Apolipoprotein D modulates lipid mediators and osteopontin in an anti-inflammatory direction.

BACKGROUND: HDL has been proposed to possess anti-inflammatory properties; however, the detail mechanisms have not been fully elucidated. METHODS: We investigated the roles of Apolipoprotein D (ApoD) in the pathogenesis of inflammation in the mouse model of diet-induced obesity and that of lipopolysaccharide-induced sepsis and the in vitro experiments. Furthermore, we analyzed serum ApoD levels in human subjects. RESULTS: The overexpression of human ApoD decreased the plasma IL-6 and TNF-a levels in both mice models. Lipidomics analyses demonstrated association of ApoD with increase of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, as well as of their metabolites, and of the anti-inflammatory molecule sphingosine 1-phosphate, and decrease of proinflammatory lysophosphatidic acids and lysophosphatidylinositol. ApoD-containing lipoproteins might directly bind eicosapentaenoic acid and docosahexaenoic acid. The modulations of the lysophosphatidic acid and sphingosine 1-phosphate levels resulted from the suppression of autotaxin expression and elevation of apolipoprotein M (ApoM), respectively. Moreover, ApoD negatively regulated osteopontin, a proinflammatory adipokine. The activation of PPARg by ApoD might suppress autotaxin and osteopontin. Serum ApoD levels were negatively correlated with the serum osteopontin and autotaxin levels and, positively with serum ApoM levels. CONCLUSION: ApoD is an anti-inflammatory apolipoprotein, which modulates lipid mediators and osteopontin in an anti-inflammatory direction.

Risk Factors for Vulnerable Plaque Detected Using Near-Infrared Spectroscopy in Patients Receiving Statin Therapy with No History of Coronary Artery Disease.

Residual risk of atherosclerosis remains high despite the use of lipid-lowering therapy with statins. Near-infrared spectroscopy intravascular ultrasound imaging (NIRS-IVUS) can identify vulnerable plaque via the detection of lipid-rich plaque. This study aimed to reveal the clinical characteristics of patients with vulnerable plaque despite statin therapy.NIRS-IVUS was used to determine the maximum 4 mm Lipid Core Burden Index (MaxLCBI4 mm) values of 38 de novo culprit lesions from 32 patients with acute coronary syndrome (53%) (mean age: 73.1 ± 13.1 years) who underwent percutaneous coronary intervention after a minimum 6 months of statin therapy for primary prevention. A patient with vulnerable plaque was defined as an individual presenting at least 1 target lesion with a vulnerable plaque (MaxLCBI4 mm > 400). Overall, the average low-density lipoprotein cholesterol (LDL-C) level was 95.5 ± 27.2 mg/dL. Patients in the vulnerable plaque group were younger and had higher LDL-C, triglycerides, and non-high-density lipoprotein cholesterol (HDL-C) levels than those in the non-vulnerable plaque group. The MaxLCBI4 mm was positively correlated with LDL-C (P = 0.0002), triglycerides (P = 0.0003), and non-HDL-C (P = 0.0001). In multivariate analysis, all 3 treatable lipid components failed to show an independent relationship with the patients with vulnerable plaque. Using receiver-operating characteristics curve analysis, the cutoff points for LDL-C, triglycerides, and non-HDL-C were determined to be 78 mg/dL, 108 mg/dL, and 111 mg/dL, respectively, at MaxLCBI4 mm > 400. In conclusion, this study supports a more comprehensive and aggressive lipid-lowering therapy for the primary prevention of coronary artery disease.

Modulation of sphingosine 1-phosphate by hepatobiliary cholesterol handling.

Hepatobiliary cholesterol handling, mediated by Niemann-Pick C1-like 1 protein (NPC1L1) and ABCG5/8, is well-known to contribute to the homeostasis of cholesterol. We attempted to elucidate the impact of hepatobiliary cholesterol handling on the homeostasis of sphingolipids and lysophospholipids, especially sphingosine 1-phosphate (S1P). We induced the overexpression of NPC1L1 or ABCG5/8 in the mouse liver. Hepatic NPC1L1 overexpression increased the plasma and hepatic S1P levels, while it decreased the biliary S1P levels, and all of these changes were inhibited by ezetimibe. The ability of HDL to activate Akt in the endothelial cells was augmented by hepatic NPC1L1 overexpression. NPC1L1-mediated S1P transport was confirmed by both in vitro and in vivo studies conducted using C17 S1P, an exogenous S1P analog. Upregulation of apolipoprotein M (apoM) was involved in these modulations, although apoM was not necessary for these modulations. Moreover, the increase in the plasma S1P levels also observed in ABCG5/8-overexpressing mice was dependent on the elevation of the plasma apoM levels. In regard to other sphingolipids and lysophospholipids, ceramides were similarly modulated by NPC1L1 to S1P, while other lipids were differently influenced by NPC1L1 or ABCG5/8 from S1P. Hepatobiliary cholesterol handling might also regulate the functional lipids, such as S1P.

