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www.biorxiv.org www.biorxiv.org
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Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors Potential Conflicts of Interest: None
PUNCHLINE This preprint reveals a novel mechanism by which nitric oxide (NO) regulates lipid uptake in endothelial cells through nitrosation of the fatty acid transporter CD36. In conditions where endothelial NO is elevated, CD36 is modified at key cysteine residues, which prevents its localization to the plasma membrane and thus inhibits lipid uptake. This nitrosation-based regulation protects endothelial cells from lipid overload while increasing circulating serum lipids. The findings establish a dynamic and reversible regulatory axis—Cav1 → NO → CD36—that links vascular signaling to metabolic control.
BACKGROUND Endothelial cells (ECs), which line the blood vessels, are uniquely positioned as gatekeepers of metabolic exchange—controlling the delivery of nutrients, including fatty acids, from the bloodstream into peripheral tissues. In the setting of metabolic syndrome, a state of chronic nutrient excess, this finely tuned lipid transport system becomes dysregulated. Excessive lipid uptake by ECs leads to lipid accumulation, mitochondrial dysfunction, and progressive endothelial impairment, which in turn contributes to the pathogenesis of cardiovascular and metabolic diseases.
While ECs appear to possess intrinsic protective mechanisms to buffer against lipid overload, the molecular basis of these protective responses is poorly understood. The authors sought to uncover how ECs might actively limit lipid uptake under stress, and what upstream signals trigger this protective state.
QUESTIONS ADDRESSED How do endothelial cells protect themselves from lipid-induced dysfunction during nutrient excess? What regulatory mechanisms allow them to limit lipid uptake under stress?
SUMMARY Reduced endothelial Cav1 leads to increased NO production and, in turn, nitrosation of CD36. This modification prevents CD36 from reaching the plasma membrane, blocking lipid uptake into ECs. As a result, circulating serum lipids increase, but endothelial function is preserved. These findings define NO-mediated nitrosation as a new mechanism of post-translational regulation of CD36, with implications for endothelial health in metabolic disease.
KEY RESULTS Cav1 is downregulated in endothelial cells in obesity Figures 1A–F, Supplementary Fig. 1A–F Goal: Identify genes affected by obesity that regulate endothelial lipid uptake. Outcome: Single-cell RNA-seq of mouse and human adipose tissues reveals consistent downregulation of Cav1 in all endothelial subtypes during obesity (Fig. 1A–F). Supplementary Fig. 1 shows quality control, cell-type identification, and confirmation of downregulated Cav1 expression in both species (Supp. Fig. 1A–F).
Loss of Cav1 increases circulating lipids and decreases EC lipid uptake Figures 2A–K, Supplementary Fig. 2A–E Goal: Determine the physiological effect of Cav1 loss on lipid homeostasis. Outcome: EC-specific Cav1 knockout mice have elevated serum triglycerides, cholesterol, and LDL (Fig. 2E–G), but reduced lipid droplet accumulation in ECs (Fig. 2J). They maintain normal weight and show improved glucose tolerance (Fig. 2H–L). Supplementary Fig. 2 confirms successful endothelial deletion of Cav1 (Supp. Fig. 2A–C) and shows that hyperlipidemia is not due to differences in dietary intake or lipid absorption (Supp. Fig. 2D–E).
Loss of Cav1 elevates NO and suppresses lipid uptake Figures 3A–J, 4A–F, Supplementary Fig. 3A–E Goal: Test whether elevated NO mediates lipid uptake defects. Outcome: Cav1 knockout increases serum nitrate/nitrite (Fig. 3J), reflecting elevated NO. Pharmacologic NO inhibition with L-NAME restores lipid uptake in HAMECs (Fig. 4A) and mouse aorta (Fig. 4B), and reduces serum lipids (Fig. 4C–D). Deletion of eNOS in ECs—but not in RBCs—rescues the phenotype (Fig. 4E–F). Supplementary Fig. 3 shows that Cav1 knockout does not impair vasodilatory responses to acetylcholine and confirms NO elevation by multiple readouts (Supp. Fig. 3A–E).
