Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans

Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?

Galectins as modulators of tumour progression

Galectin-3: an open-ended story.

Significance: Keratinocytes, a major cellular component of the epidermis, are responsible for restoring the epidermis after injury through a process termed epithelialization. This review will focus on the pivotal role of keratinocytes in epithelialization, including cellular processes and mechanisms of their regulation during re-epithelialization, and their cross talk with other cell types participating in wound healing. Recent Advances: Discoveries in epidermal stem cells, keratinocyte immune function, and the role of the epidermis as an independent neuroendocrine organ will be reviewed. Novel mechanisms of gene expression regulation important for re-epithelialization, including microRNAs and histone modifications, will also be discussed. Critical Issues: Epithelialization is an essential component of wound healing used as a defining parameter of a successful wound closure. A wound cannot be considered healed in the absence of re-epithelialization. The epithelialization process is impaired in all types o...

Epithelialization in Wound Healing: A Comprehensive Review

Oligosaccharide specificity of galectins: a search by frontal affinity chromatography.

Galectin-12, a member of the galectin family of animal lectins, is preferentially expressed in adipocytes. We recently reported that this galectin is localized on lipid droplets, specialized organelles for fat storage. Galectin-12 regulates lipid degradation (lipolysis) by modulating lipolytic protein kinase A (PKA) signaling. Mice deficient in galectin-12 exhibit enhanced adipocyte lipolysis, increased mitochondria respiration, reduced adiposity and ameliorated insulin resistance associated with weight gain. The results suggest that galectin-12 may be a useful target for treatment of obesity-related metabolic conditions, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Most previously described galectins largely reside in the cytosol, although they can also be induced to become associated with membrane-containing structures. Along with an in-depth characterization of galectin-12, this mini-review comments on this first report of a galectin normally localized specifically in an organelle that performs an important intracellular function. Further studies will help shed light on how this protein regulates cellular homeostasis, especially energy homeostasis, and provide additional insight into the intracellular functions of galectins.

/pdf/galectin-12-a-protein-associated-with-lipid-droplets-that-48vdzb2dua.pdf

Galectin-12: A protein associated with lipid droplets that regulates lipid metabolism and energy balance

Galectins are a family of animal lectins with conserved carbohydrate-recognition domains that recognize β-galactosides. Despite structural similarities, these proteins have diverse functions in a variety of cellular processes. While a large number of extracellular functions have been demonstrated for galectins, the existence of intracellular functions has been clearly shown for a number of galectins, including regulation of cell growth and apoptosis; these latter functions may not involve glycan binding. There is considerable interest in intracellular regulation by galectins of cell growth and apoptosis, as these are fundamental cellular processes in normal homeostasis. Their dysregulation can cause pathologies such as autoimmune disorders, cancer, and neural degenerative diseases. Here we describe methods that we routinely perform in the laboratory to investigate the role of galectins in cell growth and apoptosis. These include methods for cell isolation, cell maintenance, and genetic manipulations to perturb galectin gene expression, as well as assays for cell growth and apoptosis.

/pdf/analysis-of-the-intracellular-role-of-galectins-in-cell-howbysiarv.pdf

Analysis of the Intracellular Role of Galectins in Cell Growth and Apoptosis

Galectin-12 is a member of a family of mammalian lectins characterized by their affinity for β-galactosides and consensus amino acid sequences. The protein structure consists of a single polypeptide chain containing two carbohydrate-recognition domains joined by a linker region. Galectin-12 is predominantly expressed in adipose tissue, but is also detected in macrophages and other leukocytes. Downregulation of galectin-12 in mouse 3T3-L1 cells impairs their differentiation into adipocytes. Conversely, overexpression of galectin-12 in vitro induces cell cycle arrest in G1 and apoptosis. Upregulation of galectin-12 and initiation of G1 cell cycle arrest are associated with driving pre-adipocytes toward terminal differentiation. Galectin-12 deficiency increases insulin sensitivity and glucose tolerance in obese animals. Galectin-12 inhibits macrophage polarization to the M2 population, enhancing inflammation and decreasing insulin sensitivity in adipocytes. Galectin-12 also affects myeloid differentiation, which is associated with chemotherapy resistance. In addition to highlighting the above-mentioned aspects, this review also discusses the potential clinical applications of modulating the function of galectin-12.

/pdf/galectin-12-in-cellular-differentiation-apoptosis-and-4ks3grvu46.pdf

Galectin-12 in Cellular Differentiation, Apoptosis and Polarization.

The decrease of forkhead box P3-positive (FOXP3 + ) regulatory T cells (Tregs) causes an immune imbalance with effector T cells in psoriasis. Previous studies have demonstrated that in addition to its known effects on keratinocytes and effector T cells, ultraviolet (UV) irradiation alleviates psoriasis via the upregulation of FOXP3 + Tregs. However, the mechanism is unclear. Here, we found that FOXP3 + T cells were increased in psoriatic lesions after UVB irradiation (t' = 3.7006, P < 0.01), as determined by immunohistochemical staining. In addition, the levels of FOXP3 and p53, one of the downstream targets of UV irradiation, showed accordant changes after UV irradiation. Experiments that used a MAPK inhibitor, p53 mutant cell lines, p53 inhibitor and p53 shRNA showed a decrease in FOXP3 levels, suggesting that p53 is required for UV-induced FOXP3 transcription. Next, we demonstrated that there are two binding sites for p53 on FOXP3 by informatics tools, a dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. One binding site (-1771 to -1583) is located at the promoter region and is adjacent to a previously reported p53-binding region in breast cancer cells. The other (+3845 to +4042) is located within the first intron and has not been previously reported. Our study demonstrated that FOXP3 is regulated, at least in part, by the binding of p53 to several binding sites in the promoter and intron regions following UV irradiation in psoriasis. It will be helpful to further clarify the regulatory mechanism of FOXP3 transcription and to provide new insights into the mechanisms that mediate the effects of UV irradiation in autoimmune skin disorders.

Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis.

As a member of the galectin family of animal lectins, galectin-12 is preferentially expressed in adipocytes and leukocytes. In adipocytes, galectin-12 is associated with lipid droplets and regulates lipid metabolism and energy balance, whereas its role in leukocytes is not clear. Analysis of galectin-12 expression in a public data set of acute myeloid leukemia (AML) samples revealed that it is selectively overexpressed in the M3 subtype, which is also known as acute promyelocytic leukemia (APL). To investigate the role of galectin-12 in APL cells, we manipulated its expression in the APL cell line, NB4, and measured resultant effects on all-trans-retinoic acid (ATRA)-induced granulocytic differentiation. With a doxycycline-inducible gene knockdown system, we found that suppression of galectin-12 promoted ATRA-induced neutrophil differentiation but inhibited lipid droplet formation. Our results indicate that overexpression of galectin-12 contributes to a differentiation block in APL cells, and suppression of galectin-12 facilitates granulocytic differentiation. Furthermore, these data suggest that lipogenesis and other aspects of myeloid differentiation can be differentially regulated. Taken together, these findings suggest that galectin-12 may be a target for treatment of the ATRA-resistant subset of APL.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.1HI0316-134R

Ri Yao Yang

Papers

Galectin-12: A protein associated with lipid droplets that regulates lipid metabolism and energy balance

Analysis of the Intracellular Role of Galectins in Cell Growth and Apoptosis

Galectin-12 in Cellular Differentiation, Apoptosis and Polarization.

Ultraviolet irradiation promotes FOXP3 transcription via p53 in psoriasis.

Galectin-12 inhibits granulocytic differentiation of human NB4 promyelocytic leukemia cells while promoting lipogenesis