Fructo-oligosaccharides ameliorate steatohepatitis, visceral adiposity, and associated chronic inflammation via increased production of short-chain fatty acids in a mouse model of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Within the spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) in combination with hepatic inflammation and fibrosis can lead to liver cirrhosis and hepatocellular carcinoma. Dysbiosis was reported to contribute to NASH pathogenesis. This study aimed to determine the effects of fructo-oligosaccharides (FOS) on steatohepatitis and visceral adiposity in an obese mouse model of NASH. METHODS: Twelve newborn C57BL/6 J male mice were subcutaneously injected with monosodium glutamate (MSG) to induce obesity on a conventional diet. Six mice were also administered 5% FOS via drinking water from 10 weeks of age. At 18 weeks, histological characteristics of the liver and epididymal fat were compared between the groups. Hepatic mRNA expression of lipid metabolism enzymes and SCFA in feces and sera were measured. RESULTS: Hepatic steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the liver and increased hepatic mRNA expression of fatty acid synthase and glycerol-3-phosphate acyltransferase were observed in the MSG-treated mice. FOS treatment improved the liver pathology and blunted the increases in the mRNA expression levels of lipid metabolism enzymes. In addition, FOS inhibited adipocyte enlargement and formation of crown-like structures and reduced the M1 macrophage frequency in the epididymal fat of the MSG mice (39.4% ± 3.0% vs. 22.8% ± 0.7%; P = 0.001). FOS increased not only the fecal concentrations of n-butyric acid (0.04 ± 0.01 vs. 0.38 ± 0.14 mg/g, P = 0.02), propionic acid (0.09 ± 0.03 vs. 0.42 ± 0.16 mg/g, P = 0.02), and acetic acid (0.65 ± 0.16 vs. 1.48 ± 0.29 mg/g, P = 0.03) but also the serum concentration of propionic acid (3.9 ± 0.5 vs. 8.2 ± 0.5 µmol/L, P = 0.001). CONCLUSIONS: FOS ameliorates steatohepatitis, visceral adiposity, and chronic inflammation by increasing SCFA production.

Regulation of plasma glycero-lysophospholipid levels by lipoprotein metabolism.

Glycero-lysophospholipids, such as lysophosphatidic acids and lysophosphatidylserine, are gathering attention, since specific receptors have been identified. Most of these compounds have been proposed to be bound to albumin, while their associations with lipoproteins have not been fully elucidated. Therefore, in this study, we aimed to investigate the contents of glycero-lysophospholipids (lysophosphatidic acids, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylinositol, and lysophosphatidylserine) on lipoproteins and the modulation of their metabolism by lipoprotein metabolism. We observed that moderate amounts of glycero-lysophospholipids, with the exception of lysophosphatidylserine, were distributed on the LDL and HDL fractions, and glycero-lysophospholipids that had bound to albumin were observed in lipoprotein fractions when they were co-incubated. The overexpression of cholesteryl ester transfer protein decreased the plasma levels of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol and it increased their contents in apoB-containing lipoproteins, while it decreased their contents in HDL and lipoprotein-depleted fractions in mice. The overexpression of the LDL receptor (LDLr) decreased the plasma levels of lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, and lysophosphatidylinositol and decreased the contents of these compounds in the LDL, HDL, and lipoprotein-depleted fractions, while the knockdown of the LDLr increased them. These results suggest the potential importance of glycero-lysophospholipids in the pleiotropic effects of lipoproteins as well as the importance of lipoprotein metabolism in the regulation of glycero-lysophospholipids.

Regulation of the metabolism of apolipoprotein M and sphingosine 1-phosphate by hepatic PPARγ activity.

Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multifunctional bioactive lipid. Since peroxisome proliferator-activated receptor γ (PPARγ) is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARγ. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARγ in HepG2 cells and found that both the overexpression and the knockdown of PPARγ decreased apoM expression and S1P synthesis. When we activated or suppressed the PPARγ more mildly with pioglitazone or GW9662, we found that pioglitazone suppressed apoM expression and S1P synthesis, while GW9662 increased them. Next, we overexpressed PPARγ in mouse liver through adenoviral gene transfer and observed that both the plasma and hepatic apoM levels and the plasma S1P levels decreased, while the hepatic S1P levels increased, in the presence of enhanced sphingosine kinase activity. Treatment with pioglitazone decreased both the plasma and hepatic apoM and S1P levels only in diet-induced obese mice. Moreover, the overexpression of apoM increased, while the knockdown of apoM suppressed PPARγ activities in HepG2 cells. These results suggested that PPARγ regulates the S1P levels by modulating apoM in a bell-shaped manner, with the greatest levels of apoM/S1P observed when PPARγ was mildly expressed and that hepatic apoM/PPARγ axis might maintain the homeostasis of S1P metabolism.

Sitosterol prevents obesity-related chronic inflammation.

The physiological roles of phytosterols in chronic inflammation, which are believed to be involved in the underlying mechanisms for metabolic diseases, have yet to be elucidated. Therefore, in the present study, we aimed to elucidate the physiological roles of phytosterols in both clinical studies and animal experiments. We observed the existence of rather specific negative correlations between the serum sitosterol level and the serum IL-6 and the TNF-α levels in both diabetic subjects (n=46) and non-diabetic subjects (n=178). Multiple regression analyses also revealed that the serum IL-6 and TNF-α levels exhibited strong negative correlations with the serum sitosterol levels. When ABCG5/8 KO mice with markedly elevated plasma sitosterol levels and ABCG5/8 hetero mice were fed a high-fat diet, we observed that the increase in body weight, the fatty liver changes, and the expansion of perigonadal adipose tissues were suppressed in ABCG5/8 KO mice without any modulation of food intake. We also observed that the plasma IL-6 and TNF-α levels, the expressions of TNF-α and PAI-1 in the liver and the expressions of the IL-6, TNF-α, and MCP-1 levels in the adipose tissue were lower in ABCG5/8 KO mice. These results suggest that sitosterol might suppress obesity-related chronic inflammation and might be applicable to the treatment of metabolic diseases.

Involvement of CETP (Cholesteryl Ester Transfer Protein) in the Shift of Sphingosine-1-Phosphate Among Lipoproteins and in the Modulation of its Functions.

OBJECTIVE: Sphingosine-1-phosphate (S1P) is a vasoprotective lipid mediator. About two thirds of plasma S1P rides on high-density lipoprotein (HDL), and several pleiotropic properties of HDL have been ascribed to S1P. In human subjects, CETP (cholesteryl ester transfer protein) greatly influences HDL quantities. In this study, we attempted to elucidate the roles of CETP in the metabolism of S1P. APPROACH AND RESULTS: We overexpressed CETP in mice that lacked CETP and found that CETP overexpression decreased the HDL level but failed to modulate the levels of S1P and apolipoprotein M (apoM), a carrier of S1P, in the total plasma. We observed, however, that the distribution of S1P and apoM shifted from HDL to apoB-containing lipoproteins. When we administered C17S1P bound to apoM-containing lipoprotein, C17S1P and apoM were rapidly transferred to apoB-containing lipoproteins in CETP-overexpressing mice. When HDL containing C17S1P was mixed with low-density lipoprotein ex vivo, C17S1P shifted to the low-density lipoprotein fraction independent of the presence of CETP. Concordant with these results, apoM was distributed mainly to the same fraction as apo AI in a CETP-deficient subject, although apoM was also detected in apo AI-poor fractions in a corresponding hypercholesterolemia subject. About the bioactivities of S1P carried on each lipoprotein, S1P riding on apoB-containing lipoproteins induced the phosphorylation of Akt (AKT8 virus oncogene cellular homolog) and eNOS (endothelial nitric oxide synthase) in human umbilical vein endothelial cells, and CETP overexpression increased insulin secretion and sensitivity, which was inhibited by an S1P receptor 1 or 3 antagonist. CONCLUSIONS: CETP modulates the distribution of S1P among lipoproteins, which affects the bioactivities of S1P.

