A model for modulation of leptin activity by association with clusterin
Abstract
Transport, biological action, and clearance of leptin are subject to modulation by plasma components responsible for the formation of the so‐called “bound” fraction of serum leptin. Candidates for modulators have been identified previously, but mechanisms for their action, and thus their physiological roles, have remained unclear. Here we have obtained evidence for a role of serum‐borne clusterin in leptin biology and have delineated a possible mechanism for its action. We demonstrate complex formation between clusterin and leptin by several approaches and show that the binary complex retains the ability to transduce the leptin signal via binding to the leptin receptor and activation of the Janus kinase/signal transducer and activator of transcription pathway. The interaction of leptin with clusterin does not require additional serum components. Furthermore, and importantly for modulation of the bioactivity of leptin, uptake of leptin present in the complex can be mediated by members of the low density lipoprotein (LDL) receptor family, i.e., apolipoprotein receptor type‐2 and the very LDL receptor, which here are shown to efficiently endocytose both free and leptin‐associated clusterin. Thus, bioavailability of leptin at a given tissue site may be determined by the levels of clusterin and/or by the relative distribution of certain relatives of the LDL receptor vis‐à‐vis active leptin receptors.
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VLDLR is a receptor for lipoproteins containing APOE and CLU/APOJ.
“VLDLR is a receptor for lipoproteins containing APOE38 and CLU/APOJ39, another AD risk gene.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [38]
The VLDLR-5-repeat allele was found to be associated with dementia.
“Additionally, the VLDLR-5-repeat allele was found to be associated with dementia38.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [38]
There is evidence that ApoJ can bind and modulate Leptin response in cell culture.
“While there is evidence that ApoJ can bind and modulate Leptin response in cell culture56”
From IDOL regulates systemic energy balance through control of neuronal VLDLR expression (2019) · cites this paper as [56]
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- Authors
- Bajari, T. M., Strasser, V., Nimpf, J., & Schneider, W. J.
- Affiliations
- University of Vienna (AT)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2003-06-03
- Volume
- 17
- Issue
- 11
- Pages
- 1-20
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2028376971
- Cited by
- 45
- References
- 58
- Citations by year
- 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 6 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 4 · 2012: 1
- FWCI
- 0.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (P-13931, P-13940)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Oncology › Clusterin in disease pathology
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, clusterin, leptin receptor signaling, JAK/STAT signaling, LDL receptor family, VLDLR, protein-protein complex formation
- MeSH terms
- Animals, DNA-Binding Proteins, Glycoproteins, Humans, Ligands, Models, Biological, Phosphorylation, Receptors, LDL, Recombinant Fusion Proteins, Trans-Activators, PC12 Cells, Protein Structure, Tertiary, Molecular Chaperones, Protein Isoforms, Leptin, Low Density Lipoprotein Receptor-Related Protein-1, Macromolecular Substances, STAT3 Transcription Factor, Clusterin, Mice, Rats, Receptors, Leptin
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