Oxidative modification of LDL is known to elicit an array of pro-atherogenic responses, but it is generally underappreciated that oxidized LDL (OxLDL) exists in multiple forms, characterized by different degrees of oxidation and different mixtures of bioactive components. The variable effects of OxLDL reported in the literature can be attributed in large part to the heterogeneous nature of the preparations employed. In this review, we first describe the various subclasses and molecular composition of OxLDL, including the variety of minimally modified LDL preparations. We then describe multiple receptors that recognize various species of OxLDL and discuss the mechanisms responsible for the recognition by specific receptors. Furthermore, we discuss the contentious issues such as the nature of OxLDL in vivo and the physiological oxidizing agents, whether oxidation of LDL is a prerequisite for atherogenesis, whether OxLDL is the major source of lipids in foam cells, whether in some cases it actually induces cholesterol depletion, and finally the Janus-like nature of OxLDL in having both pro- and anti-inflammatory effects. Lastly, we extend our review to discuss the role of LDL oxidation in diseases other than atherosclerosis, including diabetes mellitus, and several autoimmune diseases, such as lupus erythematosus, anti-phospholipid syndrome, and rheumatoid arthritis.

Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology

Spatially fractionated high dose (grid) radiation treatment (SFGRT) involves irradiation of bulky tumors with one high, grid-delivered, dose of 15 Gy followed by multiple consecutive doses of 2 Gy each. The goal of this study is to determine the effect of this treatment on serum ceramide content and to investigate possible involvement of ceramide in tumor regression after SFGRT. Serum ceramide and Secretory SMase (S-SMase) were quantified in 11 patients before and at 24, 48 and 72 h after the dose of 15 Gy. Furthermore, LDL particles were isolated from the serum and their apoptotic ability was tested in human endothelial cells by TUNEL assay. Sixty seven per cent (6/8) of the patients with partial (PR) or complete (CR) response showed statistically significant increase in serum ceramide levels. Of the nonresponders in the study, none showed an elevation in ceramide. S-SMase activity underwent similar changes. LDL particles from serum of patients collected 72 hours after SFGRT sensitized the endothelial cells to undergo apoptosis in response to 5 Gy radiation that by itself had only modest effect on cell death. Independent elevation of ceramide content of endothelial cells that were otherwise resistant to radiation-induced cell death also was sufficient to sensitize these cells to apoptosis. Serum S-SMase activity and ceramide content increase following SFGRT and correlate with the clinical response. Apparently, these changes are in the LDL-associated ceramide and may contribute to better tumor reduction after SFGRT, due to the ability of LDL-derived ceramide to sensitize endothelial cells for apoptosis.

Elevated sphingomyelinase activity and ceramide concentration in serum of patients undergoing high dose spatially fractionated radiation treatment: Implications for endothelial apoptosis

In atherosclerosis; blood low-density lipoproteins (LDL) are subjected to multiple enzymatic and non-enzymatic modifications that increase their atherogenicity and induce immunogenicity. Modified LDL are capable of inducing vascular inflammation through activation of innate immunity; thus, contributing to the progression of atherogenesis. The immunogenicity of modified LDL results in induction of self-antibodies specific to a certain type of modified LDL. The antibodies react with modified LDL forming circulating immune complexes. Circulating immune complexes exhibit prominent immunomodulatory properties that influence atherosclerotic inflammation. Compared to freely circulating modified LDL; modified LDL associated with the immune complexes have a more robust atherogenic and proinflammatory potential. Various lipid components of the immune complexes may serve not only as diagnostic but also as essential predictive markers of cardiovascular events in atherosclerosis. Accumulating evidence indicates that LDL-containing immune complexes can also serve as biomarker for macrovascular disease in type 1 diabetes.

/pdf/modified-low-density-lipoprotein-and-lipoprotein-containing-3yoqd6ozys.pdf

Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease

Elevation of ceramide in serum lipoproteins during acute phase response in humans and mice: role of serine–palmitoyl transferase

Bosco D, Plastino M, Bosco F, Consoli A, Labate A, Pirritano D, Consoli D, Fava A. Bell’s palsy: a manifestation of prediabetes? Acta Neurol Scand: 2011: 123: 68–72. © 2010 John Wiley & Sons A/S.



Background –  Idiopathic peripheral facial nerve palsy or Bell’s palsy (BP) is the most common cause of facial nerve palsy.



Objective –  To evaluate the role of glucose metabolism abnormalities in BP. Methods– We identified 148 patients with unilateral BP and 128 control subjects. In all we evaluated glucose level at fasting and after a 2-h oral glucose tolerance test (2h-OGTT). In addition we determined insulin resistance (IR), by HOMA-index. Patients and controls were divided in to two groups, according to their Body Mass Index (BMI).



Results –  Following a 2h-OGTT, the prevalence of glucose metabolism abnormalities was significantly higher in patients with BP than in controls (P < 0.001). Impaired glucose tolerance (IGT) was found in 57 (38%) patients and in 23 (18%) controls, while a new-diagnosed DM (NDDM) was found in 29 (19%) patients and in 8 (6%) controls. The IR was significantly increased only in BP patients with BMI ≥ 24.9 (P = 0.005). BMI, waist circumference, blood pressure, tryglicerides, serum lipid, drugs use were not significantly different between patients and controls.



Conclusions –  In this study we found that prediabetes is frequently associated with facial palsy. We propose to perform a 2h-OGTT in patients with peripheral facial palsy and normal fasting glycaemia. HOMA-index should be evaluated in obese facial palsy patients.

Bell’s palsy: a manifestation of prediabetes?

Uptake and metabolism of low density lipoproteins with elevated ceramide content by human microvascular endothelial cells: implications for the regulation of apoptosis.

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Uptake and metabolism of low density lipoproteins with elevated ceramide content by human microvascular endothelial cells: implications for the regulation of apoptosis.