LDL receptor and ApoE are involved in the clearance of ApoM-associated sphingosine 1-phosphate.

Sphingosine 1-phosphate (S1P) is a vasoactive lipid mediator that is speculated to be involved in various aspects of atherosclerosis. About 70% of circulating plasma S1P is carried on HDL, and several pleiotropic properties of HDL have been ascribed to S1P. In the previous study with human subjects, however, LDL cholesterol or apoB, but not HDL cholesterol or apoA-I, had a significant positive correlation with the plasma S1P level, suggesting that the metabolic pathway for LDL might have some roles in the metabolism of S1P. In this study, we analyzed the association between LDL receptor, an important protein in the clearance of LDL, and circulating S1P. We observed that in LDL receptor-overexpressing mice, the plasma S1P levels as well as apolipoprotein M (apoM), a carrier of S1P, were decreased and that exogenously administered C17S1P bound to apoM-containing lipoproteins was cleared more rapidly. Unlike the situation in wild-type mice, LDL receptor overexpression in apoE-deficient mice did not reduce the plasma S1P or apoM levels, suggesting that apoE might be a ligand for the LDL receptor during the clearance of these factors. The present findings clarify the novel roles of the LDL receptor and apoE in the clearance of S1P, a multifunctional bioactive phospholipid.

Genome-wide association study of serum lipids confirms previously reported associations as well as new associations of common SNPs within PCSK7 gene with triglyceride.

Previous reports including genome-wide association studies (GWASs) have described associations of serum lipids with genomic variations. In the present study, we examined the association of ∼2.5 million single-nucleotide polymorphisms (SNPs) from 3041 Japanese healthy volunteers obtained from the Japan Pharmacogenomics Data Science Consortium (JPDSC) database with serum lipids. We confirmed the previously reported associations of 14 SNPs in 5 regions for low-density lipoprotein (LDL) cholesterol, 23 SNPs in 12 regions for high-density lipoprotein (HDL) cholesterol, 16 SNPs in 6 regions for triglyceride and 5 SNPs in 1 region for phospholipid. Furthermore, we identified 16 possible novel candidate genes associated with LDL cholesterol, HDL cholesterol or triglycerides, where SNPs had P-values of <1 × 10(-5). Further replication analyses of these genes with Korean data revealed significant associations of SNPs located within the PCSK7 gene and triglyceride (Pmeta=7.98 × 10(-9) and 1.91 × 10(-8) for rs508487 and rs236911, respectively). These associations remained significant even by the conditional analysis adjusting for three neighboring variations associated with triglyceride. Our present data suggest that PCSK7 as well as PCSK9 may be associated with lipids, especially triglyceride, and may serve as a candidate for a new drug target to treat lipid abnormality syndromes.

Induction of insulin secretion by apolipoprotein M, a carrier for sphingosine 1-phosphate.

BACKGROUNDS: High-density lipoprotein (HDL) has been proposed to enhance ß-cell functions. Clinical studies have suggested that apolipoprotein M (apoM), which rides mainly on HDL, is involved in diabetes; however, the underlying mechanism has not yet been elucidated. Recently, apoM was shown to be a carrier for sphingosine 1-phosphate (S1P), a bioactive lipid mediator. In the present study, we investigated the modulation of insulin secretion by apoM through the action of S1P. METHODS AND RESULTS: We overexpressed apoM in the livers of C57BL6 mice using adenovirus gene transfer and found that the blood glucose levels under ad libitum feeding conditions were lower in the apoM-overexpressing mice. While an insulin tolerance test revealed that insulin sensitivity was not significantly affected, a glucose tolerance test revealed that apoM-overexpressing mice had a better glucose tolerance because of enhanced insulin secretion, a phenomenon that was reversed by treatment with VPC 23019, an antagonist against S1P1 and S1P3 receptor. In vitro experiments with MIN6 cells also revealed that apoM-containing lipoproteins enhanced insulin secretion, which was again inhibited by VPC 23019. ApoM retarded the degradation of S1P, and an increase in Pdx1 expression, the attenuation of endoreticulum stress, and the phosphorylation of Akt, AmpK, and Erk were observed as possible underlying mechanisms for the effect of S1P, maintained at a high concentration by apoM, on the increase in insulin secretion. CONCLUSIONS: ApoM augmented insulin secretion by maintaining the S1P concentration under both in vivo and in vitro conditions.

