The dengue virus non-structural protein 1 (NS1) uses the scavenger receptor B1 as a cell receptor in cultured cells

The dengue virus NS1 is a multifunctional protein that forms part of replication complexes. NS1 is also secreted, as a hexamer, to the extracellular milieu. Circulating NS1 has been associated with dengue pathogenesis by several mechanisms. Cell binding and internalization of soluble NS1 result in endothelial hyperpermeability and in the downregulation of the innate immune response. In this work, we report that the HDL scavenger receptor B1 (SRB1) in human hepatic cells and a scavenger receptor B1-like in mosquito C6/36 cells act as cell surface binding receptors for dengue virus NS1. The presence of the SRB1 on the plasma membrane of C6/36 cells, as well as in Huh7 cells, was demonstrated by confocal microscopy. The internalization of NS1 can be efficiently blocked by anti-SRB1 antibodies and previous incubation of the cells with HDL significantly reduces NS1 internalization. Significant reduction in NS1 internalization was observed in C6/36 cells transfected with siRNAs specific for SRB1. In addition, the transient expression of SRB1 in Vero cells, which lacks the receptor, allows NS1 internalization in these cells. Direct interaction between soluble NS1 and the SRB1 in Huh7 and C6/36 cells was demonstrated in situ by proximity ligation assays and in vitro by surface plasmon resonance. Finally, results are presented indicating that the SRB1 also acts as a cell receptor for Zika virus NS1. These results demonstrate that dengue virus NS1, a bona fide lipoprotein, usurps the HDL receptor for cell entry and offers explanations for the altered serum lipoprotein homeostasis observed in dengue patients. Importance Dengue is the most common viral disease transmitted to humans by mosquitoes. The dengue virus NS1 is a multifunctional glycoprotein necessary for viral replication. NS1 is also secreted as a hexameric lipoprotein and circulates in high concentrations in the sera of patients. Circulating NS1 has been associated with dengue pathogenesis by several mechanisms, including favoring of virus replication in hepatocytes and dendritic cells and disruption of the endothelial glycocalyx leading to hyperpermeability. Those last actions require NS1 internalization. Here, we identify the scavenger cell receptor B1, as the cell-binding receptor for dengue and Zika virus NS1, in cultured liver and in mosquito cells. The results indicate that flavivirus NS1, a bona fide lipoprotein, usurps the human HDL receptor and may offer explanations for the alterations in serum lipoprotein homeostasis observed in dengue patients.

Correlation between Levels of Serum Lipoprotein-Associated Phospholipase A2 and Soluble Suppression of Tumorigenicity 2 and Condition of Acute Heart Failure Patients and Their Predictive Value for Prognosis

Objective. To explore the correlation between levels of serum lipoprotein-associated phospholipase A2 (LP-PLA2) and soluble suppression of tumorigenicity 2 (sST2) and condition of acute heart failure (AHF) patients and their predictive value for prognosis. Methods. The data of patients who complained of acute dyspnea and were treated in our hospital (January 2018–January 2020) were selected for review analysis, and those diagnosed with AHF by means of chest films, physical examination, cardiogram, and color Doppler ultrasonography (CDS) were selected as the study objects. The patients were split into the mild group (I or II, 55 cases) and the severe group (III or IV, 50 cases) according to the clinical condition grading standard in Guidelines for Diagnosis and Treatment of Acute Heart Failure. In addition, 105 healthy individuals examined in our medical center in the same period were selected as the control group. The serum LP-PLA2 and sST2 levels of all study objects were measured to analyze the correlation between these levels and AHF condition. Readmission due to heart failure and all-cause death were regarded as the endpoint events, and after one year of follow-up visits, the occurrence of the endpoint events in patients of the two groups was recorded, and with the endpoint events as the variable, the patients were divided into the event group and nonevent group to establish a logistic regression analysis model and analyze the merit of serum LP-PLA2 and sST2 in evaluating patient outcome. Results. The patients’ general information such as age and gender between the severe group and the mild group were not statistically different ( P > 0.05 ), and the levels of high-sensitivity c-reactive protein (CRP), hemoglobin, creatinine, and uric acid of the severe group were greatly different from those of the mild group ( P < 0.001 ), the comparison result of serum LP-PLA2 and sST2 levels was severe group > mild group > control group ( P all <0.001), and the serum LP-PLA2 and sST2 levels of the severe group were, respectively, 275.98 ± 50.68 ng/ml and 2,122.65 ± 568.65 ng/ml; among 105 AHF patients, 50 of them had endpoint events (47.6%), including 36 in the severe group (36/50, 72.0%) and 14 in the mild group (14/55, 25.5%), and the event group presented greatly higher serum LP-PLA2 and sST2 levels than in the nonevent group ( P < 0.001 ); according to the logistic regression analysis, serum LP-PLA2 and sST2 had independent predictive value for prognosis of AHF patients, which could be used as the independent predictive factors for 1-year prognosis. Conclusion. Serum LP-PLA2 and sST2 have a good diagnosis value for the condition and prognosis of AHF patients, which shall be promoted and applied in practice.

