Melatonin Inhibits LDL Receptor Activity and Cholesterol-Synthesis in Freshly Isolated Human Mononuclear Leukocytes
Abstract
There is some indirect evidence that the pineal hormone melatonin can suppress plasma levels of cholesterol in hypercholesterolemic rats. We have examined the effects of the hormone on cellular cholesterol metabolism in freshly isolated human mononuclear leukocytes. Incubation of cells for up to 20 h in a lipid-free medium resulted in an increase in the rate of cholesterol synthesis from [14C]acetate and the high affinity accumulation and degradation of [125I]labeled low density lipoprotein (LDL). Addition of melatonin in increasing concentrations to the incubation medium at zero time inhibited cholesterol synthesis and the specific accumulation and degradation of [125I]labeled LDL; at a concentration of 100 microM, the inhibitions were 38%, 42%, and 48%, respectively. Similar results were obtained using [14C]mevalonate as precursor. Fatty acid synthesis was not altered under these conditions. In contrast to cholesterol, the synthesis of the first cyclic compound lanosterol was not affected by the pineal hormone. These results implicate that melatonin inhibits this pathway between lanosterol and cholesterol. The action of melatonin on LDL receptor activity appeared to be mediated by a decrease in the number of LDL receptors and not by a change in binding affinity. Pharmacological characterization of the potential melatonin receptor site using several analogs like tryptamine, 5-hydroxytryptamine,N-acetyl-5-hydroxytryptamine, 5-methoxytryptamine, and 6-chloromelatonin indicated that the 5-methoxy group is indispensible for the hormone action on cholesterol synthesis. The data provide evidence that melatonin can modulate cholesterol metabolism in human cells.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The lipid-promoting effects of melatonin arise from the promotion of innate cholesterol release through the production of bilirubin acid and the prevention of low-density lipoprotein receptor function.
“The lipid-promoting effects of melatonin arise from the promotion of innate cholesterol release through the production of bilirubin acid and the prevention of low-density lipoprotein receptor function. Moreover, enhancement of irisin levels and improvement fecal cholesterol repulsion are some pathways that melatonin acts. 16,34,35”
From Melatonin supplementation improves glycemic hemostasis, lipid profile, and adipokine concentrations of obese women: A double-blind randomized clinical trial (2024) · cites this paper as [35]
Cited by
Sorted by citations
Matsubara, E., Bryant‐Thomas, T., Pacheco Quinto, J., Henry, T. L., Poeggeler, B., Herbert, D., Cruz‐Sanchez, F., Chyan, Y., Smith, M. A., Perry, G., et al. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01654.x · Cited by 332 · see citing works
“An interesting body of literature in the melatonin field suggests that melatonin plays an important regulatory role in cholesterol metabolism (Müller-Wieland et al. 1994); this raises interesting unexplored issues pertaining to AD pathogenesis, particularly in view of the emerging connection between cholesterolemia an…”
BackgroundMelatonin and circadian biology in human cardiovascular disease
Domínguez‐Rodríguez, A., Abreu-González, P., Sanchez-Sanchez, J. J., Kaski, J. C., & Reiter, R. J. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00773.x · Cited by 232 · see citing works
“It has been shown that melatonin suppresses the formation of cholesterol by 38% and reduces low-density lipoprotein accumulation by 42% in freshly isolated human mononuclear leukocytes [69].”
BackgroundMelatonin ameliorates nonalcoholic fatty liver induced by high‐fat diet in rats
Pan, M., Song, Y., Xu, J., & Gan, H. (2006) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2006.00346.x · Cited by 170 · see citing works
“related to enhancement of the catabolism of cholesterol to bile acids [35], inhibition of cholesterol synthesis and LDL receptor activity [37] and actions directly on the adipose tissue through specific MT1 and MT2 receptors [38, 39].”
BackgroundBeneficial effects of melatonin on obesity and lipid profile in young Zucker diabetic fatty rats
Agil, A., Navarro‐Alarcón, M., Ruiz, R., Abuhamdah, S. M. A., El‐Mir, M., & Vázquez, G. F. (2010) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00830.x · Cited by 168 · see citing works
“Besides the inhibition of cholesterol absorption [17], other mechanisms may also be implicated in these effects of melatonin, including an increase in LDL receptor synthesis/activity, inhibition of cholesterol synthesis, or enhancement of cholesterol catabolism to bile acids [49, 50].”
