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Hepatology (Baltimore, Md.) Mar 2024Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical...
BACKGROUND AND AIMS
Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated HSC glycolysis and the therapeutic implication for liver fibrosis.
APPROACH AND RESULTS
Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/β-catenin signaling. Nuclear translocation of lactate dehydrogenase A (LDH-A) and its interaction with hypoxia-inducible factor-1α (HIF-1α) were investigated using molecular simulation and site-directed mutation assays. The pharmacological relevance of molecular discoveries was intensified in primary cultures, rodent models, and human samples. HSC glycolysis was enhanced by Wnt3a but reduced by β-catenin inhibitor or small interfering RNA (siRNA). Wnt3a-induced rapid transactivation and high expression of LDH-A dependent on TCF4. Wnt/β-catenin signaling also stimulated LDH-A nuclear translocation through importin β2 interplay with a noncanonical nuclear location signal of LDH-A. Mechanically, LDH-A bound to HIF-1α and enhanced its stability by obstructing hydroxylation-mediated proteasome degradation, leading to increased transactivation of glycolytic genes. The Gly28 residue of LDH-A was identified to be responsible for the formation of the LDH-A/HIF-1α transcription complex and stabilization of HIF-1α. Furthermore, LDH-A-mediated glycolysis was required for HSC activation in the presence of Wnt3a. Results in vivo showed that HSC activation and liver fibrosis were alleviated by HSC-specific knockdown of LDH-A in mice. β-catenin inhibitor XAV-939 mitigated HSC activation and liver fibrosis, which were abrogated by HSC-specific LDH-A overexpression in mice with fibrosis.
CONCLUSIONS
Inhibition of HSC glycolysis by targeting Wnt/β-catenin signaling and LDH-A had therapeutic promise for liver fibrosis.
Topics: Animals; Humans; Mice; beta Catenin; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Lactate Dehydrogenase 5; Liver Cirrhosis; Wnt Signaling Pathway; Hepatic Stellate Cells
PubMed: 37733267
DOI: 10.1097/HEP.0000000000000569 -
Cancer Cell International Dec 2023Glucose transporter 3 (GLUT3) plays a major role in glycolysis and glucose metabolism in cancer cells. We aimed to investigate the correlation between GLUT3 and histone...
OBJECTIVES
Glucose transporter 3 (GLUT3) plays a major role in glycolysis and glucose metabolism in cancer cells. We aimed to investigate the correlation between GLUT3 and histone lactylation modification in the occurrence and progression of gastric cancer.
MATERIALS AND METHODS
We initially used single-cell sequencing data to determine the expression levels of GLUT3 and lactate dehydrogenase A (LDHA) in primary tumor, tumor-adjacent normal, and metastasis tumor tissues. Immunohistochemistry analysis was conducted to measure GLUT3, LDHA, and L-lactyl levels in gastric normal and cancer tissues. Transwell and scratch assays were performed to evaluate the metastatic and invasive capacity of gastric cancer cell lines. Western blotting was used to measure L-lactyl and histone lactylation levels in gastric cancer cell lines.
RESULTS
Single-cell sequencing data showed that GLUT3 expression was significantly increased in primary tumor and metastasis tumor tissues. In addition, GLUT3 expression was positively correlated with that of LDHA expression and lactylation-related pathways. Western blotting and immunohistochemistry analyses revealed that GLUT3 was highly expressed in gastric cancer tissues and cell lines. GLUT3 knockdown in gastric cancer cell lines inhibited their metastatic and invasive capacity to various degrees. Additionally, the levels of LDHA, L-lactyl, H3K9, H3K18, and H3K56 significantly decreased after GLUT3 knockdown, indicating that GLUT3 affects lactylation in gastric cancer cells. Moreover, LDHA overexpression in a GLUT3 knockdown cell line reversed the levels of lactylation and EMT-related markers, and the EMT functional phenotype induced by GLUT3 knockdown. The in vivo results were consistent with the in vitro results.