Relationship Between Lipoprotein (a) [Lp(a)] and Cognition in Different Ischemic Stroke Subtypes

Background and Purpose: Although elevated serum lipoprotein (a) [Lp(a)] is considered to be a risk factor of ischemic stroke, the relationship between Lp(a) and cognitive impairment after stroke remains unclear. This study investigated the association between serum Lp(a) and cognitive function after acute ischemic stroke (AIS) or transient ischemic attack (TIA).Methods: The study included 1,017 patients diagnosed with AIS or TIA from the cognition subgroup of the Third China National Stroke Registry (CNSR3). Montreal Cognitive Assessment (MoCA) at 2 weeks or discharge, 3 months, and 1 year was evaluated. The primary outcome was cognitive impairment at 1 year, defined as MoCA ≤ 22. The secondary outcome was cognition improvement at 1 year compared with 2 weeks. The association between Lp(a) levels and cognitive function was analyzed.Results: Among the 1,017 patients included, 326 (32.1%) had cognitive impairment at 1 year. Patients with MoCA ≤ 22 at 1 year were older, received less education, and had higher baseline NIHSS, higher proportion of ischemic stroke history, large artery atherosclerosis (LAA) subtype, and multiple infarctions (P &lt; 0.05 for all). Patients with highest Lp(a) quartile had slightly higher percentage of cognitive impairment at 1 year but without statistical difference. In subgroup analysis of LAA subtype, the patients with highest Lp(a) quartile had higher percentage of cognitive impairment at 1 year (adjusted OR:2.63; 95% CI: 1.05–6.61, P &lt; 0.05). What is more, the patients with highest Lp(a) quartile in LAA subtype had lower percentage of cognition improvement at 1 year. However, similar results were not found in small artery occlusion (SAO) subtype.Conclusion: Higher Lp(a) level was associated with cognitive impairment and less improvement of cognition in patients after AIS or TIA with large-artery atherosclerosis subtype.

