The EF-hand type calcium-binding protein S100A12 exerts numerous intra- and extracellular functions of (patho)physiological relevance. Therefore, receptors of S100A12 are of high interest for research and clinical applications. Beside the extensively studied receptor for advanced glycation endproducts (RAGE), G-protein coupled receptors and more recently, scavenger receptors are suggested to be putative S100A12 receptors. Own findings and further information from the literature predestined CD36, a class B scavenger receptor, as promising candidate. To substantiate or prove against this hypothesis, this study aimed at investigation of interaction of S100A12 and CD36 on molecular and cellular level by the use of surface plasmon resonance (SPR), radio- and fluorescence-tracer-based cell binding, and cell activation experiments. S100A12 revealed binding affinity to CD36 in the low nanomolar range, essentially, at the CD36 thrombospondin-1 binding site. Additionally, S100A12-mediated translocation of CD36 to the membrane and elevation of both CD36 and peroxisome proliferator-activated receptor γ (PPARγ) expression was observed, which suggest a potential regulatory function of S100A12-CD36 interaction.

Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival.

Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.

Scavenger receptor class B type I (SR-BI), the Scarb1 gene product, is a high-density lipoprotein (HDL) receptor which was shown to influence bone metabolism. Its absence in mice is associated with alterations of the glucocorticoid/adrenocorticotropic hormone axis, and translated in high bone mass and enhanced bone formation. Since the cellular alterations underlying the enhanced bone formation remain unknown, we investigated Scarb1-deficient marrow stromal cells (MSC) behavior in vitro. No difference in HDL3, cholesteryl ester (CE) or estradiol (E) association/binding was measured between Scarb1-null and wild-type (WT) cells. Scarb1 genic expression was down-regulated twofold following osteogenic treatment. Neither WT nor null cell proliferation was influenced by HDL3 exposure whereas this condition decreased genic expression of osteoblastic marker osterix (Sp7), and osteocyte markers sclerostin (Sost) and dentin matrix protein 1 (Dmp1) independently of genotype. Sost and Dmp1 basal expression in null cells was 40% and 50% that of WT cells; accordingly, osteocyte density was 20% lower in vertebrae from Scarb1-null mice. Genic expression of co-receptors for Wnt signaling, namely LDL-related protein (Lrp) 5 and Lrp8, was increased, respectively, by two- and threefold, and of transcription target-genes axis inhibition protein 2 (Axin2) and lymphoid enhancer-binding factor 1 (Lef1) over threefold. Gene expression of Wnt signaling agonist Wnt5a and of the antagonist dickkopfs-related protein 1 (Dkk1) were found to be increased 10- to 20-fold in null MSC. These data suggest alterations of Wnt pathways in Scarb1-deficient MSC potentially explaining their enhanced function, hence contributing to the high bone mass observed in these mice.

Scavenger receptors (SRs) are pattern recognition receptors (PRRs) vital for innate immunity. As well as their importance in immune recognition, microbe phagocytosis, and the clearance of modified endogenous molecules, they also activate downstream immune responses as co-receptors. In the current study, we identified a class B scavenger receptor in Eriocheir sinensis (EsSR-B2). The full-length gene is 2,517 bp and encodes a 517 amino acid polypeptide. EsSR-B2 is expressed widely in all tested tissues and is induced by microbial stimulation. Recombinant EsSR-B2 binds to bacteria and pathogen-associated molecular patterns in vitro. Upon knockdown of EsSR-B2 and bacterial challenge with Staphylococcus aureus or Vibrio parahaemolyticus, phagocytosis rates in hemocytes are decreased. Moreover, the expression of several antimicrobial peptides (AMPs) in response to distinct microorganism stimulation is decreased following EsSR-B2 silencing. Thus, EsSR-B2 is a PRR that protects E. sinensis against invading pathogens by promoting phagocytosis and enhancing AMP expression.

