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Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Yellow, orange, and red coloration is a fundamental aspect of avian diversity and serves as an important signal in mate choice and aggressive interactions. This coloration is often produced through the deposition of diet-derived carotenoid pigments, yet the mechanisms of carotenoid uptake and transport are not well-understood. The white recessive breed of the common canary (Serinus canaria), which carries an autosomal recessive mutation that renders its plumage pure white, provides a unique opportunity to investigate mechanisms of carotenoid coloration. We carried out detailed genomic and biochemical analyses comparing the white recessive with yellow and red breeds of canaries. Biochemical analysis revealed that carotenoids are absent or at very low concentrations in feathers and several tissues of white recessive canaries, consistent with a genetic defect in carotenoid uptake. Using a combination of genetic mapping approaches, we show that the white recessive allele is due to a splice donor site mutation in the scavenger receptor B1 (SCARB1; also known as SR-B1) gene. This mutation results in abnormal splicing, with the most abundant transcript lacking exon 4. Through functional assays, we further demonstrate that wild-type SCARB1 promotes cellular uptake of carotenoids but that this function is lost in the predominant mutant isoform in white recessive canaries. Our results indicate that SCARB1 is an essential mediator of the expression of carotenoid-based coloration in birds, and suggest a potential link between visual displays and lipid metabolism.

Understanding how cells process nanoparticles is crucial to optimize nanomedicine efficacy. However, characterizing cellular pathways is challenging, especially if non-canonical mechanisms are involved. In this Article a genome-wide forward genetic screening based on insertional mutagenesis is applied to discover receptors and proteins involved in the intracellular accumulation (uptake and intracellular processing) of silica nanoparticles. The nanoparticles are covered by a human serum corona known to target the low-density lipoprotein receptor (LDLR). By sorting cells with reduced nanoparticle accumulation and deep sequencing after each sorting, 80 enriched genes are identified. We find that, as well as LDLR, the scavenger receptor SCARB1 also mediates nanoparticle accumulation. Additionally, heparan sulfate acts as a specific nanoparticle receptor, and its role varies depending on cell and nanoparticle type. Furthermore, some of the identified targets affect nanoparticle trafficking to the lysosomes. These results show the potential of genetic screening to characterize nanoparticle pathways. Additionally, they indicate that corona-coated nanoparticles are internalized via multiple receptors. Understanding how cells process nanoparticles is crucial to improve nanomedicine efficacy. Here a genome-wide screening is used to discover proteins that are involved in silica nanoparticle accumulation by cells and shows that different apolipoprotein receptors and proteoglycans mediate their internalization.

Atherosclerotic plaques impair vascular function and can lead to arterial obstruction and tissue ischaemia. Rupture of an atherosclerotic plaque within a coronary artery can result in an acute myocardial infarction, which is responsible for significant morbidity and mortality worldwide. Prompt reperfusion can salvage some of the ischaemic territory, but ischaemia and reperfusion (IR) still causes substantial injury and is, therefore, a therapeutic target for further infarct limitation. Numerous cardioprotective strategies have been identified that can limit IR injury in animal models, but none have yet been translated effectively to patients. This disconnect prompts an urgent re-examination of the experimental models used to study IR. Since coronary atherosclerosis is the most prevalent morbidity in this patient population, and impairs coronary vessel function, it is potentially a major confounder in cardioprotective studies. Surprisingly, most studies suggest that atherosclerosis does not have a major impact on cardioprotection in mouse models. However, a major limitation of atherosclerotic animal models is that the plaques usually manifest in the aorta and proximal great vessels, and rarely in the coronary vessels. In this review, we examine the commonly used mouse models of atherosclerosis and their effect on coronary artery function and infarct size. We conclude that none of the commonly used strains of mice are ideal for this purpose; however, more recently developed mouse models of atherosclerosis fulfil the requirement for coronary artery lesions, plaque rupture and lipoprotein patterns resembling the human profile, and may enable the identification of therapeutic interventions more applicable in the clinical setting.