Loss of hepatic Lgr4 and Lgr5 promotes nonalcoholic fatty liver disease

Background & Aims: The Rspo–Lgr4/5–Znrf3/Rnf43 module is a master regulator of hepatic Wnt/β–catenin signaling and metabolic zonation, but its impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. We studied whether liver–specific loss of the Wnt/β–catenin modulators Leucine–Rich Repeat–Containing G Protein–Coupled Receptor 4/5 (Lgr4/5) promotes nonalcoholic fatty liver disease (NAFLD). Methods: Mice with liver–specific deletion of both receptors Lgr4/5 (Lgr4/5dLKO) were fed with normal diet (ND) or high fat diet (HFD). Livers of these mice were analyzed for lipid and fibrotic content by tissue staining and immunohistochemistry (IHC), and lipoproteins, inflammation and liver enzyme markers were measured in blood. Mechanistic insights into hepatic lipid accumulation were obtained by using ex vivo primary hepatocyte cultures derived from the Lgr4/5dLKO mice. Lipid analysis of mouse livers was performed by mass spectrometry (MS)–based untargeted lipidomic analysis. Results: We demonstrated that liver-specific ablation of Lgr4/5–mediated Wnt signaling resulted in hepatic steatosis, impaired bile acid (BA) secretion and predisposition to liver fibrosis. Under HFD conditions, we observed progressive intrahepatic fat accumulation, developing into macro–vesicular steatosis. Serum lipoprotein levels in HFD–fed Lgr4/5dLKO mice were decreased, rather than increased, suggesting that accumulation of fat in the liver was due to impaired lipid secretion by hepatocytes. Our lipidome analysis revealed a severe alteration of several lipid species in livers of Lgr4/5dLKO mice, including triacylglycerol estolides (TG–EST), a storage form of bioactive free fatty acid (FA) esters of hydroxy FAs (FAHFAs). Conclusions: Loss of hepatic Wnt/β–catenin activity by Lgr4/5 deletion led to deregulation of lipoprotein pathways, loss of BA secretion, intrinsic alterations of lipid homeostasis and the onset of NAFLD.

Bilateral frontal intracranial xanthoma associated with type II hyperlipidemia in a 42-year-old woman: illustrative case

BACKGROUND Xanthoma is a granulomatous lesion that develops from leakage of circulating serum lipoprotein into the surrounding tissue. An isolated intracranial xanthoma is rarely reported and usually misdiagnosed. Intracranial xanthoma is also rarely found in patients with hyperlipidemia. To the best of the authors’ knowledge, no previous studies and literature have reported bilateral involvement of intracranial xanthoma in the frontal lobe. OBSERVATIONS The authors reported an unusual case of bilateral involvement of intracranial xanthoma in the frontal lobe with associated type II hyperlipidemia in a 42-year-old woman. Macroscopically, the tumor had an appearance of greyish-yellow color with a brittle, solid consistency. Histopathological examination revealed numerous lipid-laden macrophages surrounded by a cystic, necrotic, partially hemorrhagic area, with some parts consisting of hemosiderophages and proliferative capillary blood vessels. The histopathological findings indicated the characteristics of xanthoma. LESSONS Bilateral frontal intracranial xanthoma with associated type II hyperlipidemia is an unusual finding. Despite its rarity and wide variety of radiological presentations, it should be considered one of the differential diagnoses of lesions that develop intracranially and intraaxially. Confirmation with histopathological examination is needed to exclude from other differential diagnoses.

Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility

Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyrc-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.

The Application Value of Lipoprotein Particle Numbers in the Diagnosis of HBV-Related Hepatocellular Carcinoma with BCLC Stage 0-A

Early diagnosis is essential for improving the prognosis and survival of patients with hepatocellular carcinoma (HCC). This study aims to explore the clinical value of lipoprotein subfractions in the diagnosis of hepatitis B virus (HBV)-related HCC. Lipoprotein subfractions were detected by 1H-NMR spectroscopy, and the pattern-recognition method and binary logistic regression were performed to classify distinct serum profiles and construct prediction models for HCC diagnosis. Differentially expressed proteins associated with lipid metabolism were detected by LC-MS/MS, and the potential prognostic significance of the mRNA expression was evaluated by Kaplan–Meier survival analysis. The diagnostic panel constructed from the serum particle number of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL-1~LDL-6) achieved higher accuracy for the diagnosis of HBV-related HCC and HBV-related benign liver disease (LD) than that constructed from serum alpha-fetoprotein (AFP) alone in the training set (AUC: 0.850 vs. AUC: 0.831) and validation set (AUC: 0.926 vs. AUC: 0.833). Furthermore, the panel achieved good diagnostic performance in distinguishing AFP-negative HCC from AFP-negative LD (AUC: 0.773). We also found that lipoprotein lipase (LPL) transcript levels showed a significant increase in cancerous tissue and that high expression was significantly positively correlated with the poor prognosis of patients. Our research provides new insight for the development of diagnostic biomarkers for HCC, and abnormal lipid metabolism and LPL-mediated abnormal serum lipoprotein metabolism may be important factors in promoting HCC development.