Splenic lymph follicles generate immunoglobulin M-producing B cells in primary biliary cirrhosis.

AIM: To reveal the site of immunoglobulin (Ig)M production in primary biliary cirrhosis (PBC) we performed immunohistochemical analysis on spleens collected from patients with PBC. METHODS: Splenic tissue samples were collected at the time of the autopsy from patients with hepatic failure. Immunostaining for IgM, CD21 and CXCL13 were performed using the splenic tissue samples. RESULTS: The samples from five out of eight cases with PBC but not in eight cases of chronic hepatitis C virus infection showed accumulation of IgM positive cells in CD21 positive lymph follicles. The CXCL13 positive cells also accumulated in the center of the lymph follicles where the IgM positive cells accumulated. CONCLUSION: The present results suggest that excess IgM is produced from the spleen of PBC. Furthermore, it was suggested that CXCL13 positive follicular dendritic cells possibly contribute to this process.

Apolipoprotein M/sphingosine 1-phosphate protects against diabetic nephropathy.

Diabetic nephropathy remains a common cause of end-stage renal failure and its associated mortality around the world. Sphingosine 1-phosphate (S1P) is a multifunctional lipid mediator and binds to HDL via apolipoprotein M (ApoM). Since HDL has been reported to be epidemiologically associated with kidney disease, we attempted to investigate the involvement of the ApoM/S1P axis in the pathogenesis/progression of diabetic nephropathy. In type 2 diabetic patients, the serum ApoM levels were inversely correlated with the clinical stage of diabetic nephropathy. The decline in the eGFR over a 5-year observation period proceeded more rapidly in subjects with lower serum ApoM levels. In a mouse model of streptozotocin-induced diabetes, deletion of ApoM deteriorated the phenotypes of diabetic nephropathy: the urinary albumin and plasma creatinine levels increased, the kidneys enlarged, and renal fibrosis and thickening of the basement membrane progressed. On the other hand, overexpression of ApoM ameliorated these phenotypes. These protective effects of ApoM were partially inhibited by treatment with VPC23019, an antagonist of S1P1 and S1P3, but not by treatment with JTE013, an antagonist of S1P2. ApoM/S1P axis attenuated activation of the Smad3 pathway, while augmented eNOS phosphorylation through the S1P1 pathway. Moreover, ApoM/S1P increased the SIRT1 protein levels and enhanced mitochondrial functions by increasing the S1P content of the cell membrane, which might cause selective activation of S1P1. ApoM might be a useful biomarker for predicting the progression of diabetic nephropathy, and the ApoM/S1P-S1P1 axis might serve as a novel therapeutic target for preventing the development/progression of diabetic nephropathy.

Modulation of lipid metabolism with the overexpression of NPC1L1 in mouse liver.

Niemann-Pick C1-like 1 protein (NPC1L1), a transporter crucial in intestinal cholesterol absorption, is expressed in human liver but not in murine liver. To elucidate the role of hepatic NPC1L1 on lipid metabolism, we overexpressed NPC1L1 in murine liver utilizing adenovirus-mediated gene transfer. C57BL/6 mice, fed on normal chow with or without ezetimibe, were injected with NPC1L1 adenovirus (L1-mice) or control virus (Null-mice), and lipid analyses were performed five days after the injection. The plasma cholesterol levels increased in L1-mice, and FPLC analyses revealed increased cholesterol contents in large HDL lipoprotein fractions. These fractions, which showed α-mobility on agarose electrophoresis, were rich in apoE and free cholesterol. These lipoprotein changes were partially inhibited by ezetimibe treatment and were not observed in apoE-deficient mice. In addition, plasma and VLDL triglyceride (TG) levels decreased in L1-mice. The expression of microsomal triglyceride transfer protein (MTP) was markedly decreased in L1-mice, accompanied by the reduced protein levels of forkhead box protein O1 (FoxO1). These changes were not observed in mice with increased hepatic de novo cholesterol synthesis. These data demonstrate that cholesterol absorbed through NPC1L1 plays a distinct role in cellular and plasma lipid metabolism, such as the appearance of apoE-rich lipoproteins and the diminished VLDL-TG secretion.

Isoform-Dependent Effects of Apolipoprotein E on Sphingolipid Metabolism in Neural Cells.

