1.7-Ketocholesterol is increased in the plasma of X-ALD patients and induces peroxisomal modifications in microglial cells: potential roles of 7-ketocholesterol in the pathophysiology of X-ALD.
Nury T1, Zarrouk A2, Ragot K3, Debbabi M4, Riedinger JM5, Vejux A1, Moreau T6, Aubourg P7, Lizard G8. J Steroid Biochem Mol Biol. 2016 Mar 31. pii: S0960-0760(16)30094-2. doi: 10.1016/j.jsbmb.2016.03.037. [Epub ahead of print]
X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder induced by a mutation in the ABCD1 gene, which causes the accumulation of very long-chain fatty acids in tissue and plasma. Oxidative stress may be a hallmark of X-ALD. In the plasma of X-ALD patients with different forms of the disease, characterized by high levels of C24:0 and C26:0, we observed the presence of oxidative stress revealed by decreased levels of GSH, α-tocopherol, and docosahexaenoic acid (DHA). We showed that oxidative stress caused the oxidation of cholesterol and linoleic acid, leading to the formation of cholesterol oxide derivatives oxidized at C7 (7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), and 7α-hydroxycholesrol (7α-OHC)) and of 9- and 13-hydroxyoctadecadienoic acids (9-HODE, 13-HODE), respectively. High levels of 7KC, 7β-OHC, 7α-OHC, 9-HODE and 13-HODE were found. As 7KC induces oxidative stress, inflammation and cell death, which could play key roles in the development of X-ALD, the impact of 7KC on the peroxisomal status was determined in microglial BV-2 cells.
2.Metabolomic changes in murine serum following inhalation exposure to gasoline and diesel engine emissions.
Brower JB1, Doyle-Eisele M1, Moeller B1, Stirdivant S2, McDonald JD1, Campen MJ3. Inhal Toxicol. 2016 Apr;28(5):241-250. Epub 2016 Mar 28.
The adverse health effects of environmental exposure to gaseous and particulate components of vehicular emissions are a major concern among urban populations. A link has been established between respiratory exposure to vehicular emissions and the development of cardiovascular disease (CVD), but the mechanisms driving this interaction remain unknown. Chronic inhalation exposure to mixed vehicle emissions has been linked to CVD in animal models. This study evaluated the temporal effects of acute exposure to mixed vehicle emissions (MVE; mixed gasoline and diesel emissions) on potentially active metabolites in the serum of exposed mice. C57Bl/6 mice were exposed to a single 6-hour exposure to filtered air (FA) or MVE (100 or 300 μg/m3) by whole body inhalation. Immediately after and 18 hours after the end of the exposure period, animals were sacrificed for serum and tissue collection. Serum was analyzed for metabolites that were differentially present between treatment groups and time points.
3.Quantitative profiling of oxylipins in plasma and atherosclerotic plaques of hypercholesterolemic rabbits.
Bojic LA1, McLaren DG2, Harms AC3, Hankemeier T3, Dane A3, Wang SP2, Rosa R2, Previs SF2, Johns DG2, Castro-Perez JM2. Anal Bioanal Chem. 2016 Jan;408(1):97-105. doi: 10.1007/s00216-015-9105-4. Epub 2015 Oct 28.
Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) that affect a broad range of physiological processes, including cell proliferation, inflammation, inflammation resolution, and vascular function. Moreover, oxylipins are readily detectable in plasma, and certain subsets of oxylipins have been detected in human atherosclerotic lesions. Taken together, we set out to produce a detailed quantitative assessment of plasma and plaque oxylipins in a widely used model of atherosclerosis, to identify potential biomarkers of disease progression. We administered regular chow or regular chow supplemented with 0.5 % cholesterol (HC) to male New Zealand white rabbits for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our targeted lipidomic analyses of oxylipins on plaques isolated from rabbits fed the HC diet detected 34 oxylipins, 28 of which were in compliance with our previously established quality control acceptance criteria.
4.Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells.
Maulucci G1, Daniel B2, Cohen O2, Avrahami Y2, Sasson S3. Mol Aspects Med. 2016 Mar 21. pii: S0098-2997(15)30018-2. doi: 10.1016/j.mam.2016.03.001. [Epub ahead of print]
Nutrient sensing mechanisms of carbohydrates, amino acids and lipids operate distinct pathways that are essential for the adaptation to varying metabolic conditions. The role of nutrient-induced biosynthesis of hormones is paramount for attaining metabolic homeostasis in the organism. Nutrient overload attenuate key metabolic cellular functions and interfere with hormonal-regulated inter- and intra-organ communication, which may ultimately lead to metabolic derangements. Hyperglycemia and high levels of saturated free fatty acids induce excessive production of oxygen free radicals in tissues and cells. This phenomenon, which is accentuated in both type-1 and type-2 diabetic patients, has been associated with the development of impaired glucose tolerance and the etiology of peripheral complications. However, low levels of the same free radicals also induce hormetic responses that protect cells against deleterious effects of the same radicals.