In-depth delineation of lipid metabolism in prostate cancer (PCa) is significant to open new insights into prostate tumorigenesis and progression, and provide potential biomarkers with greater accuracy for improved diagnosis. Here, we performed lipidomics and transcriptomics in paired prostate cancer tumor (PCT) and adjacent nontumor (ANT) tissues, followed by external validation of biomarker candidates. We identified major dysregulated pathways involving lipogenesis, lipid uptake and phospholipids remodeling, correlated with widespread lipid accumulation and lipid compositional reprogramming in PCa. Specifically, cholesteryl esters (CEs) were most prominently accumulated in PCa, and significantly associated with cancer progression and metastasis. We showed that overexpressed scavenger receptor class B type I (SR-BI) may contribute to CEs accumulation. In discovery set, CEs robustly differentiated PCa from nontumor (area under curve (AUC) of receiver operating characteristics (ROC), 0.90–0.94). In validation set, CEs potently distinguished PCa and non-malignance (AUC, 0.84–0.91), and discriminated PCa and benign prostatic hyperplasia (BPH) (AUC, 0.90–0.96), superior to serum prostate-specific antigen (PSA) (AUC = 0.83). Cholesteryl oleate showed highest AUCs in distinguishing PCa from non-malignance or BPH (AUC = 0.91 and 0.96). Collectively, our results unravel the major lipid metabolic aberrations in PCa and imply the potential role of CEs, particularly, cholesteryl oleate, as molecular biomarker for PCa detection.

A mouse model for hepatitis C infection The development of therapies for hepatitis C virus (HCV) infection has been hampered by the lack of a small-animal model of the disease. Now Alexander Ploss and colleagues describe the first immunocompetent rodent model for hepatitis C virus infection, using adenoviruses expressing four human factors to enable entry of HCV into mouse cells. These vectors were then used to transduce the livers of mice, which then became susceptible to HCV infection. Although the model does not enable a complete virus replication cycle, it should be useful for the evaluation of HCV vaccines and entry inhibitors. Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro 4 , we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo .

Obesity, a global public health concern, is influenced by various factors, including genetic predispositions. Although many obesity-associated genes have been identified through genome-wide association studies (GWAS), the molecular mechanisms linking these genes to adipose tissue function remain largely unexplored. This study integrates proteomic data on adipocyte fat accumulation with GWAS data on obesity to unravel the roles of the identified key candidate genes — G protein subunit beta 1 ( GNB1 ) and scavenger receptor class B member 2 ( SCARB2 ) — involved in fat accumulation. We utilized RNA interference to knock down GNB1 and SCARB2 in human subcutaneous adipocytes, followed by lipidome and proteome analyses using mass spectrometry. Knockdown of these genes resulted in a reduction in lipid droplet accumulation, indicating their role in adipocyte lipid storage. Digital PCR confirmed effective gene knockdown, with GNB1 and SCARB2 mRNA levels significantly reduced. In total, the lipidomic analysis identified 96 lipid species with significant alterations. GNB1 knockdown resulted in a decrease in cholesterol esters and an increase in phosphatidylcholines, phosphatidylinositols, and ceramides. SCARB2 knockdown also led to an increase in phosphatidylcholines, with a trend towards decreased triacylglycerols. Proteomic analysis revealed significant changes in proteins involved in lipid metabolism and adipocyte function, including PLPP1 and CDH13, which were upregulated following GNB1 knockdown, and HSPA8, which was downregulated. Conversely, SCARB2 knockdown resulted in the downregulation of PLPP1 and METTL7A, and the upregulation of PLIN2, HSPA8, NPC2, and SQSTM1. Our findings highlight the significant roles of GNB1 and SCARB2 in lipid metabolism and adipocyte function, providing insights that could inform therapeutic strategies targeting these regulatory genes in obesity.

Macrophage-derived foam cell formation is the hallmark of atherosclerotic plaques prominently attributed to excessive lipid uptake and metabolic disorders. As a classic membrane-localized ubiquitin ligase, the role of RNF128 in atherosclerosis remains unknown. We discover that RNF128 is specifically expressed in macrophages of the lipid core based on single-cell RNA sequencing data and persistent hyperlipidemia induces the high expression of RNF128 in macrophages. RNF128 ablation in macrophages ameliorates atherosclerosis in both male and female mice under the background of ApoE and LDLR deficiency. Mechanistically, RNF128 directly binds to scavenger receptor B1 (SRB1), preventing its degradation through the lysosomal system and promoting oxidized low-density lipoprotein (oxLDL)-induced foam cell formation and inflammatory response in macrophages. In addition, RNF128 catalyzes Lys63-linked polyubiquitination on the cytoplasmic C-terminus of the SRB1 at lysine 478, which promotes the endosome SRB1 recycling to the cell membrane with the assistance of Rab11, instead of entering the lysosome for degradation. Macrophages play a key role in atherosclerosis through lipid uptake and inflammation. Here, the authors show that RNF128 promotes atherosclerosis by stabilizing scavenger receptor B1 (SRB1) via polyubiquitination, enhancing foam cell formation and inflammation, while its ablation reduces plaque formation in hyperlipidemic mice.