CD36 mediates endothelial lipid uptake and is regulated by NO Figures 5A–F, Supplementary Fig. 4A–D Goal: Identify whether CD36 is necessary and sufficient for NO-regulated lipid uptake. Outcome: CD36 localizes to Cav1-enriched domains (Fig. 5A) and is required for lipid uptake (Fig. 5C). NO donors suppress CD36-mediated lipid uptake in HEK293T cells (Fig. 5D), and NO induces CD36 nitrosation (Fig. 5E). Pharmacologic CD36 inhibition abolishes the effect of eNOS deletion (Fig. 5F). Supplementary Fig. 4 confirms that CD36 expression is unaltered by NO or Cav1 loss, suggesting the effect is post-translational (Supp. Fig. 4A–D).
CD36 is nitrosated at cysteines 3 and 466, disrupting palmitoylation and lipid uptake Figures 6A–D, 7A–F, Supplementary Fig. 5A–C Goal: Identify the functional nitrosation sites and their impact on trafficking. Outcome: CD36 is nitrosated at C3 and C466. Mutating these residues abolishes nitrosation and restores lipid uptake despite NO exposure (Fig. 6C–D). Nitrosation prevents palmitoylation of CD36 (Fig. 7D), explaining the loss of plasma membrane localization (Fig. 7B–F). Supplementary Fig. 5 shows quantification of CD36 localization shifts (Supp. Fig. 5A–C).
Nitrosation restricts CD36 to the ER and blocks its trafficking Figures 7A–F, Supplementary Fig. 6A–D Goal: Understand the subcellular localization of nitrosated CD36. Outcome: In Cav1-deficient or NO-treated ECs, CD36 remains in the endoplasmic reticulum (ER) (Fig. 7B, 7E). L-NAME restores membrane localization (Fig. 7C, 7F). Supplementary Fig. 6 provides further co-localization data with ER and Golgi markers and quantifies trafficking defects (Supp. Fig. 6A–D).
NO protects ECs from lipid-induced mitochondrial dysfunction and impaired vasodilation Figures 8A–C, Supplementary Fig. 7A–E Goal: Determine the physiological consequence of NO-CD36 signaling. Outcome: Lipid exposure combined with L-NAME leads to mitochondrial dysfunction (Fig. 8A) and impaired vasodilation (Fig. 8C), both rescued by NO. Supplementary Fig. 7 shows full mitochondrial stress test profiles and validation of mitochondrial protein levels (Supp. Fig. 7A–E).
STRENGTHS Defines a novel mechanism linking Cav1, NO, and CD36 to lipid homeostasis
Broadens our understanding of endothelial metabolic self-regulation
Identifies post-translational nitrosation as a reversible toggle on lipid uptake
Uses elegant genetic models, in vivo functional assays, and biochemical rigor
Links vascular NO signaling to metabolic adaptation
Highly relevant to metabolic syndrome, lipedema, and vascular disease
FUTURE WORK & EXPERIMENTAL DIRECTIONS Investigate whether modulating CD36 nitrosation could be therapeutic in hyperlipidemia
Study whether this mechanism contributes to sex differences in metabolic disease
Explore its role in other vascular beds and tissue-specific lipid handling
Test implications for lipedema, a fat-distribution disorder involving endothelial dysfunction
Define how palmitoylation and nitrosation are balanced or dynamically regulated
AUTHORSHIP NOTE This review was drafted with the assistance of ChatGPT (OpenAI) to help organize and articulate key ideas clearly and concisely. I provided detailed prompts, interpretations, and edits to ensure the review reflects an expert understanding of the biology and the paper’s contributions. The final version has been reviewed and approved by me.
FINAL TAKEAWAY This preprint reframes endothelial cells as active regulators of systemic metabolism. By showing that nitrosation of CD36 suppresses lipid uptake and preserves endothelial function under metabolic stress, the authors reveal a previously unrecognized mechanism of cellular protection. This discovery expands our understanding of how ECs maintain homeostasis in nutrient-rich environments and opens new directions for treating lipid-associated diseases like obesity, lipedema, and atherosclerosis.
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- Feb 2023
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Each reflects the operation of psychological mechanisms that were designed through evolution to serve important adaptive functions, but that nevertheless can produce harmful consequences.
- Each of these 4 problems
- anxiety disorder
- domestic violence
- racial prejudice
- obesity
- reflects the operation of psychological mechanisms
- that were designed through evolution
- to serve important adaptive functions, - but that nevertheless can produce harmful consequences.
- Each of these 4 problems
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What do anxiety disorders, domestic violence, racial prejudice, and obesity all have in common?
- question
- What do
- anxiety disorders,
- domestic violence,
- racial prejudice, and
- obesity
- What do
- all have in common?
- answer
- maladaptive cognitive biases!
