Sera containing elevated nonesterified fatty acids from patients with angiographically documented coronary atherosclerosis cause marked lipid accumulation in cultured human arterial smooth muscle-derived cells

Laughton, Craig W.; Ruddle, D. L.; Bedord, Charles J.; Alderman, Edwin L.

doi:10.1016/0021-9150(88)90174-8

Cited by 31 publications

(11 citation statements)

References 43 publications

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“…Also noteworthy is that CE derived from intimal regions with abundant foam cells are oleate-rich, further supporting the view that lipid is derived at least partly from a cellular origin rather than exclusively from plasma lipoproteins (23)(24)(25). The preferential synthesis in vitro of TG rather than CE may reflect a characteristic function of VSMC, as suggested by TG accumulation after VSMC uptake of non-esterified FA (17,18). Alternatively, the serum-free or low serum culture conditions may restrict ACAT1 activity by limiting cholesterol substrate.…”

Section: -Hc Is An Antagonist For To901317 and 24(s)25-epoxycholestmentioning

confidence: 49%

“…The absence of macrophage scavenger receptors in VSMC indicates that other mechanisms of lipid accumulation may occur. These could include the utilization of LDL and VLDL receptors in the uptake of aggregated LDL and ␤-VLDL, a process that occurs in vitro (15,16), or the uptake of nonesterified fatty acids from serum (17,18). This mechanism of VSMC foam cell formation is of particular interest due to the elevated levels of FA in diabetes and the association of this condition with atherosclerosis (17).…”

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confidence: 99%

“…These could include the utilization of LDL and VLDL receptors in the uptake of aggregated LDL and ␤-VLDL, a process that occurs in vitro (15,16), or the uptake of nonesterified fatty acids from serum (17,18). This mechanism of VSMC foam cell formation is of particular interest due to the elevated levels of FA in diabetes and the association of this condition with atherosclerosis (17). An alternative mechanism would be de novo synthesis of lipid, and it has long been known that VSMC, human arterial tissue, and foam cells incubated with radioactive acetate synthesize phospholipids, triacylglycerols (TG), and CE (19,20), the type of lipid produced being dependent on VSMC phenotype and effected by oxysterols (21,22).…”

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confidence: 99%

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Adipocytic Differentiation and Liver X Receptor Pathways Regulate the Accumulation of Triacylglycerols in Human Vascular Smooth Muscle Cells

Davies

Carpenter

Challis

et al. 2005

Journal of Biological Chemistry

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Lipid accumulation by vascular smooth muscle cells (VSMC) is a feature of atherosclerotic plaques. In this study we describe two mechanisms whereby human VSMC foam cell formation is driven by de novo synthesis of fatty acids leading to triacylglycerol accumulation in intracellular vacuoles, a process distinct from serum lipoprotein uptake. VSMC cultured in adipogenic differentiation medium accumulated lipids and were induced to express the adipocyte marker genes adipsin, adipocyte fatty acid-binding protein, C/EBP␣, PPAR␥, and leptin. However, complete adipocyte differentiation was not observed as numerous genes present in mature adipocytes were not detected, and the phenotype was reversible. The rate of lipid accumulation was not affected by PPAR␥ agonists, but screening for the effects of other nuclear receptor agonists showed that activation of the liver X receptors (LXR) dramatically promoted lipid accumulation in VSMC. Both LXR␣ and LXR␤ were present in VSMC, and their activation with TO901317 resulted in induction of the lipogenic genes fatty acid synthetase, sterol regulatory element binding protein (SREBP1c), and stearoyl-CoA desaturase. 27-Hydroxycholesterol, an abundant oxysterol synthesized by VSMC acted as an LXR antagonist and, therefore, may have a protective role in preventing foam cell formation. Immunohistochemistry showed that VSMC within atherosclerotic plaques express adipogenic and lipogenic markers, suggesting these pathways are present in vivo. Moreover, the development of an adipogenic phenotype in VSMC is consistent with their known phenotypic plasticity and may contribute to their dysfunction in atherosclerotic plaques and, thus, impinge on plaque growth and stability.

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Section: -Hc Is An Antagonist For To901317 and 24(s)25-epoxycholestmentioning

confidence: 49%

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confidence: 99%

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confidence: 99%

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Adipocytic Differentiation and Liver X Receptor Pathways Regulate the Accumulation of Triacylglycerols in Human Vascular Smooth Muscle Cells

Davies

Carpenter

Challis

et al. 2005

Journal of Biological Chemistry

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“…However, a direct role for NEFAs in CHD is suggested by the atherogenic and thrombogenic effects of fatty acids 28 ; the association of fatty acid concentrations in serum, adipose tissue, and aortic plaque 29 ; and the relationship of elevated serum NEFAs with foam cell formation. 30 An interrelationship between defective lipolysis and glucose disposal is additionally suggested by studies showing that increased availability of NEFAs impairs insulin-mediated glucose uptake. 23,27,31 The contribution of diabetes to impaired insulin action was excluded in the BWMI patients, all of whom had normal glucose tolerance but were insulin resistant compared with BWCs.…”