The scavenger receptor class B member 1 (SCARB1), encoded by Scarb1 , is a cell surface receptor for high density lipoproteins, low density lipoproteins (LDL), oxidized LDL (OxLDL), and phosphocholine-containing oxidized phospholipids (PC-OxPLs). Scarb1 is expressed in multiple cell types, including osteoblasts and macrophages. PC-OxPLs, present on OxLDL and apoptotic cells, adversely affect bone metabolism. Overexpression of E06 IgM – a natural antibody that recognizes PC-OxPLs– increases cancellous and cortical bone at 6 months of age in both sexes and protects against age- and high fat diet- induced bone loss, by increasing bone formation. We have reported that SCARB1 is the most abundant scavenger receptor for OxPLs in osteoblastic cells, and osteoblasts derived from Scarb1 knockout mice ( Scarb1 KO) are protected from the pro-apoptotic and anti-differentiating effects of OxLDL. Skeletal analysis of Scarb1 KO mice produced contradictory results, with some studies reporting elevated bone mass and others reporting low bone mass. To clarify if Scarb1 mediates the negative effects of PC-OxPLs in bone, we deleted it in osteoblast lineage cells using Osx1-Cre transgenic mice. Bone mineral density (BMD) measurements and micro-CT analysis of cancellous and cortical bone at 6 months of age did not reveal any differences between Scarb1 ΔOSX-l mice and their wild-type (WT), Osx1-Cre, or Scarb1 fl/fl littermate controls. We then investigated whether PC-OxPLs could exert their anti-osteogenic effects via activation of SCARB1 in myeloid cells by deleting Scarb1 in LysM-Cre expressing cells. BMD measurements and micro-CT analysis at 6 months of age did not show any differences between Scarb1 ΔLysM mice and their WT, LysM-Cre, or Scarb1 fl/fl controls. Based on this evidence, we conclude that the adverse skeletal effects of PC-OxPLs in adult mice are not mediated by Scarb1 expressed in osteoblast lineage cells or myeloid cells.

Homozygous knockout of scavenger receptor class B type I (SR-B1) in mice with atherogenic mutations (such as knockout of the apolipoprotein E or low density lipoprotein receptor genes) results in spontaneous or diet-induced coronary heart disease characterized by atherosclerosis development in the aortic sinus and coronary arteries, platelet accumulation in coronary artery plaques, myocardial fibrosis, and early death. However, the extent of coronary artery atherothrombosis and myocardial fibrosis in mice lacking SR-B1 alone (homozygous SR-B1 knockout mice) has not been examined. Although age is a major risk factor for coronary artery disease, few studies directly examine the effects of age on susceptibility to atherosclerosis or coronary artery atherothrombosis and myocardial fibrosis in mice. Therefore, we set out to examine the effects of age on diet-induced atherosclerosis in female homozygous SR-B1 knockout mice. SR-B1 knockout mice exhibited little-to-no aortic sinus or coronary artery atherosclerosis at 52 weeks of age, when fed a normal diet. However when fed a high-fat, high-cholesterol, cholate-containing (HFCC) diet for 12 weeks from either 14 weeks of age (26-week-old at analysis) or 40 weeks of age (52-week-old at analysis), they developed similar degrees of atherosclerosis in their aortic sinuses. Interestingly, the older aged SR-B1 knockout mice exhibited increased coronary artery atherosclerosis, increased vascular cell adhesion molecule 1 levels and platelet accumulation in coronary arteries, and increased myocardial fibrosis and plasma levels of cardiac troponin I compared to the younger aged mice. Older-aged HFCC diet-fed SR-B1 knockout mice also exhibited reduced survival to humane endpoint. Moreover, older-aged HFCC diet-fed SR-B1 knockout mice exhibited a greater inflammatory state with increased levels of circulating interleukin-6, tumour necrosis factor alpha, and neutrophils, despite plasma lipid levels being unchanged. Consistent with the increased circulating neutrophils, older-aged HFCC diet-fed SR-B1 knockout mice exhibited increased accumulation of the neutrophil marker myeloperoxidase and increased neutrophil extracellular traps in atherosclerotic plaques in the aortic sinus and increased abundance of atherosclerotic coronary arteries containing neutrophil extracellular traps. HFCC diet-fed homozygous SR-B1 knockout mice develop occlusive coronary artery atherothrombosis and myocardial fibrosis in an age-dependent manner, and exhibit an increased inflammatory state with older age. Therefore, aged SR-B1 knockout mice may prove to be an attractive mouse model to analyze age-dependent mechanisms associated with coronary artery disease development, which may facilitate the discovery of more effective therapeutics to treat cardiovascular disease.