Metabolic & Cardiometabolic
LDL particle enters via receptor-mediated transcytosis
In plain terms: Does LDL enter the artery wall mainly by active transport (transcytosis) through the vessel lining?
Strong support Metabolic & Cardiometabolic π Non-human evidence
RefutedContestedStrong support
consensus score 1.00
Animal and cell evidence shows LDL crosses the artery's endothelial lining mainly by active receptor-mediated transcytosis (SR-B1/DOCK4, ALK1, caveolae), and inflammation/insulin signals can ramp this entry up.
π Last reviewed: 2026-07-14 β
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: Animal studies (Animal)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
6 support 0 contradict 0 tested null 0 mixed Β· 6 sources, 5 independent groups
What the evidence shows
<!-- vault-context --> Norwitz affirms this claim. Consensus below reflects independent literature only.
The evidence (14)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Bolanle IO, de Liedekerke Beaufort GC, Weinberg PD 2025 Β· Arterioscler Thromb Vasc Biol | mechanism | mixed | moderate | NARRATIVE REVIEW, no data of its own β JATS article-type 'review-article', an invited piece in the 'ATVB in Focus: Receptor-Mediated Transcytosis' series, with no Methods, no Results, no original-data figure and 268 references: 'In the following, we review targets that arise from the identification of receptors and pathways and those arising from the fundamental transcytotic machinery' and 'Here, we have described the receptors and pathways involved'. Zero weight per CONVENTIONS Β§5, retained for transparency and not counted toward this claim's independent groups. ROUTE LIMB β affirmed: 'Mechanisms have been controversial but recent evidence suggests that caveolar transcytosis across endothelial cells is the dominant pathway.' RECEPTOR LIMB β this is the paper that DISPUTES it, and it is the same Imperial College group as s35340842 (senior/corresponding author Peter D. Weinberg; 10 self-citations, including the Ghim FSTL1 and Chooi permeability-hotspot work it narrates). Its own summary is deliberately partial β 'receptor-mediated active processes are responsible for some of that transcytosis' β and the Discussion makes the qualifier an open question: 'A second unknown is whether receptors are involved in some, most, or all LDL transcytosis.' It then argues the supporting literature is biased by its method: TIRF microscopy 'visualizes, by intention, only particles that will bind to the plasma membrane; fluid-phase transcytosis and transport through patent vesicular tubes are excluded', so 'That may have exaggerated the importance of receptors', and 'The receptors may saturate at well below physiological concentrations and hence only account for a small fraction of the total LDL transport.' It states the other side fairly β 'On the other hand, eliminating endothelial expression of SR-B1 or Alk1 resulted in impressive, 50% reductions in LDL transport in vivo and 70% when both were inhibited,' 'suggesting that these receptors are of crucial importance, at least in the mouse.' β but then withdraws the inference: 'If the second mechanism also applies to LDL-receptor interactions, then eliminating those receptors will reduce fluid-phase as well as receptor-mediated transcytosis, perhaps accounting for some of the confusion.' Both directions are stated by the authors themselves, hence stance mixed, not supports. RECEPTORS NAMED: 'Receptors involved are LDLR (LDL receptor), SR-B1 (scavenger receptor class B type 1), and ALK1 (activin receptor-like kinase 1)', with LDLR restricted β 'A likely explanation is that LDLR-mediated transcytosis is confined to the BBB' (the Jang IL-1Ξ² result is given as the stated exception). CAVEOLAE ARE NOT A RECEPTOR: the previous extract listed 'caveolae' among the receptors and named ALK1 twice; this paper treats caveolin-1 as the coat protein that builds the vesicle β 'Caveolin-1 deletion likely