CONCLUSIONS
This study suggests the important role of histone lactylation in the occurrence and progression of gastric cancer, and GLUT3 may be a new diagnostic marker and therapeutic target for gastric cancer.
PubMed: 38041125
DOI: 10.1186/s12935-023-03162-8 -
Journal of Diabetes Jan 2024The purpose of our investigation is to evaluate the level of relationship between lactate dehydrogenase (LDH) and the occurrence of diabetic retinopathy (DR) in adults...
OBJECTIVES
The purpose of our investigation is to evaluate the level of relationship between lactate dehydrogenase (LDH) and the occurrence of diabetic retinopathy (DR) in adults with diabetes mellitus (DM).
METHODS
The investigation involved an analysis of five sectional data cycles acquired from the National Health and Nutrition Examination Survey from 2009 to 2018. The present study involved the selection of DM samples from a complex multistage probability sample. These samples were subsequently classified into two distinct groups, namely the No DR (NDR) and DR groups. The present study comprehensively investigated the biological and social risk factors associated with DR. The biological factors examined in this investigation included blood pressure, blood routine, hemoglobin A1c, blood glucose, and comorbidities. The social dimensions encompass education and sex.
RESULTS
After considering all factors, multivariate regression models indicated a significant relationship between DR and increased LDH (adjusted odds ratio = 1.007, 95% confidence interval: 1.003-1.011). The subgroup analysis revealed that the effect size of LDH on the existence of DR in the subgroups remained consistent, as indicated by all p values greater than .05. A statistically significant relationship was identified between elevated LDH levels > 134 U/L and a raised risk of DR in people with DM.
CONCLUSION
LDH concentrations were connected with an increased prevalence of DR in participants with DM. Our study highlights that patients with LDH > 134 U/L are distinguishably related to DM complicated by DR. DR is more common in diabetic individuals with coronary heart disease.
Topics: Adult; Humans; Diabetic Retinopathy; L-Lactate Dehydrogenase; Nutrition Surveys; Risk Factors; Glycated Hemoglobin; Prevalence; Diabetes Mellitus, Type 2
PubMed: 37746907
DOI: 10.1111/1753-0407.13476 -
Experimental & Molecular Medicine Oct 2023Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a...
Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, C-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by the cell's own status or the environmental status.
Topics: Histones; Lactic Acid; Acetylation; L-Lactate Dehydrogenase; Epigenesis, Genetic
PubMed: 37779146
DOI: 10.1038/s12276-023-01095-w -
PloS One 2023Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy...
Lactate, which is synthesized as an end product by lactate dehydrogenase A (LDHA) from pyruvate during anaerobic glycolysis, has attracted attention for its energy metabolism and oxidant effects. A novel histone modification-mediated gene regulation mechanism termed lactylation by lactate was recently discovered. The present study examined the involvement of histone lactylation in undifferentiated cells that underwent differentiation into osteoblasts. C2C12 cells cultured in medium with a high glucose content (4500 mg/L) showed increases in marker genes (Runx2, Sp7, Tnap) indicating BMP-2-induced osteoblast differentiation and ALP staining activity, as well as histone lactylation as compared to those cultured in medium with a low glucose content (900 mg/L). Furthermore, C2C12 cells stimulated with the LDH inhibitor oxamate had reduced levels of BMP-2-induced osteoblast differentiation and histone lactylation, while addition of lactate to C2C12 cells cultured in low glucose medium resulted in partial restoration of osteoblast differentiation and histone lactylation. These results indicate that lactate synthesized by LDHA during glucose metabolism is important for osteoblast differentiation of C2C12 cells induced by BMP-2. Additionally, silencing of p300, a possible modifier of histone lactylation, also inhibited osteoblast differentiation and reduced histone lactylation. Together, these findings suggest a role of histone lactylation in promotion of undifferentiated cells to undergo differentiation into osteoblasts.