Scavenger receptor class A (SR-A) proteins are type II transmembrane glycoproteins that form homotrimers on the cell surface. This family has five known members (SCARA1 to 5, or SR-A1 to A5) that recognize a variety of ligands and are involved in multiple biological pathways. Previous reports have shown that some SR-A family members can bind modified low-density lipoproteins (LDLs); however, the mechanisms of the interactions between the SR-A members and these lipoproteins are not fully understood. Here, we systematically characterize the recognition of SR-A receptors with lipoproteins and report that SCARA1 (SR-A1, CD204), MARCO (SCARA2), and SCARA5 recognize acetylated or oxidized LDL and very-low-density lipoprotein in a Ca2+-dependent manner through their C-terminal scavenger receptor cysteine-rich (SRCR) domains. These interactions occur specifically between the SRCR domains and the modified apolipoprotein B component of the lipoproteins, suggesting that they might share a similar mechanism for lipoprotein recognition. Meanwhile, SCARA4, a SR-A member with a carbohydrate recognition domain instead of the SRCR domain at the C terminus, shows low affinity for modified LDL and very-low-density lipoprotein but binds in a Ca2+-independent manner. SCARA3, which does not have a globular domain at the C terminus, was found to have no detectable binding with these lipoproteins. Taken together, these results provide mechanistic insights into the interactions between SR-A family members and lipoproteins that may help us understand the roles of SR-A receptors in lipid transport and related diseases such as atherosclerosis.

Altered lipid metabolism is a well-documented hallmark of neoplastic transformation and impacts disease progression. Two major lipoprotein receptors, the low-density lipoprotein receptor (LDL-R) and scavenger receptor class B, type 1 (SR-BI) are overexpressed in a number of cancer types in people. These receptors serve to deliver cholesterol to the tumor cells and have been used to target drug therapies. In this study, we performed a retrospective analysis of LDL-R and SR-B1 expression in canine lymphoma using archived formalin-fixed tissue samples. Cases were immunophenotyped and classified according to World Health Organization (WHO) standards prior to immunostaining for the LDL_R and SR-B1. A total of 45 cases were evaluated; 21 high grade B (HGB), 11 low grade B (LGB), 7 high grade T (HGT), and 6 low grade T (LGT) lymphomas. One sided Wilcoxon rank sum tests were used to compare staining intensity between neoplastic and hyperplastic lymphoid tissue. The relationships between histological score and tumor grade and score and stage at presentation were assessed using non-parametric Kruskal-Wallis tests. Neoplastic lymphoid tissue expressed higher levels of both receptors compared to reactive lymph nodes. Median LDL-R score was 85.0 (interquartile range = 101.7), Median SR-B1 score was 209.0 (interquartile range 105.2). No relationship between LDL-R or SR-B1 staining score and tumor grade or phenotype was found. Serum cholesterol concentration was compared between dogs with high and low grade tumors using a two sample T-test, and correlations between cholesterol concentration and histological score, and between the score for the two receptors were determined using a Spearman correlation. The high expression level of these lipoprotein receptors on most of the tumors could underlie the lack of relationship between score and tumor grade. The overexpression of LDL-R and SR-B1 in canine lymphoma holds therapeutic potential particularly in dogs that overexpress one or both of these receptors, and this warrants further investigation.

Thyroid hormone (thyroxine, T4) is essential for the normal function of all cell types and is carried in serum bound to several proteins including transthyretin. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. Transthyretin and transthyretin bound T4 are endocytosed by placental trophoblasts through the high-density lipoprotein receptor, Scavenger Receptor Class B Type 1 (SR-B1). High density lipoprotein (HDL) affects the expression and function of SR-B1 in trophoblast cells. SR-B1 is also expressed in hepatocytes and we sought to determine if hepatocyte SR-B1 was involved in transthyretin or transthyretin-T4 uptake and whether uptake was affected by HDL. Transthyretin and transthyretin-T4 uptake by hepatocytes is not dependent on SR-B1. HDL treatment reduced SR-B1 expression. However, pretreatment of hepatocytes with HDL increased uptake of transthyretin-T4. Knockdown of SR-B1 expression using siRNA also increased transthyretin-T4 uptake. Coaddition of HDL to transthyretin uptake experiments blocked both transthyretin and transthyretin-T4 uptake. Hepatocyte uptake of transthyretin-T4 uptake is influenced by, but is not dependent on, SR-B1 expression. HDL also decreases transthyretin-T4 uptake and therefore diet or drugs may interfere with this process. This suggests that multiple lipoprotein receptors may be involved in the regulation of uptake of transthyretin-T4 in a cell-type specific manner. Further study is required to understand this important process.