had an effect on LDL transport simply because caveolae cannot form without it.' CD36 and LOX-1 appear nowhere in the full text. The review also argues against the standard vesicle model: 'The near absence of free vesicles and the apparent immobility of caveolae appear to invalidate the concept of vesicles as cargo-carrying ferry boats.' TIER: everything narrated is cultured endothelium (human-derived cells), mice, rabbits and rats β no measurement of LDL transport across human endothelium in a person; this row implies no human confirmation. Funding: 'I.O. Bolanle was supported by project grant PG/23/11466 from the British Heart Foundation.'; Disclosures: none declared. Full JATS text read from the local PMC cache (PMC11936472), so the source note's 'provenance: abstract' and 'abstract-only' tag are wrong. |
| Jang E, Ghaffari S, Henry A, Wen G, Ho TWW, Cheng WH, Lyu Y, Wei K, Wang C, Romanoski CE, Wang Y, Cybulsky MI, Lee WL 2025 Β· Proc Natl Acad Sci U S A | in-vitro | supports | moderate | PRIMARY research, not a review β its own caveolin-1 membrane proteomics, siRNA/blebbistatin knockdown, TIRF live-cell transcytosis counting, endothelial-specific knockout mice and atherosclerosis arm. WHICH LIMB: it affirms the CAVEOLAR TRANSCYTOSIS ROUTE and adds intracellular machinery; it does NOT establish the claim's receptor-mediated qualifier. ROUTE, cultured human coronary artery endothelial monolayers (HCAECs): 'We confirmed that depletion of clathrin heavy chain (CLTC) by short interfering RNA (siRNA) had no effect on LDL transcytosis' while caveolin-1 knockdown reduced it (n=4 each) β caveolar, not clathrin. Cav-1 is the caveolar COAT protein, not a receptor. ROUTE, mouse aorta: EC-Myh9β/β mice given 200 Β΅g Alexa568-LDL retro-orbitally and read at 30 min showed less LDL in the lesser curvature (n=5 animals per group) with a 2β3 nm dextran unchanged β 'The decreased deposition of LDL in the context of absent dextran deposition is consistent with a reduction in transcytosis rather than altered paracellular leakage.' That separates transcellular from PARACELLULAR, not receptor-mediated from fluid-phase. RECEPTOR LIMB β indirect only: SR-BI/ALK1 double-knockdown cells were the negative control for the mass spectrometry ('proteins that increased in abundance upon LDL treatment and decreased in abundance upon SR-BI and ALK1 knockdown in two or more out of four independent replicates'), so what is receptor-dependent here is MYH9's recruitment to caveolae, not a measured transcytosis rate. The protein identified is explicitly not a receptor and sits downstream of one: 'Despite causing a significant reduction in LDL transcytosis, knockdown of MYH9 did not affect protein levels or mRNA expression of the known receptors SR-BI and ALK1' and 'These data suggested that MYH9 was mediating a common element of endothelial transcytosis downstream of receptor binding.' Its action is basal exocytosis β 'MYH9 depletion caused an accumulation of LDL-containing vesicles at the base of the cell; overexpression caused an increase in LDL exocytosis' β while cytoplasmic transit is a deliberate null ('NM IIA inhibition did not significantly affect cytosolic mobility of caveolae in cells that had internalized LDL'). CANNOT DISTINGUISH RECEPTOR FROM FLUID-PHASE: the assay pre-binds LDL in the cold and discards the rest β 'at 4 Β°C for 10 min to allow for membrane-binding of LDL. Coverslips were washed to remove unbound DiI-LDL' β so the membrane-bound pool is the only pool counted ('Exocytosis events were quantified at the basal side of each cell'). This is precisely the design s40013359 and s35340842 argue 'may have exaggerated the importance of receptors'; this row is one of the disputed TIRF rows, not a reply to the dispute. TIER: cultured human cells and mice only β NO measurement of LDL transport in a person. The human material is MYH9/CD31 immunostaining of one explanted coronary artery plus reanalysis of public