BACKGROUND: Sphingosine 1-phosphate (S1P) and ceramides have been implicated in the development of Alzheimer's disease. Apolipoprotein E (ApoE) isoforms are also involved in the development of Alzheimer's disease. OBJECTIVE: We aimed at elucidating the potential association of the ApoE isoforms with sphingolipid metabolism in the central nervous system. METHODS: We investigated the modulations of apolipoprotein M (apoM), a carrier of S1P, S1P, and ceramides in Apoeshl mice, which spontaneously lack apoE, and U251 cells and SH-SY5Y cells infected with adenovirus vectors encoding for apoE2, apoE3, and apoE4. RESULTS: In the brains of Apoeshl mice, the levels of apoM were lower, while those of ceramides were higher. In U251 cells, cellular apoM and S1P levels were the highest in the cells overexpressing apoE2 among the apoE isoforms. The cellular and medium contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 and increased in the cells overexpressing apoE4. In SH-SY5Y cells, apoM mRNA and medium S1P levels were also the highest in the cells overexpressing apoE2. The cellular contents of ceramides decreased in the order of the cells overexpressing apoE3 > apoE2 = apoE4 and those in medium decreased in the order of the cells overexpressing apoE3 > apoE2, while increased in the cells overexpressing apoE4. CONCLUSION: The modulation of apoM and S1P might partly explain the protective effects of apoE2 against Alzheimer's disease, and the modulation of ceramides might be one of the mechanisms explaining the association of apoE4 with the development of Alzheimer's disease.

LXR agonist increases apoE secretion from HepG2 spheroid, together with an increased production of VLDL and apoE-rich large HDL.

BACKGROUND: The physiological regulation of hepatic apoE gene has not been clarified, although the expression of apoE in adipocytes and macrophages has been known to be regulated by LXR. METHODS AND RESULTS: We investigated the effect of TO901317, a LXR agonist, on hepatic apoE production utilizing HepG2 cells cultured in spheroid form, known to be more differentiated than HepG2 cells in monolayer culture. Spheroid HepG2 cells were prepared in alginate-beads. The secretions of albumin, apoE and apoA-I from spheroid HepG2 cells were significantly increased compared to those from monolayer HepG2 cells, and these increases were accompanied by increased mRNA levels of apoE and apoA-I. Several nuclear receptors including LXRα also became abundant in nuclear fractions in spheroid HepG2 cells. Treatment with TO901317 significantly increased apoE protein secretion from spheroid HepG2 cells, which was also associated with the increased expression of apoE mRNA. Separation of the media with FPLC revealed that the production of apoE-rich large HDL particles were enhanced even at low concentration of TO901317, and at higher concentration of TO901317, production of VLDL particles increased as well. CONCLUSIONS: LXR activation enhanced the expression of hepatic apoE, together with the alteration of lipoprotein particles produced from the differentiated hepatocyte-derived cells. HepG2 spheroids might serve as a good model of well-differentiated human hepatocytes for future investigations of hepatic lipid metabolism.

Malaria Parasites Hijack Host Receptors From Exosomes to Capture Lipoproteins.

Malaria parasites cannot multiply in host erythrocytes without cholesterol because they lack complete sterol biosynthesis systems. This suggests parasitized red blood cells (pRBCs) need to capture host sterols, but its mechanism remains unknown. Here we identified a novel high-density lipoprotein (HDL)-delivery pathway operating in blood-stage Plasmodium. In parasitized mouse plasma, exosomes positive for scavenger receptor CD36 and platelet-specific CD41 increased. These CDs were detected in pRBCs and internal parasites. A low molecular antagonist for scavenger receptors, BLT-1, blocked HDL uptake to pRBCs and suppressed Plasmodium growth in vitro. Furthermore, platelet-derived exosomes were internalized in pRBCs. Thus, we presume CD36 is delivered to malaria parasites from platelets by exosomes, which enables parasites to steal HDL for cholesterol supply. Cholesterol needs to cross three membranes (RBC, parasitophorous vacuole and parasite's plasma membranes) to reach parasite, but our findings can explain the first step of sterol uptake by intracellular parasites.

Protection Against Insulin Resistance by Apolipoprotein M/Sphingosine-1-Phosphate.

Subjects with low serum HDL cholesterol levels are reported to be susceptible to diabetes, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (apoM) is a carrier of sphingosine-1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the current study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes and that they were negatively correlated with BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also by improving the mitochondrial functions through upregulation of SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that apoM/S1P exerts protective roles against the development of insulin resistance.