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    • br Methods br Results br Discussion This is

    2018-10-30


    Methods
    Results
    Discussion This is the first study reporting normal values of blood LAL activity in healthy adult subjects; we found a median value of LAL activity of 1.15nmol/spot/h, with no age and sex differences. We also investigated LAL activity in a cohort of adult patients with NAFLD, and we found a significant reduction of LAL activity in NAFLD patients, compared to healthy subjects. In particular, patients with NAFLD had a 27.0% reduction of LAL activity, which increased to 41.8% in the subgroup of patients with biopsy proven NASH. Patients with LAL activity below median had a significant elevation of serum liver AMG 925 and a worse lipid profile (higher total and LDL cholesterol). This last finding is in keeping with data by Muntoni S et al. showing a similar lipid profile with a polygenic hypercholesterolemia phenotype in E8SJM LAL mutation carriers (Muntoni et al., 2013). Of note, there are no data in the literature on the correlation between circulating and hepatic LAL activity, and there is no general agreement on whether a reduced blood LAL activity directly reflects hepatic content of triglycerides and cholesterol esters (Puri et al., 2007). In this context, Singh et al. (Singh et al., 2009) described a direct involvement of autophagy and lysosomal pathway in the degradation of intracellular lipid droplets in the liver. This may suggest that a reduction of LAL activity might reduce droplets clearance and promote accumulation of both esterified and unesterified cholesterol in hepatocytes. The association between statin use and improved LAL function is another interesting finding of the study. The use of statins is controversial in patients with genetic deficiency of LAL, as in some CESD patients dyslipidaemia persisted despite the lipid-lowering treatment, and liver histology did not improve with statins (Reiner et al., 2014). Interestingly, Fouchier and Defesche (Fouchier and Defesche, 2013) proposed a combined approach with statins and LAL replacement therapy in patients with mutations of Lysosomal Acid Lipase gene. Finally, it has been recently reported that LAL released by macrophages in the extracellular space contributes to modification of LDL within the artery wall (Dubland and Francis, 2015). The Authors speculated that early stage atherosclerosis may involve normal or increased LAL activity, whereas later stages of atherosclerosis may have an acquired dysfunction in LAL hydrolytic activity leading to lysosomal cholesterol sequestration. Thus, LAL may represent one possible mechanism contributing to the accelerated atherosclerosis and increased cardiovascular risk reported in patients with NAFLD (Sookoian and Pirola, 2008; Pastori et al., 2015b). However, further research on this issue is needed.
    Conclusions
    Declaration of Interests
    Research in Context
    Author Contributions
    Acknowledgements
    Introduction The autoimmune disease systemic lupus erythematosus (SLE) affects multiple organs; most organ damage is initiated by autoantibody deposition that triggers subsequent inflammatory reaction (Tsokos, 2011). Neuropsychiatric lupus (NPSLE) refers to the neurologic manifestations of SLE that are present in 30–80% of patients (Nowicka-Sauer et al., 2011). These symptoms develop insidiously, cause disability, and significantly diminish quality of life (Appenzeller et al., 2009). Impaired cognition is reported frequently in clinically stable SLE patients that do not have other NPSLE manifestations or inflammation in the central nervous system (CNS) (Toledano et al., 2013). Despite the high prevalence of cognitive dysfunction and emotional disturbance in NPSLE patients, the wide array of symptoms attributable to NPSLE has hampered mechanistic understanding. When DNRAbs access the brain through a damaged blood–brain barrier (BBB) (Hirohata et al., 2014), they are likely to cause non-focal CNS manifestations of NPSLE (reviewed in Diamond et al., 2013). Notably, DNRAbs have been extracted from brain tissue of SLE patients (Kowal et al., 2006) and elevated DNRAb titers in cerebrospinal fluid (CSF) associate with NPSLE symptoms (Arinuma et al., 2008; DeGiorgio et al., 2001; Lauvsnes and Omdal, 2012; Yoshio et al., 2006). DNRAbs bind a consensus sequence (D/E W D/E Y S/G, or DWEYS for short) present in the extracellular domains of the GluN2A and GluN2B subunits (Paoletti, 2011). Mechanistic studies show that DNRAbs preferentially bind the open configuration of the NMDAR, augment NMDAR-mediated synaptic potentials, and, at higher concentration, trigger mitochondrial stress and apoptosis through binding specifically to GluN2A-containing NMDARs (Faust et al., 2010). DNRAbs that have been isolated from serum of SLE patients and intravenously transferred to mice lead to death of hippocampal neurons and impaired memory flexibility after the mice are given lipopolysaccharide (LPS) to impair the integrity of the BBB within the hippocampus (Kowal et al., 2006).