Despite increased global interest in Chinook salmon aquaculture, little is known of their viral immune defenses. This study describes the establishment and characterization of a continuous cell line derived from Chinook salmon spleen, CHSS, and its use in innate immune studies. Optimal growth was seen at 14-18 °C when grown in Leibovitz's L-15 media with 20% fetal bovine serum. DNA analyses confirmed that CHSS was Chinook salmon and genetically different from the only other available Chinook salmon cell line, CHSE-214. Unlike CHSE-214, CHSS could bind extracellular dsRNA, resulting in the rapid and robust expression of antiviral genes. Receptor/ligand blocking assays confirmed that class A scavenger receptors (SR-A) facilitated dsRNA binding and subsequent gene expression. Although both cell lines expressed three SR-A genes: SCARA3, SCARA4, and SCARA5, only CHSS appeared to have functional cell-surface SR-As for dsRNA. Collectively, CHSS is an excellent cell model to study dsRNA-mediated innate immunity in Chinook salmon.

The scavenger receptors (SRs) comprise structurally and functionally divergent groups of cell surface and secreted proteins that play an important role in innate immune defenses. Searching translated chicken genomic databases revealed many proteins homologous to mammalian SRs. SR mediated immune functions (oxidative burst, degranulation, phagocytosis, nitric oxide (NO) production, and cytokine expression) were evaluated in chicken heterophils, peripheral blood mononuclear cells (PBMC), and a chicken macrophage cell line (HD11) using various SR class A and B ligands. Results showed that the SR-A ligands, fucoidan, poly(I) and poly(G), but not SR-B ligands, phosphatidylserine and LDL, stimulated dose-dependent NO production in HD11 cells. However, SR-A ligands failed to induce NO in chicken monocytes. Quantitative RT-PCR indicated that SR ligands differentially regulated the gene expression of cytokines and chemokine in HD11 cells with a strong up-regulation of the cytokines IL-1 beta and IL-6 and the chemokine MIP-1 beta, but had no effect on IL-4, IL-12, IFN-gamma, and IFN-beta. SR-B ligands did not alter expression of these genes. SR-A ligands had no stimulatory effect on functional response in heterophils. However, LDL, a SR-B ligand stimulated oxidative burst in both heterophils and PBMC. Additionally, results indicate that SRs are involved in bacterial binding in macrophages.

The class A scavenger receptor (SR-A, CD204), one of the principal receptors expressed on macrophages, has been found to regulate inflammatory response and attenuate septic endotoxemia. However, the detailed mechanism of this process has not yet been well characterized. To clarify the regulative mechanisms of lipopolysaccharide (LPS)-induced macrophage activation by SR-A, we evaluated the activation of Toll-like receptor 4 (TLR4)-mediated signaling molecules in SR-A-deficient (SR-A(-/-)) macrophages. In a septic shock model, the blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and interferon (IFN)-β were significantly increased in SR-A(-/-) mice compared to wild-type mice, and elevated nuclear factor kappa B (NFκB) activation was detected in SR-A(-/-) macrophages. SR-A deletion increased the production of pro-inflammatory cytokines, and the phosphorylation of mitogen-activated protein kinase (MAPK) and NFκB in vitro. SR-A deletion also promoted the nuclear translocation of NFκB and IFN regulatory factor (IRF)-3. In addition, a competitive binding assay with acetylated low-density lipoprotein, an SR-A-specific ligand, and anti-SR-A antibody induced significant activation of TLR4-mediated signaling molecules in wild-type macrophages but not in SR-A(-/-) macrophages. These results suggest that SR-A suppresses the macrophage activation by inhibiting the binding of LPS to TLR4 in a competitive manner and it plays a pivotal role in the regulation of the LPS-induced inflammatory response.