artery expression data (GTEx phs000424.v8.p2, N=145β206; GSE40231, N=40, patient-matched), i.e. mRNA abundance, not flux. INDEPENDENCE: same lab as s38479648 (Warren L. Lee, ORCID 0000-0002-1788-6587, Keenan/St. Michael's + University of Toronto; Tse Wing Winnie Ho on both bylines), and NOT independent of s39196046 either β first author Erika Jang and Warren L. Lee are on that Sessa/FernΓ‘ndez-Hernando paper, whose contribution statement reads 'E.J. and W.L.L. performed TIRF imaging and analysis'; the assay itself is this lab's (Armstrong 2015, PMID 26334034, cited here as refs 8 and 53). CORRECTION: PNAS 122(50) e2533488122, PMID 41370348 (10 Dec 2025) β Fig. 5D's dataset was misdescribed and is GTEx, not GSE116243; methods attribution only, no result changed. QUALITY moderate: internally well controlled (clathrin negative control, myoferlin positive control, dextran paracellular control, littermate controls, unchanged plasma lipids) but small throughout β 'Experiments were performed with at least three independent replicates', n=3β5 per in-vitro panel, n=5β7 mice per group, mass-spec hits accepted on 2 of 4 replicates, and blinding/randomisation of the animal endpoints is not described in the main-text Methods (SI Appendix not read). Funding: CIHR 197769 to Warren L. Lee. Full JATS text read from the local PMC cache (PMC12582289), so the source note's 'provenance: abstract' and 'abstract-only' tag are wrong. β οΈ CORRECTION on file (PMID 41370348) β Fig 5D dataset is GTEx, not GSE116243. Methods only; no data retracted. NOT a retraction: zero-weighting does not apply. |
| Zhang Yifei, Jia Xiong, Wang Yayu, Zheng Qijun 2025 Β· Atherosclerosis | mechanism | supports | low | Narrative review, no data of its own. PubMed types it 'Review' and the authors state their own contribution plainly: 'We provide a comprehensive overview of recent research on the interplay between caveolin-1 and atherosclerosis' - so under CONVENTIONS Β§5 this is evidence_role: review, retained for transparency at zero weight and NOT counted toward this claim's independent groups. ROUTE: it does back the transcellular route - 'LDL must cross the intact endothelium to reach the subendothelial space, with caveolin-1 assuming a crucial role in this process' - but that is a restatement of others' experiments ('Previous investigations have demonstrated the pivotal role of caveolin-1...'), not a finding. RECEPTOR QUALIFIER: it adds nothing to this claim's 'receptor-mediated' term. Caveolin-1 is described as a structural caveolar coat protein, 'a 21-24 kDa membrane protein located in caveolae and highly expressed in endothelial cells', not as a receptor; no receptor (SR-B1, ALK1, LDLR, CD36, LOX-1) is named; and the authors concede 'However, how caveolin-1 regulates LDL transcytosis across endothelial cells in atherosclerosis remains unclear.' Whether the body engages Weinberg's fluid-phase dissent is cannot-tell from available text. No transport measurement of any kind, and no human transport data - this row implies no human confirmation. Abstract-grade: full text is CC-BY but Cloudflare-blocked at Elsevier; local cache, PMC/idconv/elink, NCBI BioC, Europe PMC, Unpaywall, OpenAlex, Semantic Scholar, Elsevier TDM and the publisher PDF/HTML were all tried and all refused. |
| Chen B, Prabhu A, Li G, ..., Guillamat Prats R, Steffens S 2026 Β· Nat Commun | animal | supports | moderate | Ex vivo perfused mouse carotids: 'Two-photon laser scanning microscopy (TPLSM) revealed that lack of Cnr1 in ECs resulted in significantly reduced retention of LDL particles across the endothelial layer' (Cnr1 EC-WT n = 5 vs Cnr1 EC-KO n = 6, 4 weeks western diet), with fewer apical caveolae ('The quantification of apical caveolae in atheroprone aortic arch regions confirmed that deficiency of Cnr1 reduces their number on the endothelial luminal site') and ALK1 dependence in human aortic ECs ('silencing of the ALK1-encoding gene ACVRL1 blunted the CB1 agonist-induced upregulation of LDL uptake'). Supports the caveolae/ALK1 route indirectly only: the authors state 'It should be acknowledged that only the initial step of subendothelial lipid deposition was assessed in our study, while we did not directly measure lipid transcytosis' and that 'the observed changes in caveolae-dependent LDL uptake and plaque lipid content are merely correlational'. |
