High-fat meals impair flow-mediated dilation, a marker of endothelial function (19). Endothelial function is also impaired in patients with insulin resistance including abdominal obesity and diabetes mellitus (20). The adverse effects of high-fat meals, central obesity, and diabetes on endothelial function may be mediated by NEFAs. NEFAs, especially cis-unsaturated fatty acids, produce a concentration dependent inhibition of Ca2+-calmodulin dependent nitric oxide synthase activity in endothelial cells (21,22). Moreover, short-term elevations of plasma NEFAs produced by simultaneous infusion of intralipid, a source of triglycerides, and heparin, which activates endothelial lipo-protein lipase, also reduce endothelial cell nitric oxide production and impair responses to endothelium-dependent vasodilators such as metacholine and acetylcholine (23). In addition to suppressing endothelial nitric oxide synthase activity, NEFAs also enhance
Ncurocardiovascular & Renal Changes
Ncurocardiovascular T sympathetic; lone T plasma catecholamines t «[-vasoreactivity 4- Bar ore ilex sensitivity
Vascular Smooth Muscle T Growth T Proliferation T Migration T Oxidative stress
Endothelium i NO (eNOS) i EDV t ET-1 t PAI-I
Kidney t Oxidative stress f Cell # <oleic> T Fibronectrn (oleic) 4- Cell # (linoleate)
• 4 HR variability
• T Vascular reactivity
• Vascular remodeling
* ? Plaque rupture
Hypercoagualahle state Chronic Kidney Disease
* Insulin resistance
* p-cell loss and DM
Hepatoçytes ? gluconeogenesis T VLDL & TG synth T Apo B synthesis 4- Insulin clearance
T PAl-1 Tagt
4 Glucose uptake
Islet Cells ? Basal insulin 4GS1S ÎNO (iNOS)
Skeletal Muscle 4 Glucose uptake 4 Glucose oxidation 4 Glycogenosis
Fig. 1. Selected target organ system and cellular effects of NEFAs are shown at key sites mediating hemodynamic, cardiovascular, renal, and metabolic effects of fatty acids. The pathophysiological consequences reflect an interplay of the neurocardiovascular, renal, and metabolic derangements. The interactions between these factors are bidirectional and reinforcing, which help explain the high incidence of cardiovascular and renal disease and long-term worsening of metabolic disturbances in metabolic syndrome patients. For example, impairment of nitric oxide synthase can impair renal pressure natriuresis, raise in blood pressure, and worsen insulin resistance, whereas hypertension, dyslipidemia, and hyperglycemia exacerbate endothelial dysfunction. See text for further discussion and references.
endothelin and plasminogen activator inhibitor-1 (PAI-1) production in cultured endothelial cells (24,25).
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