We have recently reported that phosphatidylethanolamine (PE)-containing liposomes are endocytosed and then induce lipid droplets (LDs) in HEK293T cells. In this study, we elucidated a mechanism responsible for endocytosis of PE-containing liposomes and induction of LDs. By using fluorescence-labeled liposomes and flow cytometry, we found that PE-containing liposomes were very efficiently internalized in HEK293T cells. However, Block lipid transporter-1 (BLT-1) only marginally suppressed the uptake of these liposomes, indicating that entire liposomes were mostly taken up in these cells. They were therefore inferred to express abundant PE receptors responsible for endocytosis of PE-containing liposomes. We examined the expression of 52 candidate genes through transcriptomic analyses and eventually narrowed it down to four candidate genes, which were abundantly expressed in HEK293T cells. Among siRNAs targeting these candidates, scavenger receptor class B type 1 (SR-B1) siRNA showed the most profound reduction in PE liposomal uptake. Conversely, the expression of SR-B1 by transfection of an expression plasmid enhanced the uptake of PE-containing liposomes. After the internalization of PE-containing liposomes, they were colocalized with endosomes/lysosomes and SR-B1, which indicates that these liposomes are taken up in HEK293T cells at least partially through the endosomal/lysosomal pathway. A specific anti-SR-B1-antibody blocked the uptake of PE-containing liposomes in HEK293T cells while LD formation in these cells induced by PE-containing liposomes was suppressed by treatment with SR-B1 siRNA. These results demonstrate that SR-B1 functions as a receptor for the endocytosis of PE-containing liposomes and regulates the formation of LDs induced by PE-containing liposomes in HEK293T cells.

Previous studies have documented the binding of low density lipoproteins (LDLs) to the tegumental surface of the mammalian stage of the human blood fluke Schistosoma mansoni, and that such binding may be functioning in the acquisition of host lipids for nutritional and/or immune evasion purposes. To determine if the intramolluscan mother sporocyst stage of S. mansoni also possess the ability to acquire exogenous LDL, live sporocysts, derived by in vitro transformation of isolated miracidia, were treated with DiI-labeled LDL (LDL-DiI) or acetylated LDL (acLDL-DiI). Sporocysts markedly differed in their binding, exhibiting strong labeling at the tegumental surface with acLDL-DiI, and only weak binding of LDL-DiI. As scavenger receptors (SRs) are known to selectively bind modified (acetylated or oxidized) LDL and other polyanionic molecules, various potential ligands of known SRs were used in an acLDL-DiI binding inhibition assay. Significant acLDL-DiI binding inhibition was observed for fucoidan, polyinosinic acid and dextran sulfate, but not for polycytidylic acid and dextran, a binding inhibition pattern consistent with SR class A or C activity. From a S. mansoni EST sequence, we cloned a scavenger receptor homologue from sporocyst cDNA that encoded a protein with 31% amino acid sequence identity and 50% similarity to a SR class B (SRB) molecule, belonging to the CD36 superfamily. Using an RNA interference assay, treatment of miracidia with a 517bp double-stranded RNA of the S. mansoni SRB gene resulted in a significant and specific knockdown (60-70%) of SRB transcript levels in sporocysts after 6 days of dsRNA exposure and was associated with a significant reduction in acLDL-DiI binding to sporocysts at 8 and 10 days post-dsRNA incubation. There also was a time-dependent decrease in sporocyst length following dsRNA treatments. The functional linkage of acLDL binding to the cloned SRB-like S. mansoni gene using RNA interference (RNAi) suggests a possible role of the tegumental SRB-like protein as a receptor for modified LDL. Inhibition of sporocyst growth also indicates a potential involvement of this SR homologue in some aspect of larval growth and/or development.