| Cabodevilla 2026 Β· J Clin Invest | in-vitro | supports | moderate | Maps the LIGAND side of receptor-mediated LDL entry: APOB N-terminal residues binding SR-BI and ALK1; 'competition with APOB18 led to a significant (39.72% Β± 9.94%) reduction of DiI-LDL uptake compared with control'. SCOPE, stated because the claim's object is receptor-mediated TRANSCYTOSIS and this paper measures only the first step for LDL: the measured LDL endpoint here is APICAL UPTAKE, not transit across the cell. The paper's own framing keeps them apart β 'The sites required for uptake and transcytosis of APOB by ECs have not been defined.' LDL transcytosis itself is carried as CITED PREMISE ('In contrast, APOB100-containing LDL undergoes endothelial transcytosis, which is mediated by both SR-BI and ALK1'), and the only direct transcytosis-event assay (TIRF) was run on CHYLOMICRONS. So this row supports the RECEPTOR-MEDIATION half of the claim and is silent on the crossing half β silence, not contradiction. Adjudicated 2026-08-23 after the blind calibration read disagreed with the primary (off-scope vs no-change); neither was right: the measurements are a proper subset of the claim, not elsewhere. |
| Weinberg 2022 Β· Front Bioeng Biotechnol | mechanism | mixed | moderate | Sole-author narrative review (self-review: the decisive experiments are his own Imperial group). Backs the transcellular route for LDL β in cultured endothelium 'the LDL-sized tracer crossed only through the cells' and 'These observations are consistent with transport by a vesicular pathway of some type' β but disputes this claim's receptor-mediated qualifier: 'The influence of receptors may have been over-estimated in some of these investigations' and 'fluid phase transcytosis seems the most plausible mechanism at least for this tracer, and perhaps also for LDL itself'. Fairly cites the dissent (Cancel 2007, 'they determined that leaky junctions were the dominant route') and concedes 'There are no relevant transport data in people' β preclinical only, hence mechanism grade, not observational. |
| Huang 2019 Β· Nature | animal | supports | high | Primary experiments (not a review). In mice, endothelium-specific SR-B1 deletion cut DiI-LDL entry into the aorta and lesion area across apoE-/-, LDLR-/- and PCSK9 models, with 'no change in circulating total cholesterol, triglyceride or HDL levels, or lipoprotein profile' and unaltered Evans-blue permeability; in cultured human aortic endothelial cells, LDL transcytosis required direct LDL binding to SR-B1 plus its cytoplasmic IQAYSESL motif (residues 487-494), which recruits DOCK4 to activate Rac1. Route-specific: 'whereas LDLR, CD36 and SR-B1 all promote LDL uptake by human endothelial cells, SR-B1 drives LDL transcytosis' - LDLR and CD36 blockade left transcytosis intact, LOX-1 did nothing, and ALK1 was a separate additive route; caveolae were not tested as a route. Preclinical only: no human measurement of transcytosis, the human data being SR-B1/DOCK4 mRNA in atherosclerotic vs normal artery. |
