Galectin-1 accelerates high-fat diet-induced obesity by activation of peroxisome proliferator-activated receptor gamma (PPARγ) in mice.

Galectin-1 contains a carbohydrate-recognition domain (CRD) as a member of the lectin family. Here, we investigated whether galectin-1 regulates adipogenesis and lipid accumulation. Galectin-1 mRNA is highly expressed in metabolic tissues such as the muscle and adipose tissues. Higher mRNA expression of galectin-1 was detected in white adipose tissues (WATs) of mice that were fed a high-fat diet (HFD) than in those of mice fed a normal-fat diet (NFD). Protein expression of galectin-1 also increased during adipocyte differentiation. Galectin-1 silencing inhibited the differentiation of 3T3-L1 cells and the expression of lipogenic factors, such as PPARγ, C/EBPα, FABP4, and FASN at both mRNA and protein levels. Lactose, an inhibitor by the binding with CRD of galectin-1 in extracellular matrix, did not affect adipocyte differentiation. Galectin-1 is localized in multiple cellular compartments in 3T3-L1 cells. However, we found that DMI (dexamethasone, methylisobutylxanthine, insulin) treatment increased its nuclear localization. Interestingly, galectin-1 interacted with PPARγ. Galectin-1 overexpression resulted in increased PPARγ expression and transcriptional activity. Furthermore, we prepared galectin-1-knockout (Lgals1-/-) mice and fed a 60% HFD. After 10 weeks, Lgals1-/- mice exhibited lower body weight and gonadal WAT (gWAT) mass than wild-type mice. Fasting glucose level was also lower in Lgals1-/-mice than that in wild-type mice. Moreover, lipogenic genes were significantly downregulated in the gWATs and liver tissues from Lgals1-/- mice. Pro-inflammatory cytokines, such as CCL2, CCL3, TNFα, and F4/80, as well as macrophage markers, were also drastically downregulated in the gWATs and liver tissues of Lgals1-/- mice. In addition, Lgals1-/-mice showed elevated expression of genes involved in thermogenesis in the brown adipose tissue. Collectively, galectin-1 exacerbates obesity of mice fed HFD by increment of PPARγ expression and activation. Our findings suggest that galectin-1 could be a potential therapeutic target for obesity and needed further study for clinical application.

Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells.

BACKGROUND: Galectins are beta-galactose specific binding proteins. In human cancers, including hepatocellular carcinoma (HCC), galectin-1 (Gal-1) is often found to be overexpressed. In order to combat the dismal diagnosis and death rates of HCC, gene silencing and targeted inhibition of Gal-1 was investigated for its improved therapeutic potential. METHODS: Cellular and secretory Gal-1 levels were analyzed using HCC clinical samples. The study of Gal-1 was carried by both knockdown and overexpression approaches. The stable clones were tested by in vitro assays and in vivo experiments. Mass spectrometry was used to identify downstream targets of Gal-1. The upstream regulator of Gal-1, microRNA-22 (miR-22) was characterized by functional assays. The therapeutic effect of inhibiting Gal-1 was also analyzed. RESULTS: Gal-1 overexpression was observed in HCC and correlated with aggressive clinicopathological features and poorer survival. The loss of Gal-1 resulted in hindered cell migration, invasion and anchorage independent growth. This was also observed in the animal models, in that when Gal-1 was knocked down, there were fewer lung metastases. Proteomic profiling of control and Gal-1 knockdown cells identified that the level of retention in endoplasmic reticulum 1 (RER1) was suppressed when Gal-1 level was reduced. The cell motility of Gal-1 knockdown cells was enhanced upon the rescue of RER1 expression. In HCC tissues, Gal-1 and RER1 expressions displayed a significant positive correlation. The upstream regulator of Gal-1, miR-22 was observed to be underexpressed in HCC tissues and negatively correlated with Gal-1. Silencing of miR-22 resulted in the upregulation of Gal-1 and enhanced cell growth, migration and invasion. However, such enhancement was abolished in cells treated with OTX008, an inhibitor of Gal-1. Combinational treatment of OTX008 and sorafenib significantly reduced tumor growth and size. CONCLUSIONS: Gal-1 overexpression was detected in HCC and this played a role in promoting tumorigenic processes and metastasis. The function of Gal-1 was found to be mediated through RER1. The correlations between miR-22, Gal-1 and RER1 expressions demonstrated the importance of miR-22 regulation on Gal-1/RER1 oncogenic activity. Lastly, the combinational treatment of OTX008 and sorafenib proved to be an improved therapeutic option compared to when administering sorafenib alone.