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Diabetes type 1 is a common autoimmune disease manifesting by insulin deficiency and hyperglycemia, which can lead to dementia-like brain dysfunctions. The factors triggering the pathological processes in hyperglycemic brain remain unknown. We reported in this study that brain areas with different susceptibility to diabetes (prefrontal cortex (PFC), hippocampus, striatum and cerebellum) revealed differential alterations in ceramide (Cer) and sphingomyelin (SM) profiles in rats with streptozotocin-induced hyperglycemia. Employing gas-liquid chromatography, we found that level of total Cer increased significantly only in the PFC of diabetic animals, which also exhibited a broad spectrum of sphingolipid (SLs) changes, such as elevations of Cer-C16:0, -C18:0, -C20:0, -C22:0, -C18:1, -C24:1 and SM-C16:0 and -C18:1. In opposite, only minor changes were noted in other examined structures. In addition, de novo synthesis pathway could play a role in generation of Cer containing monounsaturated fatty acids in PFC during hyperglycemia. In turn, simultaneous accumulation of Cers and their SM counterparts may suggest that overproduced Cers are converted to SMs to avoid excessive Cer-mediated cytotoxicity. We conclude that broad changes in SLs compositions in PFC induced by hyperglycemia may provoke membrane rearrangements in some cell populations, which can disturb cellular signaling and cause tissue damage., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Liver regeneration after partial hepatectomy (PH) is achieved by intense cells proliferation. Sphingosine-1-phosphate stimulates proliferation but ceramide and sphingosine induce apoptosis. The aim of the study was to investigate the influence of high-fat diet (HFD) on the sphingolipid metabolism during the first 24h of liver regeneration in rats. Rats were fed HFD or standard diet for 7 days prior to the PH. The content of sphingolipids and the activity of sphingomyelinases (n and aSMase), ceramidases (n and aCDase) and sphingosine kinase (SPHK) were measured. It has been found that HFD increased the activity of aSMase and nCDase at 4th hour after PH. The content of ceramide and sphingosine decreased in HFD group at each time point. This was accompanied by elevated content of sphingosine-1-phosphate and sphinganine-1-phosphate. Decrease in SPHK activity in cytosol after partial hepatectomy was inversely correlated (r=-0.7538) with increase in S1P, which suggest translocation of SPHK to plasma membrane. Shingosine-1-phosphate to ceramide ratio was higher in rats fed HFD. It is concluded that HFD stimulates the pro-mitotic action of the sphingolipid signaling in regenerating rat liver., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Serine palmitoyltransferase (SPT) is a key enzyme in de novo sphingolipid biosynthesis. SPT activity in liver is up-regulated by pro-inflammatory cytokines, which play an important role in initiation of liver regeneration after partial hepatectomy (PH). The aim of the study was to investigate the impact of a high-fat diet or PPARα activation by bezafibrate on the activity and protein expression of SPT in rat liver after PH. The animals were divided into three groups: those fed a standard chow (SD), those fed a high-fat diet (HFD), and those treated with bezafibrate (BF). It has been found that the expression and activity of SPT increased in regenerating liver. This was accompanied by the elevation of plasma NEFA concentration. Moreover, in both diet groups, the content of sphinganine increased. Bezafibrate decreased protein expression of SPT at the 4th and 12th hour, and inhibited SPT activity at the 4th hour after PH. Both, the plasma NEFA concentration and sphinganine content decreased in the groups treated with bezafibrate. We conclude that partial hepatectomy stimulates de novo sphingolipid synthesis. Activation of PPARα by bezafibrate negatively affects this process, presumably by decreasing the availability of plasma-borne fatty acids., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Liver regeneration after partial hepatectomy (PH) is achieved through proliferation of hepatocytes and non-parenchymal cells. The nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) is involved in regulation of lipid metabolism and proliferation of hepatic cells. The sphingomyelin signal transduction pathway is involved in the regulation of the cell cycle in eukaryotic organisms. Sphingosine-1-phosphate (S1P) and ceramide (CER)-- the intermediates of the pathway--are known to stimulate and to inhibit cellular proliferation. The aim of the present study was to investigate the effect of PPARalpha activation by bezafibrate on the sphingomyelin signaling pathway during the first 24h of liver regeneration after PH in the rat. The content of sphingomyelin, ceramide, sphingosine, sphinganine, sphingosine-1-phosphate and the activity of sphingomyelinases and ceramidases were determined at various time points after PH. It has been found that the activity of neutral Mg(2+)-dependent sphingomyelinase (nSMase) increased, whereas the activity of acidic sphingomyelinase (aSMase) decreased in the regenerating liver. Activation of PPARalpha by bezafibrate lower the activity of nSMase and increased the activity of aSMase in the regenerating rat liver. The content of ceramide was higher in bezafibrate-treated rats, whereas the content of sphingosine-1-phosphate was markedly lower as compared to the untreated rats. Therefore, it is concluded that activation of PPARalpha by bezafibrate decreases the growth-stimulatory activity of the sphingomyelin pathway in regenerating rat liver.

Sphingomyelin signal transduction pathway regulates cell cycle through a number of lipid second messengers, which stimulate cell proliferation (sphingosine-1-phosphate), initiate growth arrest or induce apoptosis (sphingosine, ceramide). To asses the functioning of sphingomyelin pathway during liver regeneration after partial hepatectomy in rat (PH) we measured the content of sphingomyelin (SM), ceramide (CER), sphingosine (SPH), sphingosine-1-phosphate (S1P), the activity of neutral Mg(2+)-dependent and acidic sphingomyelinases and ceramidases, in the remnant liver lobes during the first 24h after PH in rat. The activity of acidic ceramidase was highest at 4th hour after PH, whereas the activity of neutral ceramidases peaked at 12th hour after the operation. At these time points the activity Mg(2+)-dependent sphingomyelinase was also elevated, together with the content of SPH, S1P and the ratio of S1P to CER. The activity of acidic sphingomyelinase increased gradually from 4th to 24th hour after the operation. This was accompanied by significant increase in the content of ceramide between 4th and 24th hour and reduction in the content of S1P and S1P to CER ratio. It is concluded that partial hepatectomy induces production of the pro-mitogenic intermediates of sphingomyelin signaling pathway during the first 12h of liver regeneration in rat.