linolenic acid increases cholesterol export. Trans fatty acids increase macrophage cholesterol content by reducing ABCA minus 1 expression, leading to strong atherosclerotic plaque formation. As isomers of conjugated linoleic acid (CLAs) are strong PPAR gamma ligands, they induce cluster of differentiation (CD36) expression, increasing intracellular cholesterol content. Considering the multiple effects of fatty acids on intracellular signaling pathways, the purpose of this review is to address the role of dietary fat in several mechanisms that control macrophage lipid content, which can determine the fate of atherosclerotic lesions. (Authors abstract)
Atherosclerosis is characterized as a chronic inflammatory disease that is initiated by the subendothelial retention of low density lipoprotein (LDL), followed by physicochemical modifications such as oxidation. Macrophages located in the arterial intima layer present several scavenger receptors that uptake modified LDL. This contributes to intracellular cholesterol accumulation and inflammation and leads to monocyte recruitment.  Atherosclerotic lesions are characterized by progressive macrophage lipid accumulation, which leads to foam cell formation. All of the steps in these processes are mediated, in part, by dietary fatty acids. Macrophage lipid homeostasis is determined by the balance between cholesterol uptake and the efflux of excess cholesterol to extracellular acceptors such as high density lipoprotein (HDL) and Apo lipoprotein A minus I (apo A , minus I). Cholesterol is delivered to these cells mainly from modified lipoproteins as well as in a minor amount from native LDL. The accumulation of lipids within macrophagic cells is detrimental to arterial wall thickening because these cells engulf cholesterol depending on the amount of modified lipoproteins available and the expression of scavenger receptors. Lipid laden macrophages ultimately generate foam cells, a hallmark of the early stages of atherosclerosis. ATP binding transporters A minus 1 (ABCA minus 1) and G minus 1 (ABCG minus 1) play a central role in maintaining the macrophage lipid content by driving reverse cholesterol transport (RCT), an antiatherogenic system that promotes the trafficking of excess cholesterol from arterial wall macrophages to the liver for excretion in the bile and feces .
According to clinical and epidemiological studies, dietary fat plays an important role in the plasma cholesterol concentration and also modulates several steps in RCT. However, the specific role of each fatty acid in the signaling pathways that modulate macrophage cholesterol homeostasis remains elusive. In addition, depending on
the experimental protocol, fatty acids exert multiple effects that can be dose dependent and/or tissue specific and also related to the animal model utilized. Furthermore, the same fatty acid may exhibit different actions in similar metabolic contexts. Therefore, this review explores the role of different fatty acids in the cellular and molecular mechanisms involved in macrophage cholesterol balance, which is an important factor in the initiation, progression and outcome of atherosclerotic lesions.
Experimental studies of the impact of dietary fatty acids on macrophage cholesterol homeostasis do not necessarily reflect the roles of these fatty acids in the whole organism. Not all of the data indicating beneficial or detrimental effects of macrophage lipid accumulation are coincident with the cardiovascular endpoints stated in important clinical and epidemiological studies, which have results that support essential nutritional guidelines. Even when experimental protocols utilize the same fatty acid, divergent results may be attributed to the macrophage cell lineage, cholesterol loading, the concentration of the fatty acid in the culture medium and presence or absence of transcriptional nuclear agonists that may induce different responses in the pathophysiological background concerning metabolic stress.
SAFAs impair macrophage cholesterol homeostasis because of their deleterious effects on scavenger receptor expression, ER stress, inflammation and apoptosis. UFAs counteract most of these SAFA mediated mechanisms, although they are also shown to reduce cholesterol efflux. CLAs induce the expression of CD36, an important scavenger receptor involved in atherosclerosis development. TFAs enrich macrophages in cholesterol, impair ABCA minus 1 expression and elicit inflammation.  The differential effects found in cells exposed to fatty acids can result from a series of macrophage adaptive responses that act synergistically to maintain cholesterol balance and harmonic intracellular mechanisms. In this regard, advances in cellular and molecular biology in the field of nutrition will facilitate the elucidation and comprehension of important phenomena involved in the effects of different fatty acids on foam cell formation and
atherosclerotic outcomes. (Editors comments)

Back to Databases

Affiliated Organizations

Flax Focus Newsletter

Stay up-to-date with important flax news and announcements with our FLAX FOCUS newsletter.