| Lee, Fernandez-Hernando, Eichmann, Sessa 2023 Β· Nat Cardiovasc Res | animal | supports | moderate | PRIMARY experiments, not a review (own conditional mouse line, own monoclonal antibody, own transport assays). Speaks to the claim's RECEPTOR limb and affirms it: arterial-EC-specific Alk1 deletion cut en-face aortic DiI-LDL uptake (P=0.0002) and aortic apoB content (P<0.0001, n=6 mice) while 'the loss of ALK1 in ECs did not impact circulating lipids', and a de-novo anti-ALK1 antibody (SPR Kd 5 +/- 2 nM) 'dose-dependently blocked DiI-LDL uptake into HUVECs' and 'markedly reduced LDL transcytosis' in human coronary artery ECs measured by TIRF counting of basolateral delivery (P=0.0004). Specificity is controlled: 'the expression of ALK1 was required because silencing of ALK1 abrogated the effect of the monoclonal antibody to block LDL uptake', and the antibody leaves BMP9/BMP10 p-SMAD1/5 signalling intact, separating ALK1's LDL handling from its signalling. WHAT IT DOES NOT SHOW: it does NOT exclude LDLR or SR-B1 - its own siRNA data read 'DiI-LDL uptake was reduced to 60% when ALK1, SR-BI or LDLR was individually silenced', residual entry being 'probably mediated by other LDL-binding proteins such as LDLR, SR-B1 or other proteoglycans'; caveolae, CD36, LOX-1 and the paracellular/fluid-phase route are never tested (no permeability control), so it cannot answer the fluid-phase dissent. TIER: mice and cultured cells only, no human transport data - the human material is ALK1 expression from public GEO reanalysis ('Cohorts contained 32 subjects in each group'). QUALITY moderate, not high: the plaque endpoints are well powered (n=10-12/group, blinded histology) but the transcytosis-bearing measurements are thin - the in-vivo uptake readout is 'Three images were counted per mouse in two mice per group for a total of n = 6' and the TIRF assay reports no effect magnitude, being 'repeated twice and the representative dots were combined from the two independent experiments'; 'No statistical methods were used to predetermine sample size'; pending patent PCT/US2023/011339 names corresponding author W.C. Sessa as coinventor and he is a Pfizer employee. NOT an independent lab: the byline carries Fernandez-Hernando, Sessa and Xinbo Zhang (the fernandez-hernando-a author set), plus Shaul (utsw-shaul) and W.L. Lee with Jang (toronto-lee), who ran the TIRF assay. |
| Zhang, Sessa, Fernandez-Hernando 2018 Β· Front Cardiovasc Med | mechanism | supports | moderate | Narrative review (Yale; Zhang, Sessa, Fernandez-Hernando), no new data: 'In this review article, we briefly summarize the function of the EC barrier in regulating lipoprotein transport'. Affirms the claim's direction β 'The LDL transcytosis from the apical to the basolateral compartment in ECs is dependent on the function of caveolae, SR-B1, or ALK1' β but explicitly EXCLUDES LDLR outside the brain: 'LDLR-mediated LDL transcytosis only occurred in brain ECs, but not in ECs from system circulation', since 'PCSK9-mediated LDLR degradation has no effect on LDL transcytosis'. Authors' own ceiling: 'most of the present findings were investigated by in vitro assays, the observation of lipoprotein transcytosis through ECs in vivo are needed to prove the physiological relevance'. |
| Fung, Ho, Xu, Neculai, Beauchemin, Lee, Fairn 2024 Β· J Lipid Res | in-vitro | supports | moderate | TIRF on human coronary endothelial monolayers counted basolateral LDL exocytosis events directly: 20x excess APOA1-WT or human HDL cut DiI-LDL transcytosis ~40% (p<0.05 and p<0.01), and at the physiological 1x ratio reconstituted HDL still cut it 20.7% (p=0.001) β 'This degree of inhibition is comparable to siRNA-mediated silencing of SR-B1.' SR-B1 competition is therefore rate-limiting for LDL transit, corroborating receptor-mediated transcytosis (SR-B1 Kd for APOA1 6.87 uM). In vivo (n=5 male mice) HDL cut acute aortic LDL deposition ~40% (p=0.02), but that arm measures deposition, not transcytosis. Caveats: primary-cell internalization assay was highly variable (95% CI 0.035-150.4) and the 40% figure used a supraphysiological 20-fold excess. |