Functional kleptoplasty is a photosymbiotic relationship, in which photosynthetically active chloroplasts serve as an intracellular symbiont for a heterotrophic host. Among Metazoa, functional kleptoplasty is only found in marine sea slugs belonging to the Sacoglossa and recently described in Rhabdocoela worms. Although functional kleptoplasty has been intensively studied in Sacoglossa, the fundamentals of the specific recognition of the chloroplasts and their subsequent incorporation are unknown. The key to ensure the initiation of any symbiosis is the ability to specifically recognize the symbiont and to differentiate a symbiont from a pathogen. For instance, in photosymbiotic cnidarians, several studies have shown that the host innate immune system, in particular scavenger receptors (SRs) and thrombospondin-type-1 repeat (TSR) protein superfamily, is playing a major role in the process of recognizing and differentiating symbionts from pathogens. In the present study, SRs and TSRs of three Sacoglossa sea slugs, Elysia cornigera, Elysia timida, and Elysia chlorotica, were identified by translating available transcriptomes into potential proteins and searching for receptor specific protein and/or transmembrane domains. Both receptors classes are highly diverse in the slugs, and many new domain arrangements for each receptor class were found. The analyses of the gene expression of these three species provided a set of species-specific candidate genes, that is, SR-Bs, SR-Es, C-type lectins, and TSRs, that are potentially relevant for the recognition of kleptoplasts. The results set the base for future experimental studies to understand if and how these candidate receptors are indeed involved in chloroplast recognition.

Scavenger receptors (SRs) are involved in innate immunity through recognizing pathogen-associated molecular patterns (PAMPs) and in pathogenesis of diseases through interactions with damage-associated molecular patterns (DAMPs). The roles of SRs in invertebrate innate immunity still need to be elucidated. Here we identify a class B scavenger receptor from kuruma shrimp, Marsupenaeus japonicus, designated MjSR-B1. The recombinant MjSR-B1 agglutinated bacteria in a calcium dependent manner and bound lipopolysaccharide and lipoteichoic acid. After knockdown of MjSR-B1, both the bacterial clearance and phagocytotic ability of M. japonicus against V. anguillarum and S. aureus were impaired, and several phagocytosis related genes were downregulated. The expression levels of antimicrobial peptides were also downregulated. Overexpression of MjSR-B1 led to enhanced bacterial clearance, phagocytosis rate and upregulation of phagocytosis-related and antimicrobial peptide genes. However, overexpression of mutant MjSR-B1ΔC, which lacks the carboxyl tail of MjSR-B1, had none of these effects. Our results indicate that MjSR-B1 can protect shrimp from bacteria by promoting phagocytosis and by enhancing the expression of antimicrobial peptides.

The retinal phagocytic machinery resembles the one used by macrophages to clear apoptotic cells. However, in the retina, the permanent contact between photoreceptor outer segments (POS) and retinal pigment epithelial (RPE) cells requires a tight control of this circadian machinery. In addition to the known receptors synchronizing POS internalization, several others are expressed by RPE cells. Notably, scavenger receptor CD36 has been shown to intervene in the internalization speed. We thus investigated members of the scavenger receptor family class A SR-AI and MARCO and class B CD36, SR-BI and SR-B2/LIMP-2 using immunoblotting, immunohisto- and immunocytochemistry, lipid raft flotation gradients, phagocytosis assays after siRNA/antibody inhibition, RT-qPCR and western blot analysis along the light:dark cycle. All receptors were expressed by RPE cell lines and tissues and colocalized with POS, except SR-BI. All receptors were associated with lipid rafts, and even more upon POS challenge. SR-B2/LIMP-2 inhibition suggested a role in the control of the internalization speed similar to CD36. In vivo, MARCO and CD36 displayed rhythmic gene and protein expression patterns concomitant with the phagocytic peak. Taken together, our results indicate that CD36 and SR-B2/LIMP-2 play a direct regulatory role in POS phagocytosis dynamics, while the others such as MARCO might participate in POS clearance by RPE cells either as co-receptors or via an indirect process.