BackgroundEl-Missiry, M. A., ., T. A. F., El-Sawi, M. R., & El-Sayed, A. A. (2006) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2006.03.008 · Cited by 142 · see citing works
Mechanisms of Melatonin in Obesity: A Review
Guan, Q., Wang, Z., Cao, J., Dong, Y., & Chen, Y. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010218 · Cited by 142 · see citing works
“The hypocholesterolemic effect of melatonin works through the augmentation of endogenous cholesterol clearance mechanisms, via the synthesis of bilirubin acid and inhibition of low-density lipoprotein receptor activity [43,44].”
BackgroundDisturbed Tryptophan Metabolism in Cardiovascular Disease
Mangge, H., Stelzer, I., Reininghaus, E., Weghuber, D., Postolache, T., & Fuchs, D. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666140304105526 · Cited by 115 · see citing works
“Further, melatonin has been shown to significantly suppress the formation of cholesterol and reduce LDL-C in isolated human mononuclear leucocytes [56].”
BackgroundEffects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism
Morgan, L., Arendt, J., Owens, D., Folkard, S., Hampton, S., Deacon, S., English, J., Ribeiro, D., & Taylor, K. (1998) · Journal of Endocrinology · doi:10.1677/joe.0.1570443 · Cited by 124 · see citing works
Melatonin improves metabolic syndrome induced by high fructose intake in rats
Kitagawa, A., Ohta, Y., & Ohashi, K. (2012) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00955.x · Cited by 116 · see citing works
“Such an improving effect of melatonin on dyslipidemia and hepatic steatosis in rats with high fructose intake may be attributed to the following actions of the indoleamine: the catabolism to bile acid [54], inhibition of cholesterol synthesis and low-density lipoprotein receptor activity [55], and direct actions on th…”
BackgroundMelatonin and the Metabolic Syndrome: Physiopathologic and Therapeutical Implications
Cardinali, D. P., Cano, P., Jiménez‐Ortega, V., & Esquifino, A. I. (2011) · Neuroendocrinology · doi:10.1159/000324699 · Cited by 110 · see citing works
“Indeed, as shown in animal studies, several mechanisms can be responsible for the hypolipidemic effects of melatonin, e.g. decrease in intestinal cholesterol absorption [”
BackgroundMetabolic Effects of Melatonin on Oxidative Stress and Diabetes Mellitus
Nishida, S. (2005) · Endocrine · doi:10.1385/endo:27:2:131 · Cited by 103 · see citing works
Hussein, M. R., Ahmed, O. G., Hassan, A. F., & Ahmed, M. A. (2006) · International Journal of Experimental Pathology · doi:10.1111/j.1365-2613.2006.00512.x · Cited by 100 · see citing works
Mohammadi-Sartang, M., Ghorbani, M., & Mazloom, Z. (2018) · Clinical Nutrition · doi:10.1016/j.clnu.2017.11.003 · Cited by 94 · see citing works
Melatonin and Human Cardiovascular Disease
Pandi-Perumal, S. R., BaHammam, A. S., Ojike, N. I., Akinseye, O. A., Kendzerska, T., Buttoo, K., Dhandapany, P. S., Brown, G. M., & Cardinali, D. P. (2016) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248416660622 · Cited by 94 · see citing works
“Melatonin also decreases the formation of cholesterol and reduces LDL accumulation in freshly isolated human mononuclear leukocyte.(42) However, not all studies have reported the LDLlowering effect of melatonin.”
BackgroundEbaid, H., Bashandy, S. A. E., Alhazza, I. M., Rady, A. M., & El-Shehry, S. (2013) · Nutrition & Metabolism · doi:10.1186/1743-7075-10-20 · Cited by 91 · see citing works
“This effect may be related to the enhancement of the catabolism of cholesterol to form bile acids [51] and the inhibition of cholesterol synthesis and LDL receptor activity [52].”
BackgroundKakhaki, R. D., Ostadmohammadi, V., Kouchaki, E., Aghadavod, E., Bahmani, F., Tamtaji, O. R., Reiter, R. J., Mansournia, M. A., & Asemi, Z. (2020) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2020.105878 · Cited by 87 · see citing works
Melatonin and its atheroprotective effects: A review
Favero, G., Rodella, L. F., Reiter, R. J., & Rezzani, R. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.11.016 · Cited by 79 · see citing works
“, 2007), inhibition of cholesterol synthesis, or enhancement of cholesterol catabolism to bile acids or inhibition of fatty acid transport by several subtypes of white adipose tissue (Chan and Tang, 1995; Dauchy et al., 2003; Müller-Wieland et al., 1994).”