| Zhang, Fernandez-Hernando 2020 Β· Curr Opin Lipidol | mechanism | supports | moderate | Narrative review (no new data): 'In this review article, we have summarized the recent findings in the field.' Argues LDL crosses the endothelium by receptor-mediated transcytosis rather than junctional leak on size grounds β LDL is 22-28 nm and 'the paracellular transport of lipoproteins with a diameter > 6 nm through the endothelium is limited by inter-endothelial junctions' β and names three routes: caveolae/Cav-1, SR-B1 (via DOCK4 and Rac1) and ALK1. Explicitly EXCLUDES the LDL receptor for arterial endothelium: 'LDLR has been reported to coordinate the LDL transcytosis in the blood-brain barrier (BBB) ... however, it's unlikely to be required for endothelial LDL transcytosis in the athero-prone regions since degradation of LDLR by PCSK9 did not influence the LDL transcytosis in EC.' Evidence narrated is cultured human endothelial cells and knockout mice only; human material is expression staining, not function, and the authors state that 'due to the technical limitation for in vivo imaging ... the precise mechanisms and molecular regulation of LDL transcytosis in vivo are still unclear.' Retained for transparency, zero weight per CONVENTIONS Β§5. |
| Zhang C, Hu W, Zhang J, Wang Z, Lu H 2026 Β· J Am Heart Assoc | mechanism | supports | low | NARRATIVE REVIEW, no data of its own - JATS article-type 'review-article', no Methods, no Results, no original-data figure, and no author with a data-collection role ('Author contributions: ZC: conception, writing-original draft, writing-review and editing.'). Its only self-generated element is a caveolin/cavin expression heat map where 'The data are collected from GTEx project.', which speaks to expression, not transport. Zero weight per CONVENTIONS Β§5, retained for transparency and NOT counted toward this claim's independent groups. RECEPTOR LIMB - affirmed, flatly: 'In caveolae, scavenger receptor class B type I (SR-B1) and activin receptor-like kinase 1 (ALK1) also facilitate LDL transportation, mainly for transcytosis.', with the mechanism spelled out - 'When SR-B1 binds to LDL, it recruits DOCK4, activating LDL-bound SR-B1 and Rac1, facilitating SR-B1-mediated transcytosis and transporting LDL to the subendothelial space.' and 'ALK1-mediated transcytosis of LDL is kinase-independent and exhibits weaker binding affinity for LDL compared with SR-B1.' It also narrows what 'receptor-mediated' means: LDLR is put on the degradative side, not the transcytotic one - it 'mediates endocytosis, forming endosomes that transport LDL to lysosomes for degradation.' ROUTE LIMB - affirmed with the authors' own hedge: 'the atherosclerosis protective effect of Cav1 KO is independent of eNOS function and probably through reduced LDL transcytosis and inflammation attenuation.' CAV1 is treated throughout as the caveolar coat/scaffold protein, not as a receptor. CANNOT DISTINGUISH THE LIMBS: this paper performs no transport measurement, reports no rate, flux, permeability coefficient or binding constant, and never mentions fluid-phase transcytosis, the TIRF selection-bias objection, or the possibility that deleting a receptor also cuts fluid-phase transport - the words 'fluid phase', 'TIRF' and 'controversial' appear nowhere in it. It restates the affirmative account as settled without engaging the dissent, so it is repetition, not corroboration, and the primary work behind its receptor sentences traces to the Shaul (SR-B1) and Fernandez-Hernando/Sessa (ALK1) experiments already in this claim's pool. TIER: no human transport data - everything narrated on transcytosis is cultured endothelium and mouse knockouts; the paper's only human data are a GTEx expression map and one genotype-disease association ('The human CAV1 genomic variant (rs3807989), associated with higher CAV1 expression, correlates with higher cardiovascular disease risk.'), neither of which measures LDL transport in a person. This row implies NO human confirmation. The previous extract was written from the abstract alone and named neither LDL, nor transcytosis, nor any receptor, substituting the abstract's generic 'lipid trafficking' and the disease endpoint 'implicated in atherosclerosis' for the transport endpoint and pooling LDL influx with HDL/ABCA1 cholesterol efflux. Full JATS text (174 KB, PMC13055843) read from the local fulltext cache, so the source note's 'provenance: abstract' and this note's 'locus: abstract' are both wrong. Funding: Chinese national/Guangdong/Shenzhen public grants, 'Funders do not have any role related to paper design, data collection, or writing of the paper.'; Disclosures: None. |
