On the Impairment of Stress-Induced Changes in Triglyceride Levels via a Sub-Toxic Dose of Unmethylated Cytidine Phosphate Guanosine Oligodinucleotide (a Toll-Like Receptor 9 Ligand)

Changes in lipid metabolism have been implicated in protection against infectious diseases. In the first experiment of this study, we measured clinical lipid parameters in a murine model where the unmethylated cytidine phosphate guanosine (CpG) oligodinucleotide (ODN1826), a Toll-like receptor 9 (TLR9) agonist was administered in combination with D-galactosamine (GalN) that caused relatively liver-specific inflammation and toxicity. In the control mice group injected with phosphate-buffered saline (PBS) (acute psychological stress model associated with blood sampling), the serum triglyceride (TG) levels showed a rapid decrease followed by a rebound at 24 h as we have recently reported. However, such a TG rebound was impaired in the CpG/GalN- and solely CpG-treated groups of mice despite an absence of liver injury based on serum alanine aminotransferase levels in the latter group. Thus, the stress-associated serum TG rebound was abrogated by the injection of a sub-hepatotoxic CpG dose. In the second experiment, we simply measured the hepatic CD36 and SACRB1 (the gene for scavenger receptor B1 (SR-B1)) transcripts after the i.p. administration of PBS, CpG or CpG/GalN. There was a remarkable elevation of hepatic CD36 transcript expression in both the CpG- and CpG/GalN-treated mice at 8 h post-CpG injection whereas the increase in the PBS-treated mice was slower than the former two groups, suggesting that hepatic CD36 transcript expression is more pronounced in the combined stress models than under psychological stress alone. The individual mice data showed that the increase in CD36 expression was accompanied by a reduction in SCARB1 mRNA, showing reciprocal regulation between these two genes. Together with our previously reported findings, these data suggest that, in a murine model combining psychological stress with TLR-triggered hepatic inflammation, the psychological stress facilitates liver uptake of plasma TG (and its components fatty acids), but the subsequent re-esterification and/or release of TG-rich lipoproteins from the liver is impaired due to the concomitant TLR-signaling. We hypothesize that lipid metabolism during acute stress shifts toward an elevated hepatic uptake of lipids due to concomitant TLR signaling, facilitating the clearance of bacterial lipids by the liver.

Upregulation of caveolin-1 and SR-B1 in mice with non-alcoholic fatty liver disease

BACKGROUND:Non-alcoholic fatty liver disease(NAFLD)is one of the most frequent causes of liver diseases,with markedly increased prevalence.However,its mechanisms are not clear.The present study was undertaken to illustrate the role of caveolin-1(cav1)and the scavenger receptor class B type 1(SR-B1)in NAFLD.METHODS:Adult male C57BL/6 mice were fed with a normal diet or high fat and cholesterol(HFC)diet for 14 weeks.The mice were sacrificed to collect plasma and harvest the liver;their plasma lipid concentration was measured.Hepatic cav1and SR-B1 mRNA and protein expression were determined by real-time quantitative polymerase chain reaction(qPCR)and Western blotting,respectively.In order to study cav1 and SR-B1distribution and change in hepatocytes,immunohistochemical analysis was performed.RESULTS:HFC diet increased plasma lipids,induced NAFLD and increased the liver/body weight ratio.Compared to the control mice(n=6),the mRNA and protein levels of cav1 and SR-B1 in liver tissue of the NAFLD mice(n=12)increased significantly(cav1 mRNA:1.536±0.226 vs 0.980±0.272,P【0.05;protein:0.643±0.240 vs 0.100±0.130,P【0.01;SR-B1 mRNA:1.377±0.125 vs 0.956±0.151,P【0.01;protein:2.156±0.507vs 0.211±0.211,P【0.01).Furthermore,both cav1 and SR-B1immunoreactivity increased and their distribution was also changed,mainly in the plasma membrane of hepatocytes,cytoplasm and membrane of lipid droplets and around.CONCLUSION:NAFLD is associated with increased concentration of plasma lipids and upregulation of hepatic cav1 and SR-B1 gene and protein expressions,which indicate that cav1 and SR-B1 might play crucial roles in the pathogenesis of NAFLD.