BackgroundFatty Acids and Brain Peptides
Yehuda, S., Rabinovitz, S., Carasso, R. L., & Mostofsky, D. I. (1998) · Peptides · doi:10.1016/s0196-9781(97)00295-7 · Cited by 75 · see citing works
Melatonin and metabolic regulation: a review
Navarro‐Alarcón, M., Ruiz‐Ojeda, F. J., Blanca-Herrera, R. M., A‐Serrano, M. M., Acuña-Castroviejo, D., Fernández‐Vázquez, G., & Agil, A. (2014) · Food & Function · doi:10.1039/c4fo00317a · Cited by 76 · see citing works
Ebaid, H., Bashandy, S. A. E., Abdel-Mageed, A. M., Al‐Tamimi, J., Hassan, I., & Alhazza, I. M. (2020) · Nutrition & Metabolism · doi:10.1186/s12986-019-0419-7 · Cited by 72 · see citing works
RetractedSubramanian, P., Mirunalini, S., Pandi-Perumal, S. R., Trakht, I., & Cardinali, D. P. (2007) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.06.011 · Cited by 70 · see citing works
Domínguez‐Rodríguez, A., Abreu-González, P., García‐González, M. J., Ferrer-Hita, J. J., Vargas, M., & Reiter, R. J. (2004) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2004.11.003 · Cited by 70 · see citing works
Zaitone, S. A., Hassan, N., El-Orabi, N. F., & El‐Awady, E. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.04.049 · Cited by 64 · see citing works
Loloei, S., Sepidarkish, M., Heydarian, A., Tahvilian, N., Khazdouz, M., Heshmati, J., & Pouraram, H. (2019) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2019.04.043 · Cited by 58 · see citing works
Ou, T.-H., Tung, Y., Yang, T.-H., & Chien, Y. (2019) · Nutrients · doi:10.3390/nu11040748 · Cited by 51 · see citing works
Tung, Y.-T., Chiang, P.-C., Chen, Y.-L., & Chien, Y.-W. (2020) · Molecules · doi:10.3390/molecules25153329 · Cited by 49 · see citing works
Baydaş, G., Yılmaz, Ö., Çeli̇k, S., Yaşar, A., & Gürsu, M. F. (2002) · Archives of Medical Research · doi:10.1016/s0188-4409(02)00414-9 · Cited by 46 · see citing works
Li, H., Leu, Y., Wu, Y.-C., & Wang, S. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.8b06217 · Cited by 44 · see citing works
Wakatsuki, A., Okatani, Y., Ikenoue, N., Kaneda, C., & Fukaya, T. (2001) · Maturitas · doi:10.1016/s0378-5122(00)00221-8 · Cited by 43 · see citing works
Şener, G., Balkan, J., Çevikbaş, U., Keyer‐Uysal, M., & Uysal, M. (2004) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2004.00122.x · Cited by 42 · see citing works
“Although the mechanism of its hypolipidemic action is not known, this effect may be related to enhancement of the catabolism of cholesterol to bile acids [12] and inhibition of cholesterol synthesis and LDL receptor activity [24].”
BackgroundVenkataraman, P., Krishnamoorthy, G., Selvakumar, K., & Arunakaran, J. (2009) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2009.00406.x · Cited by 42 · see citing works
Esquifino, A. I., Agrasal, C., Velázquez, E., Villanúa, M. A., & Cardinali, D. P. (1997) · Life Sciences · doi:10.1016/s0024-3205(97)00613-9 · Cited by 34 · see citing works
Csoma, B., & Bikov, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814145 · Cited by 33 · see citing works
Ebaid, H., Al‐Tamimi, J., Hassan, I., et al. (2021) · Applied Sciences · doi:10.3390/app11073044 · Cited by 31 · see citing works
Pita, M. L., Hoyos, M. G., Martín‐Lacave, I., et al. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2002.1o851.x · Cited by 31 · see citing works
“Although the mechanism of the hypocholesterolemic effect of melatonin is not known, it has been reported that this agent enhances the catabolism of cholesterol to bile acids in rats [16] and inhibits cholesterol synthesis and decreases LDL uptake in human mononuclear leukocytes [19].”