Lipoprotein-associated phospholipase A2 and carotid intima-media thickness in primary Sjögren syndrome

Objectives: This study aims to evaluate serum lipoprotein-associated phospholipase A2 (Lp-PLA2) level and carotid intima-media thickness in primary Sjögren syndrome (pSS) as an indicator of atherosclerosis. Patients and methods: Between July 2019 and July 2020, a total of 33 female pSS patients (mean age: 44.5±11.2 years; range, 23 to 60 years) and 37 female age- and sex-matched healthy individuals (mean age: 40.9±7.2 years; range, 25 to 54 years) were included. Carotid intima-media thickness and serum Lp-PLA2 levels were measured in the patient and control groups. Results: The patients had a higher median serum Lp-PLA2 of 560 (range, 108 to 1,222) ng/mL vs. 328 (range, 0 to 1,280) ng/mL in the controls (p=0.024) and a similar mean intima-media thickness of carotid artery (0.64±0.14 mm vs. 0.62±0.15 mm, respectively; p=0.595). Serum Lp-PLA2 was positively correlated with platelet count (r=0.411, p=0.018) and negatively correlated with erythrocyte sedimentation rate (r=-0.409, p=0.018). The mean value of carotid intima-media thickness was positively correlated with disease duration (r=0.316, p=0.074) and was negatively correlated with the level of leucocyte (r=-0.458, p=0.007). Conclusion: Our study suggests that the patients of pSS have a potential risk of atherosclerotic cardiovascular disease, independent of traditional cardiovascular risk factors and disease severity.

Preprocedural Lp(a) level and ApoB/ApoA-Ι ratio and the risk for contrast-induced acute kidney injury in patients undergoing emergency PCI

Background High serum Lipoprotein(a) (Lp(a)) level and Apolipoprotein B/Apolipoprotein AΙ (ApoB/ApoA-Ι) ratio are risk factors for cardiovascular disease and kidney disease and have been found to be correlated with the prevalence and prognosis of various kidney diseases. However, it is not clear whether the serum Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI are correlated with the prevalence of contrast-induced acute kidney injury (CI-AKI). Methods A total of 931 participants undergoing emergency PCI from July 2018 to July 2020 were included. According to whether the serum creatinine concentration was higher than the baseline concentration (by ≥25% or ≥ 0.5 mg/dL) 48–72 h after contrast exposure, these participants were divided into a CI-AKI group (n = 174) and a non-CI-AKI group (n = 757). Serum Lp(a), ApoA-Ι and ApoB concentration were detected in the patients when they were admitted to hospital, and the ApoB/ApoA-Ι ratio was calculated. Logistic regression and restricted cubic spline analyses were used to explore the correlation between the Lp(a) concentration or the ApoB/ApoA-Ι ratio and the risk of CI-AKI. Results Among the 931 participants undergoing emergency PCI, 174 (18.69%) participants developed CI-AKI. Compared with the non-CI-AKI group, the Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI in the CI-AKI group were significantly higher (P < 0.05). The incidence of CI-AKI was positively associated with the serum Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI in each logistic regression model (P < 0.05). After adjusting for all the risk factors included in this study, restricted cubic spline analyses found that the Lp(a) level and the ApoB/ApoA-Ι ratio before PCI, within certain ranges, were positively associated with the prevalence of CI-AKI. Conclusion High Lp(a) levels and high ApoB/ApoA-Ι ratios before PCI are potential risk factors for CI-AKI.