Scavenger receptors class B (SR-B) are multifunctional transmembrane proteins, which in vertebrates participate in lipid transport, pathogen clearance, lysosomal delivery and intracellular sorting. Drosophila has 14 SR-B members whose functions are still largely unknown. Here, we reveal a novel role for the SR-B family member Debris buster (Dsb) in Drosophila airway physiology. Larvae lacking dsb show yeast avoidance behavior, hypoxia, and severe growth defects associated with impaired elongation and integrity along the airways. Furthermore, in dsb mutant embryos, the barrier function of the posterior spiracles, which are critical for gas exchange, is not properly established and liquid clearance is locally impaired at the spiracular lumen. We found that Dsb is specifically expressed in a group of distal epithelial cells of the posterior spiracle organ and not throughout the entire airways. Furthermore, tissue-specific knockdown and rescue experiments demonstrate that Dsb function in the airways is only required in the posterior spiracles. Dsb localizes in intracellular vesicles, and a subset of these associate with lysosomes. However, we found that depletion of proteins involved in vesicular transport to the apical membrane, but not in lysosomal function, causes dsb-like airway elongation defects. We propose a model in which Dsb sorts components of the apical extracellular matrix which are essential for airway physiology. Since SR-B LIMP2-deficient mice show reduced expression of several apical plasma membrane proteins, sorting of proteins to the apical membrane is likely an evolutionary conserved function of Dsb and LIMP2. Our data provide insights into a spatially confined function of the SR-B Dsb in intracellular trafficking critical for the physiology of the whole tubular airway network.

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.

Class-A scavenger receptors (SR-A) are cellular pattern recognition receptors that bind and traffic a variety of endogenous and microbial ligands. However, despite an emerging role for SR-A as a contributor to the innate immune system, little is known of the regulation or function of SR-A on dendritic cells (DCs). Here we show that SR-A expression is upregulated during murine DC differentiation and that SR-A expression levels correlate with the expression of the murine DC marker CD11c. Using bone marrow-derived DCs (BMDCs) from SR-A knockout (SR-A(-/-)) mice, we investigated the contribution of SR-A to BMDC particulate phagocytosis. Functional analyses demonstrated that SR-A is a critical phagocytic receptor for BMDC internalization of the gram-negative bacteria E. coli. SR-A(-/-) BMDCs were impaired in their ability to phagocytose bacteria, and this deficit varied with the bacteria:BMDC cell ratio. Microscopic and biochemical analyses revealed that SR-A is broadly distributed on the surface of BMDCs and is not physically associated with lipid rafts. However, cholesterol depletion demonstrated dependence of SR-A-mediated phagocytosis upon lipid rafts. These data demonstrate a functional contribution for SR-A in the BMDC phagocytic pathway.

The scavenger receptor class B type 1 (SR-B1), a high-density lipoprotein (HDL) receptor, is a membrane glycoprotein that mediates selective uptake of HDL-cholesterol and cholesterol ester (CE) into cells. SR-B1 is subject to posttranslational regulation; however, the underlying mechanisms still remain obscure. Here, we identified a novel SR-B1-interacting protein, GIPC1 (GAIP-interacting protein, C terminus 1) that interacts with SR-B1 and stabilizes SR-B1 by negative regulation of its proteasomal and lysosomal degradation pathways. The physiological interaction between SR-B1 and GIPC1 was supported by co-immunoprecipitation of wild-type and mutant GIPC1 constructs in SR-B1 ± GIPC1 overexpressing cells, in native liver cells, and in mouse liver tissues. Overexpression of GIPC1 increased endogenous SR-B1 protein levels, subsequently increasing selective HDL-cholesterol/CE uptake and cellular triglyceride (TG) and total cholesterol (TC) levels, whereas silencing of GIPC1 in the mouse liver was associated with blunted hepatic SR-B1 levels, elevated plasma TG and TC, and attenuated hepatic TG and TC content. A positive correlation was identified between GIPC1 and SR-B1 expression, and both expressions of GIPC1 and SR-B1 from human liver samples were inversely correlated with body mass index (BMI) from human subjects. We therefore conclude that GIPC1 plays a key role in the stability and function of SR-B1 and can also effectively regulate hepatic lipid and cholesterol metabolism. These findings expand our knowledge of the regulatory roles of GIPC1 and suggest that GIPC1 exerts a major effect on cell surface receptors such as SR-B1 and its associated hepatic lipid and cholesterol metabolic processes.