- question
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- Sep 2022
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dspace.mit.edu dspace.mit.edu
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wehave found instances of people using relatively heavy-weightJavascript frameworks like Exhibit [11] just for the compar-atively minuscule feature of sortable HTML tables
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- May 2022
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medium.com medium.com
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People with eating disorders are often found to have a history of insecure-ambivalent attachment styles. It is thought that sufferers believe they have earned the closeness of others only when they meet their expectations. They then transfer this to their appearance and thus to their eating behaviour
ambivalent attachment eating disorder
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- Apr 2022
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What was new was a realization for me that I didn’t have a very good language to defend the value of my life, the worthiness of my life
writing about disability Chloe
- [I] i don't have rich vocabulary to express my ability of my physical (leg) and mental (ADHD) disability in the form of arguments and writing
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- Feb 2022
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ideal percentage for adult men will be between 50 and 65% of the total body. For the real athletic body types it is even recommended to have 5% more body water than the average adult range.
Ideal water content in adult men
- my body water content is low (40%) 😔🚾
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- Jan 2022
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www.theguardian.com www.theguardian.com
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Nigg said it might help me grasp what’s happening if we compare our rising attention problems to our rising obesity rates. Fifty years ago there was very little obesity, but today it is endemic in the western world. This is not because we suddenly became greedy or self-indulgent. He said: “Obesity is not a medical epidemic – it’s a social epidemic. We have bad food, for example, and so people are getting fat.” The way we live changed dramatically – our food supply changed, and we built cities that are hard to walk or cycle around, and those changes in our environment led to changes in our bodies. We gained mass, en masse. Something similar, he said, might be happening with the changes in our attention.
Obesity is a social epidemic and not a medical one. It's been caused by dramatic shifts in our surroundings in the past century. Food is cheaper and more abundant. It's also been heavily processed and designed to be fattier, saltier, and higher in carbohydrates. There is less encouragement to physically move our own bodies whether by walking, bicycling, running, etc. Our cities have become more driver focused. Our lives have become much more sedentary.
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- Dec 2021
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book4you.org book4you.org
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half of the calories you consume can be burned off simply by fidgeting
[[+ Stomach Breathing Body movements-DrRaja#Repetitive Strain Injury]]
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- Oct 2021
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conscienhealth.org conscienhealth.org
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For Teens with Obesity, COVID Vaccines Save Lives. (2021, October 21). ConscienHealth. https://conscienhealth.org/2021/10/for-teens-with-obesity-covid-vaccines-save-lives/
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- Feb 2021
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Edwards, D. A., Ausiello, D., Salzman, J., Devlin, T., Langer, R., Beddingfield, B. J., Fears, A. C., Doyle-Meyers, L. A., Redmann, R. K., Killeen, S. Z., Maness, N. J., & Roy, C. J. (2021). Exhaled aerosol increases with COVID-19 infection, age, and obesity. Proceedings of the National Academy of Sciences, 118(8). https://doi.org/10.1073/pnas.2021830118
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- Aug 2020
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www.cdc.gov www.cdc.gov
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Killerby. M. E., (2020) Characteristics Associated with Hospitalization Among Patients with COVID-19 — Metropolitan Atlanta, Georgia, March–April 2020. Centers for Disease Control and Prevention. Retrieved from: https://www.cdc.gov/mmwr/volumes/69/wr/mm6925e1.htm
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www.thelancet.com www.thelancet.com
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Endocrinology, T. L. D. &. (2020). Obesity and COVID-19: Blame isn’t a strategy. The Lancet Diabetes & Endocrinology, 0(0). https://doi.org/10.1016/S2213-8587(20)30274-6
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www.theguardian.com www.theguardian.com
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editor, P. B. S. policy. (2020, August 13). UK’s poorest ‘skip meals and go hungry’ during coronavirus crisis. The Guardian. https://www.theguardian.com/uk-news/2020/aug/12/coronavirus-lockdown-hits-nutritional-health-of-uks-poorest
Tags
- UK
- food
- insecurity
- food insecurity
- COVID-19
- obesity
- lang:en
- health
- malnutrition
- healthy food
- is:news
- government
- wellbeing
- household income
- poverty
- NHS
- risk
Annotators
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- Jul 2020
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Knittel, C. R., & Ozaltun, B. (2020). What Does and Does Not Correlate with COVID-19 Death Rates (Working Paper No. 27391; Working Paper Series). National Bureau of Economic Research. https://doi.org/10.3386/w27391