Section: Discussionmentioning

confidence: 99%

Abdominal Obesity, Impaired Nonesterified Fatty Acid Suppression, and Insulin-Mediated Glucose Disposal Are Early Metabolic Abnormalities in Families With Premature Myocardial Infarction

Kooner

Baliga

Wilding

et al. 1998

ATVB

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Abstract-British Indian Asian men aged Ͻ40 years have a twofold to threefold increased risk of death from coronary heart disease (CHD) compared with British whites. Epidemiological studies have suggested an association between glucose intolerance and hyperinsulinemia with premature CHD in Indian Asians. We tested the association of insulin action with myocardial infarction (MI) by using the hyperinsulinemic-euglycemic clamp in 17 MI patients: 8 Punjabi Sikhs (PSMIs), 9 British whites (BWMIs), and 17 control subjects (9 PSCs and 8 BWCs Key Words: myocardial infarction Ⅲ abdominal obesity Ⅲ nonesterified fatty acids Ⅲ insulin resistance P remature CHD mortality is higher in British Indian Asians than in British whites. 1 Increased mortality in Indian Asians is particularly marked in men aged 30 to 39 years, in whom the relative risk of death from CHD is 2, and in men aged 20 to 29, for whom the relative risk is 3, compared with age-matched whites.1 Conventional risk factors, including smoking, hypercholesterolemia, or hypertension, do not account for the higher cardiovascular mortality in this population group.2 In fact, the prevalence of these risk factors is generally reduced in Indian Asians compared with whites.2 Insulin resistance and its metabolic consequences are increasingly recognized as risk factors for CHD.3-11 However, the association of insulin action with MI has not been formally examined in Indian Asians or in British whites. We studied Punjabi Sikh (Indian Asian [PS]) survivors of premature MI for defects of insulin action. A comparable group of white MI survivors (BWMI) was also studied. Familial aggregation of defective insulin action was examined by investigating first-degree relatives of Sikh MI patients to search for early markers of MI. Methods SubjectsSeventeen male MI patients (8 PSMIs and 9 BWMIs) and 17 control subjects (9 PSCs and 8 BWCs) underwent the hyperinsulinemiceuglycemic clamp study to test the association of insulin action with MI. Fifty-one male MI patients (24 PSMIs and 27 BWMIs) and 53

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“…[1][2][3][4] Elevated plasma levels of nonesterified fatty acids (NEFA) are commonly present in individuals with insulin resistance or type 2 diabetes, and it has been suggested that these chronically elevated levels of NEFA may contribute to the development of atherosclerosis in these conditions, in part, through their direct effects on vascular cells. 5,6 There is evidence that elevated levels of free fatty acids may contribute to both activation of inflammatory cells and their adhesion to endothelium.…”

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confidence: 99%

Elevated Concentrations of Nonesterified Fatty Acids Increase Monocyte Expression of CD11b and Adhesion to Endothelial Cells

Zhang

Schwartz

Wang

et al. 2006

ATVB

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Objective-Monocyte proinflammatory activity has been demonstrated in obesity, insulin resistance, and type 2 diabetes, metabolic conditions that are frequently associated with elevated levels of nonesterified fatty acids (NEFA). We therefore tested the hypothesis that NEFA may induce monocyte inflammation. Methods and Results-Monocytes exposed to NEFA for 2 days demonstrated a dose-related increase in intracellular reactive oxygen species (ROS) formation and adhesion to endothelial cells. All of these effects were inhibited by the coaddition of antioxidants such as glutathione or butylated hydroxytoluene, by inhibition of ROS generation by NADPH oxidase inhibitors, and by inhibition of protein kinase C, a recognized stimulator of NAPDH oxidase.

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Sera containing elevated nonesterified fatty acids from patients with angiographically documented coronary atherosclerosis cause marked lipid accumulation in cultured human arterial smooth muscle-derived cells

Cited by 31 publications

References 43 publications

Adipocytic Differentiation and Liver X Receptor Pathways Regulate the Accumulation of Triacylglycerols in Human Vascular Smooth Muscle Cells

Adipocytic Differentiation and Liver X Receptor Pathways Regulate the Accumulation of Triacylglycerols in Human Vascular Smooth Muscle Cells

Abdominal Obesity, Impaired Nonesterified Fatty Acid Suppression, and Insulin-Mediated Glucose Disposal Are Early Metabolic Abnormalities in Families With Premature Myocardial Infarction

Elevated Concentrations of Nonesterified Fatty Acids Increase Monocyte Expression of CD11b and Adhesion to Endothelial Cells

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