Assessment of the role of plasmalogen in the modulation of oxidative stress and inflammation in atherosclerosis

© 2015 Dr. Aliki RasmienaOxidative stress is a contributing factor to atherosclerosis. Circulating levels of plasmalogens (phospholipids with potential anti-oxidant properties) have been shown to be negatively associated with coronary artery disease, suggesting an elevated level of oxidative stress in these patients. We hypothesised that: (1) oxidative stress affects lipoprotein lipid composition and function; and (2) regulation of the level of plasmalogen can influence atherosclerosis progression and inflammation. Low density and high density lipoproteins (LDL and HDL) were oxidised with copper chloride at different time points. Liquid chromatography combined with tandem mass spectrometry analysis showed a myriad of changes in the lipid composition of lipoproteins during oxidation. Plasmalogen was one of the lipids that were most affected, early in the oxidation of lipoproteins. Incubation of THP1- derived macrophages with HDL of differing levels of oxidative stress showed that the capacity of mildly- and heavily oxidised HDL to efflux cholesterols was significantly reduced as compared to native HDL. Similarly, the ability of HDL to delay LDL oxidation and to accept oxidised lipids from oxidised LDL deteriorated progressively under mild- and heavy oxidative stress. To investigate the effect of plasmalogen enrichment in atherosclerosis, ApoE- and ApoE/glutathione peroxidase 1-deficient (ApoE-/- and ApoE-/-GPx1-/-) mice were fed a high-fat diet with or without 2% batyl alcohol (BA, precursor to plasmalogen synthesis) for 12 weeks. Mass spectrometry analysis of lipids in plasma, heart, liver and adipose tissue showed that plasmalogen concentration was increased in all tissues of the BA-treated ApoE-/- and ApoE-/-GPx1-/- mice. Oxidation of plasmalogen in the treated mice was apparent by the increase in sn-2 lysophosphatidylcholine in circulation. En face analysis showed that compared to the untreated mice, aortic plaque accumulation in the BA-treated ApoE-/- and ApoE-/-GPx1- /- mice was significantly reduced (70%). Immunohistochemistry of the aortic sinus and aorta indicated that the levels of the inflammatory marker, VCAM-1 and the oxidative stress marker, nitrotyrosine were reduced only in the BA-treated ApoE-/-GPx1-/- mice. Treatment with BA also resulted in a decrease in the body weight gain and fasting blood glucose without any effect on the fasting insulin level in these mice. Further lipidomic analysis demonstrated that diacyl- and triacylglycerols in the liver were lowered whereas that in the plasma was increased. Flow cytometry analysis of the peripheral whole blood of C57/BL6 mice showed that treatment with an alkylglycerol mix for 12 weeks lowered the levels of total monocytes and neutrophils. In conclusion, oxidation affected lipids in both the surface layer and core of the lipoproteins and this translated to a deterioration of the lipoprotein function with increasing level of oxidative stress. In addition, the modulation of plasmalogen levels via treatment with alkylglycerol alleviated atherosclerosis in vivo potentially via a plethora of mechanisms involving inflammation and oxidative stress, and the regulation of glucose and body weight. Plasmalogen modulation represents a potential therapy to prevent atherosclerosis and reduce cardiovascular disease risk

Oral Supplementation of an Alkylglycerol Mix Comprising Different Alkyl Chains Effectively Modulates Multiple Endogenous Plasmalogen Species in Mice

Plasmalogens or alkenylphospholipids are a sub-class of glycerophospholipids with numerous biological functions and are thought to have protective effects against metabolic disease. Dietary supplementation with alkylglycerols (AKGs) has been shown to increase endogenous plasmalogen levels, however effective modulation of different molecular plasmalogen species has not yet been demonstrated. In this study, the effects of an orally-administered AKG mix (a mixture of chimyl, batyl and selachyl alcohol at a 1:1:1 ratio) on plasma and tissue lipids, including plasmalogens, was evaluated. Mice on a Western-type diet were treated with either an AKG mix or vehicle (lecithin) for 1, 2, 4, 8 and 12 weeks. Treatment with the AKG mix significantly increased the total plasmalogen content of plasma, liver and adipose tissue as a result of elevations in multiple plasmalogen species with different alkenyl chains. Alkylphospholipids, the endogenous precursors of plasmalogens, showed a rapid and significant increase in plasma, adipose tissue, liver and skeletal muscle. A significant accumulation of alkyl-diacylglycerol and lyso-ether phospholipids was also observed in plasma and tissues. Additionally, the dynamics of plasmalogen-level changes following AKG mix supplementation differed between tissues. These findings indicate that oral supplementation with an AKG mix is capable of upregulating and maintaining stable expression of multiple molecular plasmalogen species in circulation and tissues

Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC

Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.info:eu-repo/semantics/publishe