Tags
- is:article
- commute
- correlate
- transport
- employment
- COVID-19
- Colorado
- binomial
- obesity
- lang:en
- telecommuting
- economy
- health care
- public transport
- Michigan
- socio-economic
- poverty
- county
- ICU
- Louisiana
- linear regression
- temperature
- climate
- Iowa
- USA
- energy
- African American
- pollution
- Indiana
- elderly
- environment
- California
- health economics
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academic.oup.com academic.oup.com
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Lighter, J., Phillips, M., Hochman, S., Sterling, S., Johnson, D., Francois, F., & Stachel, A. (n.d.). Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciaa415
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- May 2020
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www.thelancet.com www.thelancet.com
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Jordan, R. E., & Adab, P. (2020). Who is most likely to be infected with SARS-CoV-2? The Lancet Infectious Diseases, S1473309920303959. https://doi.org/10.1016/S1473-3099(20)30395-9
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- Apr 2020
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jamanetwork.com jamanetwork.com
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Richardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., Barnaby, D. P., Becker, L. B., Chelico, J. D., Cohen, S. L., Cookingham, J., Coppa, K., Diefenbach, M. A., Dominello, A. J., Duer-Hefele, J., Falzon, L., Gitlin, J., Hajizadeh, N., Harvin, T. G., … Zanos, T. P. (2020). Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. https://doi.org/10.1001/jama.2020.6775
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- Dec 2018
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Alzheimer's disease (AD) is not normally diagnosed until later in life, although evidence suggests that the disease starts at a much earlier age. Risk factors for AD, such as diabetes, hypertension and obesity, are known to have their affects during mid-life, though events very early in life, including maternal over-nutrition, can predispose offspring to develop these conditions. This study tested whether over-nutrition during pregnancy and lactation affected the development of AD in offspring, using a transgenic AD mouse model. Female triple-transgenic AD dam mice (3xTgAD) were exposed to a high-fat (60% energy from fat) or control diet during pregnancy and lactation. After weaning (at 3 weeks of age), female offspring were placed on a control diet and monitored up until 12 months of age during which time behavioural tests were performed. A transient increase in body weight was observed in 4-week-old offspring 3xTgAD mice from dams fed a high-fat diet. However, by 5 weeks of age the body weight of 3xTgAD mice from the maternal high-fat fed group was no different when compared to control-fed mice. A maternal high-fat diet led to a significant impairment in memory in 2- and 12-month-old 3xTgAD offspring mice when compared to offspring from control fed dams. These effects of a maternal high-fat diet on memory were accompanied by a significant increase (50%) in the number of tau positive neurones in the hippocampus. These data demonstrate that a high-fat diet during pregnancy and lactation increases memory impairments in female 3xTgAD mice and suggest that early life events during development might influence the onset and progression of AD later in life.
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- Apr 2018
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www.medicalnewstoday.com www.medicalnewstoday.com
- Feb 2018
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www.sciencenews.org www.sciencenews.org
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Cilia in the brain may be busier than previously thought
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- Jul 2017
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Subject ID, age, race, sex, visit age, BMI, BODE index, distance walked, forced expiratory volume, GOLD stage, MRC dyspnoea score, prognostic index, SGRQ, subject group, and visit description of participants with or without lung disease and involved in the \"Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)\" project.
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This subject phenotype table includes gender, race, age, asthma status, anthropometric measurements (n=3 variables; height, weight, and bmi), and smoking status (n=6 variables; ever, current, and former smoking status, number of cigarettes/day, average cigarettes and packs/year).
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
- May 2016
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Slower metabolisms were not the only reason the contestants regained weight, though. They constantly battled hunger, cravings and binges. The investigators found at least one reason: plummeting levels of leptin. The contestants started out with normal levels of leptin. By the season’s finale, they had almost no leptin at all, which would have made them ravenous all the time. As their weight returned, their leptin levels drifted up again, but only to about half of what they had been when the season began, the researchers found, thus helping to explain their urges to eat.Leptin is just one of a cluster of hormones that control hunger, and although Dr. Hall and his colleagues did not measure the rest of them, another group of researchers, in a different project, did. In a one-year study funded by Australia’s National Health and Medical Research Council, Dr. Joseph Proietto of the University of Melbourne and his colleagues recruited 50 overweight people who agreed to consume just 550 calories a day for eight or nine weeks. They lost an average of nearly 30 pounds, but over the next year, the pounds started coming back.
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