| Zegeye 2026 Β· Mol Med | in-vitro | mixed | moderate | In-vitro HUVEC study of LDL UPTAKE, not transcytosis: IL-6 trans-signaling degraded surface LDL-R yet raised uptake of native LDL, and that uptake survived both LDL-R siRNA and sLDL-R competition while being blocked by Cytochalasin D and EIPA β 'IL-6 trans-signaling downregulates LDL-R yet increases LDL-C uptake via an LDL-Rβindependent, actin-dependent macropinocytosis pathway.' Crossing was never measured: 'Although it was not tested directly in the current study, it is possible that the internalized LDL-C may undergo transcellular trafficking to be released to the opposite side of endothelial cells.' Receptor-mediated transcytosis via SR-BI/ALK1 appears only as cited background, so this paper bears on inflammatory modulation of endothelial LDL ENTRY, not on the transcytosis claim. |
| Goldberg IJ, Cabodevilla AG, Younis W 2024 Β· J Atheroscler Thromb | mechanism | supports | moderate | NARRATIVE REVIEW (Goldberg IJ, Cabodevilla AG, Younis W; NYU Grossman) β no new data: 'This review will address these two topics', zero figures, zero tables, no Methods or Results, every datum attributed to a numbered reference including the authors' own prior work. Zero weight per CONVENTIONS Β§5; retained for transparency. WHAT IT AFFIRMS, and on what: both limbs of the claim, but by assertion and secondhand citation. Route limb β 'The movement of large proteins and certainly macromolecules like lipoproteins between endothelial cells is unlikely' and 'Multiple studies tracking labeled lipoproteins have also failed to demonstrate paracellular lipoprotein transport', with the premise for a leaky route removed because 'the majority of atherosclerotic plaque lesions contain an intact endothelium'. Receptor limb β it sets the two options side by side ('Lipoproteins could cross the endothelial cell barrier via non-specific uptake into transcellular vesicles, as well as via a receptor-mediated saturable process') and then resolves for receptors on one group's cultured-cell TIRF work: 'Their studies in cultured cells established that specific receptors mediate lipoprotein transcytosis.' It does not engage the fluid-phase counter-argument at all. RECEPTORS NAMED: SR-B1 ('They then used TIRF microscopy to show that LDL transcytosis was blocked by HDL and knockdown of SR-BI'; 'Endothelial cell specific knockout of SR-BI protected hyperlipidemic mice from atherosclerosis') and ALK1 ('activin-like kinase 1 (ACVLR1, ALK1) mediated LDL uptake and transcytosis of LDL'), with LDL using both. EXCLUDED: the paracellular route; lipolysis-induced arterial barrier leak (LpL/GPIHBP1 'primarily reside on capillaries'); ALK1 for chylomicrons ('Unlike LDL, chylomicrons are not internalized by ALK1'); and very large particles by size (diabetic-rabbit lipoproteins >4000 mg/dL 'were unable to cross the endothelial cell barrier'). SILENT ON: caveolae/Cav-1, PCSK9, clathrin and LOX-1 β zero mentions each; do not cite this paper for the caveolae limb or the LDLR exclusion. Its 13 CD36 mentions are all about albumin-bound NEFA uptake into heart/muscle/adipose, a different cargo in a different vascular bed, not LDL transcytosis. TIER: cultured cells, isolated mouse aortas, mice and rabbits only β no human transport data. The human material is postprandial vascular dysfunction and outcome epidemiology, not measured lipoprotein flux across human endothelium. Public NHLBI funding (HL151328, HL160470-01, HL045095, HL164949); 'Conflicts of Interest None.' |
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