No abstract

This article is available online at http://www.jlr.org lipoproteins. Agonist-induced lipolysis is mediated by consecutive activation of the adenylate cyclase (AC), resulting in cAMP production and protein kinase A (PKA) activation by cAMP, followed by PKA-induced phosphorylation of hormone-sensitive lipase (HSL) at three serine residues (563, 659, and 660), resulting in its activation and translocation from the cytosol to the lipid-droplet surface. Concomitant with HSL phosphorylation, the phosphorylation of perilipin by PKA at multiple sites (S81, S222, S276, and S517) results in a dynamic restructuring of the lipid-droplet surface, in facilitating the translocation of phosphorylated HSL to the lipid droplet, and in activating its hydrolyzing activity. Perilipin phosphorylation by PKA further results in releasing CGI-58 from the lipid droplet, in its association with adipose triacylglycerol lipase (ATGL), and in activating its lipolytic activity. Activated ATGL, HSL, and monoglyceride lipase may act now consecutively in hydrolyzing adipose triacyglycerols to diacylglycerol, monoacylglycerol, and fi nally to free glycerol and LCFA. Agonist-induced cAMP and lipolysis is restrained by insulin due to cAMP hydrolysis by insulin-activated phosphodiesterase3B (PDE3B) ( 2 ), combined with insulin-induced reesterifi cation of LCFA into adipose fat (reviewed in Ref.3 ). Indeed, increased adipose effl ux of free LCFA, due to increased adipose lipolysis and/or suppression of adipose LCFA reesterifi cation, is considered a cornerstone of diabetes. Agonist-induced lipolysis is further robustly inhibited by the LCFA generated during lipolysis ( 4, 5 ). In fact, agonist-induced lipolysis is made possible only by removing the free nonesterifi ed LCFA product through their binding to medium albumin or by frequent medium replacement Lipolysis of adipose fat stores results in the production of nonesterifi ed long-chain fatty acids (LCFA) in response to changes in energy requirements and availability (reviewed in Ref. 1 ). Fatty acids derived by adipose fat lipolysis may either be reesterifi ed into adipose fat, or serve as major source of oxidizable substrate for muscle activity and as precursor for the hepatic production of triacylglycerol-richFunded by Eurostars project E!5138.

failure is associated with aortic valve calcification. Using our rat model of uremiainduced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n ϭ 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n ϭ 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosisrelated genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.growth arrest-specific 6; uremia CARDIOVASCULAR CALCIFICATION is one of the highest causes of morbidities and mortalities in patients with end-stage renal disease. These patients develop aortic valve calcification (AVC) and coronary calcification at an accelerated rate. Associated with this cardiovascular calcification are increased rates of myocardial infarctions and valvular heart disease. The pathogenesis of AVC in renal failure (RF) is not fully elucidated. It has been suggested that the process involves active osteoblast transformation of valve tissue, which results in increased formation of bone matrix (4, 25). Most of the data regarding the pathogenesis of AVC were obtained from animal models based on various components of the metabolic syndrome, emphasizing the role of atherogenesis in AVC (26, 37). In patients with RF, AVC and aortic stenosis are common and progress especially rapidly (18). The prevalence and extent of AVC in this population is poorly explained by traditional cardiovascular risk factors; abnormalities of mineral metabolism are likely to contribute to its development and progression. Current models of RF and accelerated calcification have demonstrated that calcium phosphate metabolism is critical for disease development (13), and inhibitors of calcification (fetuin A) are important in its prevention...

No abstract

The complexity of central nervous system (CNS) degenerative/inflammatory diseases and the lack of substantially effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. We suggest a novel approach directed for the elimination of pathogenic agents from the CNS and, in parallel, its enrichment with an array of neuroprotective substances, using a “cerebrospinal fluid (CSF) exchange” procedure, in which endogenous (pathogenic) CSF is removed and replaced by artificial CSF (aCSF) enriched with secretions of human mesenchymal stem cells (MSCs). MSCs produce a variety of neuroprotective agents and have shown beneficial effects when cells are transplanted in animals and patients with CNS diseases. Our data show that MSCs grown in aCSF secrete neurotrophic factors, anti-inflammatory cytokines, and anti-oxidant agents; moreover, MSC-secretions-enriched-aCSF exerts neuroprotective and immunomodulatory effects in neuronal cell lines and spleen lymphocytes. Treatment of experimental-autoimmune-encephalomyelitis (EAE) mice with this enriched-aCSF using an intracerebroventricular (ICV) CSF exchange procedure (“CSF exchange therapy”) caused a significant delay in the onset of EAE and amelioration of the clinical symptoms, paralleled by a reduction in axonal damage and demyelination. These findings point to the therapeutic potential of the CSF exchange therapy using MSC-secretions-enriched-aCSF in inflammatory/degenerative diseases of the CNS.