BackgroundThe Mystery behind the Pineal Gland: Melatonin Affects the Metabolism of Cholesterol
Karolczak, K., & Watała, C. W. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/4531865 · Cited by 29 · see citing works
Ciortea, R., Costin, N., Braicu, E. I., Haragâş, D., Hudacsko, A., Bondor, C. I., Mihu, D., & Mihu, C. M. (2011) · PubMed · Cited by 28 · see citing works
Can melatonin prevent or improve metabolic side effects during antipsychotic treatments?
Porfirio, M. C., de Almeida, J.-P. G., Stornelli, M., Giovinazzo, S., Purper‐Ouakil, D., & Masi, G. (2017) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s127564 · Cited by 26 · see citing works
“31,66 A 72–74 Melatonin may contribute to lower BP, possibly through improved functioning of the biological clock.”
Esalatmanesh, K., Loghman, A. H., Esalatmanesh, R., Soleimani, Z., Khabbazi, A., Mahdavi, A. M., & Mousavi, S. G. A. (2021) · Clinical Rheumatology · doi:10.1007/s10067-021-05670-2 · Cited by 26 · see citing works
Antioxidative Capacity of Melatonin
Tan, D. X., Reiter, R. J., Calvo, J. R., & Manchester, L. C. (2001) · CRC Press eBooks · doi:10.1201/9780203904046.pt8 · Cited by 16 · see citing works
Lee, J., & Lee, D. (2014) · Maturitas · doi:10.1016/j.maturitas.2014.03.010 · Cited by 7 · see citing works
Serum lipid levels in seasonal affective disorder
Pjrek, E., Winkler, D., Abramson, D. W., et al. (2006) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-006-0706-y · Cited by 6 · see citing works
“Interestingly, melatonin is also thought to lower serum cholesterol as demonstrated in vitro [32], in animal models [16, 44] and in clinical studies in humans [42, 50].”
BackgroundArasteh, A., Aliyev, A., Khamnei, S., Delazar, A., Abbasi, M. M., & Mehmannavaz, Y. (2010) · AFRICAN JOURNAL OF BIOTECHNOLOGY · Cited by 5 · see citing works
Adikwu, E. B., Nelson, B., & Obianime, A. W. (2016) · Macedonian Pharmaceutical Bulletin · doi:10.33320/maced.pharm.bull.2016.62.01.004 · Cited by 3 · see citing works
Keskın, E., & Uluışık, D. (2019) · Turkish Journal of Sport and Exercise · doi:10.15314/tsed.541829 · Cited by 4 · see citing works
Mesri Alamdari, N., Namazi Shabestari, A., Najafipour, F., & Mirmazhari, A. (2024) · Biomedicine Advances · doi:10.34172/bma.05 · Cited by 4 · see citing works
“16,34,35 39-42 It was reported that melatonin is effective in weight reduction in those subjects with mental disease and consumed drugs led to adverse effects like weight variations.”
Arasteh, A. (2011) · Scientific Research and Essays · doi:10.5897/sre11.1521 · Cited by 3 · see citing works
Role of Kynurenine Pathway in Cardiovascular Diseases
Mangge, H., Reininghaus, E., & Fuchs, D. (2015) · Springer eBooks · doi:10.1007/978-3-319-11870-3_10 · Cited by 2 · see citing works
Ismail, H. S., & Mahmood, M. S. (2022) · Journal of Baghdad College of Dentistry · doi:10.26477/jbcd.v34i1.3092 · Cited by 3 · see citing works
Ghosh, S., Khatoon, R., Sarkar, S., & Bandyopadhyay, D. (2023) · Melatonin Research · doi:10.32794/mr112500138 · Cited by 3 · see citing works
Gut Microbiota: A New Marker of Cardiovascular Disease
Pontarollo, G., Kiouptsi, K., Bayer, F., & Reinhardt, C. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819265-8.00028-0 · Cited by 2 · see citing works
A Study on Effect of Melatonin in Dyslipidemia Caused by Experimentally Diabetes
Uluışık, D., Keskın, E., & Hatipoğlu, D. (2019) · Turkish Journal of Sport and Exercise · doi:10.15314/tsed.541834 · Cited by 2 · see citing works
“bile acids, increased LDL receptor activity (2, 29), and inhibition of metabotropic receptors involved in”
BackgroundLachner, A., Weidenfeld, S., & Schutzbach, F. (2018) · aw&I Conference · doi:10.14464/awic.v3i0.296 · Cited by 2 · see citing works
Kozel'tsev, V. L., Volodina, T. V., Guseva, V. V., et al. (2007) · Biochemistry (Moscow) Supplement Series B Biomedical Chemistry · doi:10.1134/s1990750807030079 · Cited by 1 · see citing works
Melatonin as a Medicament for the 24/7 Society: Metabolic Syndrome
Cardinali, D. P. (2016) · Springer eBooks · doi:10.1007/978-3-319-41679-3_12 · Cited by 1 · see citing works
Azadi, H. G., Baghishani, H., & Shahsavani, D. (2013) · DOAJ (DOAJ: Directory of Open Access Journals) · doi:10.22067/veterinary.v5i2.17601 · Cited by 1 · see citing works
“Long term melatonin treatment may decrease cholesterol synthesis (Muller-Wieland et al., 1994) and augment endogenous cholesterol clearance mechanisms (Chan and Tang, 1995).”