Topics: Histones; Lactic Acid; Cell Differentiation; Osteoblasts; Glucose
PubMed: 38051708
DOI: 10.1371/journal.pone.0293676 -
Journal of Biomedical Research Nov 2023Endometriosis is defined as a condition with endometrium-like tissues migrating outside of the pelvic cavity. However, the mechanism of endometriosis is still unclear....
Endometriosis is defined as a condition with endometrium-like tissues migrating outside of the pelvic cavity. However, the mechanism of endometriosis is still unclear. Lactate can be covalently modified to lysine residues of histones and other proteins, which is called lactylation. The results showed that the higher level of lactate and lactate dehydrogenase A enhanced the histone H3 lysine 18 lactylation (H3K18lac) in ectopic endometrial tissues and ectopic endometrial stromal cells than that in normal endometrial tissues and normal endometrial stromal cells. Lactate promoted cell proliferation, migration, and invasion in endometriosis. Mechanistically, lactate induced H3K18lac to promote the expression of high-mobility group box 1 (HMGB1) in endometriosis, and HMGB1 knockdown significantly reduced the cell proliferation, migration, and invasion of the lactate-treated cells through the phosphorylation of AKT. In conclusion, lactate could induce histone lactylation to promote endometriosis progression by upregulating the expression of HMGB1, which may provide a novel target for the prevention and treatment of endometriosis.
PubMed: 37945340
DOI: 10.7555/JBR.37.20230095 -
Nutrients Nov 2023Adipose tissue (AT) is the primary reservoir of lipid, the major thermogenesis organ during cold exposure, and an important site for lactate production. However, the...
Adipose tissue (AT) is the primary reservoir of lipid, the major thermogenesis organ during cold exposure, and an important site for lactate production. However, the utilization of lactate as a metabolic substrate by adipocytes, as well as its potential involvement in the regulation of adipocyte thermogenesis, remain unappreciated. In vitro experiments using primary stromal vascular fraction preadipocytes isolated from mouse inguinal white adipose tissue (iWAT) revealed that lactate dehydrogenase B (LDHB), the key glycolytic enzyme that catalyzes the conversion of lactate to pyruvate, is upregulated during adipocyte differentiation, downregulated upon chronic cold stimulation, and regained after prolonged cold exposure. In addition, the global knockout of significantly reduced the masses of iWAT and epididymal WAT (eWAT) and impeded the utilization of iWAT during cold exposure. In addition, loss of function impaired the mitochondrial function of iWAT under cold conditions. Together, these findings uncover the involvement of LDHB in adipocyte differentiation and thermogenesis.
Topics: Animals; Mice; Adipocytes, Beige; Lactic Acid; Adipose Tissue; Adipose Tissue, White; Thermogenesis; Mice, Inbred C57BL; Adipose Tissue, Brown
PubMed: 38004240
DOI: 10.3390/nu15224846 -
BMC Cancer Aug 2023Lung cancer is reported to be the leading cause of death in males and females, globally. Increasing evidence highlights the paramount importance of Lactate dehydrogenase...
BACKGROUND
Lung cancer is reported to be the leading cause of death in males and females, globally. Increasing evidence highlights the paramount importance of Lactate dehydrogenase D (LDHD) in different types of cancers, though it's role in lung adenocarcinoma (LUAD) is still inadequately explored. In this study, we aimed to investigate and determine the relationship between LDHD and LUAD.
METHODS
The collection of the samples was guided by The Cancer Genome Atlas (TCGA) datasets and Gene Expression Omnibus (GEO). To ascertain various aspects around LDHD function, we analyzed different expression genes (DEGs), functional enrichment, and protein-protein interaction (PPI) networks. The predictive values for LDHD were collectively determined using the Kaplan-Meier method, Cox regression analysis, and a nomogram. Evaluation of the immune infiltration analysis was completed using Estimate and ssGSEA. The prediction of the immunotherapy response was based on TIDE and IPS. The LDHD expression levels in LUAD were validated through Western blot, qPCR, and immunohistochemistry methods. Wound healing and transwell assays were also performed to illustrate the aggressive features in LUAD cell lines.