Scavenger Receptor Class B type 1(SR-B1)and the modifiable risk factors of stroke

Stroke is a devastating disease that occurs when a blood vessel in the brain is either blocked or ruptured,consequently leading to deficits in neurological function.Stroke consistently ranked as one of the top causes of mortality,and with the mean age of incidence decreasing,there is renewed interest to seek novel therapeutic treatments.The Scavenger Receptor Class B type 1(SR-B1)is a multifunctional protein found on the surface of a variety of cells.Research has found that that SR-B1 primarily functions in an anti-inflammatory and antiatherosclerotic capacity.In this review,we discuss the characteristics of SR-B1 and focus on its potential correlation with the modifiable risk factors of stroke.SR-B1 likely has an impact on stroke through its interaction with smoking,diabetes mellitus,diet,physical inactivity,obesity,hypercholesterolemia,atherosclerosis,coronary heart disease,hypertension,and sickle cell disease,all of which are critical risk factors in the pathogenesis of stroke.

HDL signaling and protection against coronary artery atherosclerosis in mice

Atherosclerosis is a leading underlying factor in cardiovascular disease and stroke,important causes of morbidity and mortality across the globe.Abundant epidemiological studies demonstrate that high levels of high density lipoprotein（HDL） are associated with reduced risk of atherosclerosis and preclinical,animal model studies demonstrate that this association is causative.Understanding the molecular mechanisms underlying the protective effects of HDL will allow more strategic approaches to development of HDL based therapeutics.Recent evidence suggests that an important aspect of the ability of HDL to protect against atherosclerosis is its ability to trigger signaling responses in a variety of target cells including endothelial cells and macrophages in the vessel wall.These signaling responses require the HDL receptor,scavenger receptor class B type 1（SR-B1）,an adaptor protein（PDZK1） that binds to the cytosolic C terminus of SR-B1,Akt1 activation and（at least in endothelial cells） activation of endothelial NO synthase（eNOS）.Mouse models of atherosclerosis,exemplified by apolipoprotein E or low density lipoprotein receptor gene inactivated mice（apoE or LDLR KO） develop atherosclerosis in their aortas but appear generally resistant to coronary artery atherosclerosis.On the other hand,inactivation of each of the components of HDL signaling（above）in either apoE or LDLR KO mice renders them susceptible to extensive coronary artery atherosclerosis suggesting that HDL signaling may play an important role in protection against coronary artery disease.

Coupled single-cell and bulk RNA-seq analysis reveals the engulfment role of endothelial cells in atherosclerosis

The clearance of apoptotic cell debris,containing professional phagocytosis and non-professional phagocytosis,is essential for maintaining the homeostasis of healthy tissues.Here,we discovered that endothelial cells could engulf apoptotic cell debris in atherosclerotic plaque.Single-cell RNA sequencing(RNA-seq)has revealed a unique endothelial cell subpopulation in atherosclerosis,which was strongly associated with vascular injury-related pathways.Moreover,integrated analysis of three vascular injury-related RNA-seq datasets showed that the expression of scavenger receptor class B type 1(SR-B1)was up-regulated and specifically enriched in the phagocytosis pathway under vascular injury circumstances.Single-cell RNA-seq and bulk RNA-seq indicate that SR-B1 was highly expressed in a unique endothelial cell subpopulation of mouse aorta and strongly associated with the reorganization of cellular adherent junctions and cytoskeleton which were necessary for phagocytosis.Furthermore,SR-B1 was strongly required for endothelial cells to engulf apoptotic cell debris in atherosclerotic plaque of both mouse and human aorta.Overall,this study demonstrated that apoptotic cell debris could be engulfed by endothelial cells through SR-B1 and associated with the reorganization of cellular adherent junctions and cytoskeleton.