BackgroundWpływ melatoniny na czynność układu sercowo-naczyniowego
profesor (2010)
Georgopoulos, A. (1997) · Principles of medical biology · doi:10.1016/s1569-2582(97)80072-4
Influence of light on serum cholesterol levels in complete (by birth) blind people
Rani, J. S., & Raju, D. S. S. K. (2018) · International Journal of Research in Medical Sciences · doi:10.18203/2320-6012.ijrms20184038
“Melatonin itself has been shown to inhibit LDL receptor activity and cholesterol synthesis in human mononuclear leucocytes Melatonin also influences lipoprotein lipase (LPL) activity, a key regulatory enzyme in circulating TAG clearance, in adipose tissue.(16) LPL is activated by”
BackgroundO papel da melatonina na regulação do tecido adiposo marrom
Halpern, B. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.5.2018.tde-31102018-131724
Serum melatonin concentrations in coronary heart disease patients with hypercholesterolaemia
Editorial Office (2001) · Suid-Afrikaanse Tydskrif vir Natuurwetenskap en Tegnologie · doi:10.4102/satnt.v20i1.246
Comparative study on the effect of cerium nano composite on juvenile hormones in adult and aged rats
Gheriany, E. I., Abbas, O. A., & El-Sherbiny, E. M. (2022) · Journal of Radiation Research and Applied Sciences · doi:10.1016/j.jrras.2022.04.005
Multidimensional role of melatonin
Olajide, P. A., Adetuyi, B. O., Oni, P. G., Oyebanjo, O. T., Ambali, O. A., & Ogunlana, O. O. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13814-0.00008-9
Koziróg, M., Poliwczak, A. R., Duchnowicz, P., Koter-Michalak, M., Sikora, J., & Broncel, M. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2010.00835.x · Cited by 299 · see citing works
“The results of animal studies suggest several mechanisms that may be responsible for the hypolipidemic effects of melatonin: decrease in intestinal cholesterol absorption [33], inhibition of cholesterol biosynthesis and LDL-C accumulation [34], interactions with LDL-C receptors [35], or inhibition of fatty acid transp…”
Background
- Authors
- Mullerwieland, D., Behnke, B., Koopmann, K., & Krone, W.
- Affiliations
- University of Cologne (DE)
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 1994-08
- Volume
- 203
- Issue
- 1
- Pages
- 416-421
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W1970130937
- Cited by
- 64
- References
- 0
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 3 · 2013: 3
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- melatonin, LDL receptor, cholesterol biosynthesis, mononuclear leukocytes, cholesterol metabolism, lanosterol, mevalonate, hypercholesterolemia, melatonin receptors, tryptamine analogs, 5-methoxytryptamine, serum cholesterol
- MeSH terms
- Acetates, Carbon Radioisotopes, Cholesterol, Chromatography, Ion Exchange, Dose-Response Relationship, Drug, Humans, Iodine Radioisotopes, Kinetics, Leukocytes, Mononuclear, Lipoproteins, LDL, Melatonin, 5-Methoxytryptamine, Mevalonic Acid, Receptors, LDL, Serotonin, Tryptamines, In Vitro Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