RESULTS
The results showed that LDHD was generally downregulated in LUAD patients, with the low LDHD group presenting a decline in OS, DSS, and PFI. Enriched pathways, which include pyruvate metabolism, central carbon metabolism, and oxidative phosphorylation were observed through KEGG analysis. It was also noted that the expression of LDHD expression was inversely related to immune cell infiltration and typical checkpoints. The high LDHD group's response to immunotherapy was remarkable, particularly in CTAL4 + /PD1- therapy. In vitro studies revealed that the overexpression of LDHD caused tumor migration and invasion to be suppressed.
CONCLUSION
In conclusion, our study revealed that LDHD might be an effective predictor of prognosis and immune filtration, possibly leading to better choices for immunotherapy.
Topics: Female; Male; Humans; Prognosis; Biomarkers; Adenocarcinoma of Lung; Lung Neoplasms; Lactate Dehydrogenases
PubMed: 37587457
DOI: 10.1186/s12885-023-11221-6 -
Journal of Pharmacological Sciences Dec 2023Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/macrophage lineage. Excessive resorbing activities of osteoclasts are...
Osteoclasts are multinucleated, specializes bone-resorbing cells that are derived from the monocyte/macrophage lineage. Excessive resorbing activities of osteoclasts are involved in destructive bone diseases. The detailed mechanism of acidification at the bone adhesion surface during the bone resorption process of osteoclasts remains to be defined. During glycolysis, pyruvate proceeds to the tricarboxylic cycle under aerobic conditions and pyruvate is converted to lactate via lactate dehydrogenase A (LDHA) under anaerobic conditions. However, tumor cells produce ATP during aerobic glycolysis and large amounts of pyruvate are converted to lactate and H by LDHA. Lactate and H are excreted outside the cell, whereby they are involved in invasion of tumor cells due to the pH drop around the cell. In this study, we focused on aerobic glycolysis and investigated the production of lactate by LDHA in osteoclasts. Expression of LDHA and monocarboxylate transporter 4 (MCT4) was upregulated during osteoclast differentiation. Intracellular and extracellular lactate levels increased with upregulation of LDHA and MCT4, respectively. FX11 (an LDHA inhibitor) inhibited osteoclast differentiation and suppressed the bone-resorbing activity of osteoclasts. We propose that inhibition of LDHA may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.
Topics: Humans; Osteogenesis; Lactate Dehydrogenase 5; Osteoclasts; Bone Resorption; Lactates; Glycolysis; Pyruvates; L-Lactate Dehydrogenase
PubMed: 37973217
DOI: 10.1016/j.jphs.2023.09.005 -
Molecular and Cellular Endocrinology Oct 2023Antioxidant actions of melatonin and its impact on testicular function and fertility have already been described. Considering that Sertoli cells contribute to provide...
Antioxidant actions of melatonin and its impact on testicular function and fertility have already been described. Considering that Sertoli cells contribute to provide structural support and nutrition to germ cells, we evaluated the effect of melatonin on oxidative state and lactate metabolism in the immature murine TM4 cell line and in immature hamster Sertoli cells. A prooxidant stimulus applied to rodent Sertoli cells expressing MT1/MT2 receptors, increased lipid peroxidation whereas decreased antioxidant enzymes (superoxide dismutase 1, catalase, peroxiredoxin 1) expression and catalase activity. These changes were prevented by melatonin. Furthermore, melatonin stimulated lactate dehydrogenase (LDH) expression/activity via melatonin receptors, and increased intracellular lactate production in rodent Sertoli cells. Interestingly, oral melatonin supplementation in infertile men positively regulated LDHA testicular mRNA expression. Overall, our work provides insights into the potential benefits of melatonin on Sertoli cells contributing to testicular development and the future establishment of a sustainable spermatogenesis.
Topics: Male; Cricetinae; Mice; Animals; Sertoli Cells; Melatonin; Catalase; Antioxidants; Rodentia; Oxidative Stress; Lactates
PubMed: 37516434
DOI: 10.1016/j.mce.2023.112034