An immune-adrenergic pathway induces lethal levels of platelet-activating factor in mice.

Acute immune responses with excess production of cytokines, lipid/chemical mediators, or coagulation factors, often result in lethal damage. In addition, the innate immune system utilizes multiple types of receptors that recognize neurotransmitters as well as pathogen-associated molecular patterns, making immune responses complex and clinically unpredictable. We here report an innate immune and adrenergic link inducing lethal levels of platelet-activating factor. Injecting mice with toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS), cell wall N-glycans of Candida albicans, and the α2-adrenergic receptor (α2-AR) agonist medetomidine induces lethal damage. Knocking out the C-type lectin Dectin-2 prevents the lethal damage. In spleen, large amounts of platelet-activating factor (PAF) are detected, and knocking out lysophospholipid acyltransferase 9 (LPLAT9/LPCAT2), which encodes an enzyme that converts inactive lyso-PAF to active PAF, protects mice from the lethal damage. These results reveal a linkage/crosstalk between the nervous and the immune system, possibly inducing lethal levels of PAF.

LPCAT2-mediated lipid droplet production supports pancreatic cancer chemoresistance and cell motility.

Lipid droplet (LD) accumulation is one of the features in various tumors, whereas the significance of LD accumulation in pancreatic cancer progression remains unclear under chemotherapeutic condition. Since chemoresistance towards gemcitabine (GEM) is an obstacle for clinical therapy of pancreatic cancer, we sought to investigate the contribution of LD accumulation to GEM resistance. Herein, triacsin C (an inhibitor of LD production) dampened the proliferation, migration, and invasion of pancreatic cancer cells. The inhibition of LD accumulation induced by triacsin C or silencing of perilipin 2 (a marker of LD) sensitized cells to GEM treatment. Next, 75 paraffin-embedded samples and 5 pairs of frozen samples from pancreatic cancer patients were obtained for the detection of lysophosphatidylcholine acyltransferase 2 (LPCAT2; a LD-located enzyme contributing phosphatidylcholine synthesis) expression. The results revealed that LPCAT2 was upregulated in pancreatic cancer tissues, and its expression was correlated with clinical parameters and the basal LD content of cancer cell lines. Loss of LPCAT2 repressed the LD accumulation, GEM resistance, and cell motility. The enhancement of chemotherapy sensitivity was further confirmed in a xenograft model of mice in vivo. The carcinogenesis role of LPCAT2 was at least partly mediated by the LD accumulation. Then, signal transducer and activator of transcription 5B (STAT5B) activated the transcription of LPCAT2. Both LPCAT2 downregulation and triacsin C reversed the STAT5B-induced potentiation of malignant phenotypes in pancreatic cancer cells. In conclusion, LPCAT2-mediated lipid droplet production supported pancreatic cancer chemoresistance and cell motility, which was triggered by STAT5B.

Arachidonic Acid Mobilization and Peroxidation Promote Microglial Dysfunction in Aß Pathology.

Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aß pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female App NL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aß plaques and promoting the compaction of Aß deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression.

Identification of LPCAT1 as a key biomarker for Crohn's disease based on bioinformatics and machine learnings and experimental verification.

Epithelial-mesenchymal transition (EMT) plays a crucial role in regulating inflammatory responses and fibrosis formation. This study aims to explore the molecular mechanisms of EMT-related genes in Crohn's disease (CD) through bioinformatics methods and identify potential key biomarkers. In our research, we identified differentially expressed genes (DEGs) related to EMT based on the GSE52746 dataset and the gene set in the GeneCards database. Key genes were identified through Lasso-cox and Random Forest and validated using the external dataset GSE10616. Immune infiltration analysis showed that Lysophosphatidylcholine acyltransferase 1 (LPCAT1) was positively correlated with Neutrophils and Macrophages M1. The Gene Set Enrichment Analysis (GSEA) results for LPCAT1 showed associations with celladhesionmolecules and ECM receptor interaction. Additionally, a lncRNA-miRNA-mRNA ceRNA network was constructed. Finally, we validated that knocking down LPCAT1 could inhibit the release of inflammatory factors, EMT, and the elevation of fibrosis indices as well as the activation of NF-κB signaling pathway in LPS-induced HT-29 cells. LPCAT1 plays an important role in the occurrence and development of CD and may become a new biomarker.

LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

Lysophospholipid acyltransferase-mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation.

Adaptation to hypoxia has attracted much public interest because of its clinical significance. However, hypoxic adaptation in the body is complicated and difficult to fully explore. To explore previously unknown conserved mechanisms and key proteins involved in hypoxic adaptation in different species, we first used a yeast model for mechanistic screening. Further multi-omics analyses in multiple species including yeast, zebrafish and mice revealed that glycerophospholipid metabolism was significantly involved in hypoxic adaptation with up-regulation of lysophospholipid acyltransferase (ALE1) in yeast, a key protein for the formation of dipalmitoyl phosphatidylcholine [DPPC (16:0/16:0)], which is a saturated phosphatidylcholine. Importantly, a mammalian homolog of ALE1, lysophosphatidylcholine acyltransferase 1 (LPCAT1), enhanced DPPC levels at the cell membrane and exhibited the same protective effect in mammalian cells under hypoxic conditions. DPPC supplementation effectively attenuated growth restriction, maintained cell membrane integrity and increased the expression of epidermal growth factor receptor under hypoxic conditions, but unsaturated phosphatidylcholine did not. In agreement with these findings, DPPC treatment could also repair hypoxic injury of intestinal mucosa in mice. Taken together, ALE1/LPCAT1-mediated DPPC formation, a key pathway of glycerophospholipid metabolism, is crucial for cell viability under hypoxic conditions. Moreover, we found that ALE1 was also involved in glycolysis to maintain sufficient survival conditions for yeast. The present study offers a novel approach to understanding lipid metabolism under hypoxia and provides new insights into treating hypoxia-related diseases.

LPCAT1 promotes melanoma cell proliferation via Akt signaling.

Melanoma is the most lethal type of skin cancer with an increasing cutaneous cancer­related mortality rate worldwide. Despite therapeutic advances in targeted therapy and immunotherapy, the overall survival of patients with melanoma remains unsatisfactory. Thus, a further understanding of the pathogenesis of melanoma may aid towards the development of therapeutic strategies. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is a key enzyme that converts lysophosphatidylcholine into phosphatidylcholine in lipid remodeling. In the present study, LPCAT1 was found to play a pro­proliferative role in melanoma. Firstly, the expression of LPCAT1 was found to be upregulated in tissues from patients with melanoma compared with that in benign nevi. Subsequently, LPCAT1 knockdown was performed, utilizing short hairpin RNA, which induced melanoma cell cycle arrest at the G1/S transition and promoted cell death. Moreover, LPCAT1 facilitated melanoma cell growth in an Akt­dependent manner. In summary, the results of the present study indicate that targeting LPCAT1 may impede cell proliferation by inhibiting Akt signaling, thus providing a promising therapeutic strategy for melanoma in clinical practice.

Lysophospholipid Acyltransferase 9 Promotes Emphysema Formation via Platelet-activating Factor.

Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9-/-) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9-/- mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9-/- mice compared with LPLAT9+/+ mice. Notably, these phenotypes were again worsened by LPLAT9+/+ bone marrow transplantation in LPALT9-/- mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.

Using multi-scale genomics to associate poorly annotated genes with rare diseases.

BACKGROUND: Next-generation sequencing (NGS) has significantly transformed the landscape of identifying disease-causing genes associated with genetic disorders. However, a substantial portion of sequenced patients remains undiagnosed. This may be attributed not only to the challenges posed by harder-to-detect variants, such as non-coding and structural variations but also to the existence of variants in genes not previously associated with the patient's clinical phenotype. This study introduces EvORanker, an algorithm that integrates unbiased data from 1,028 eukaryotic genomes to link mutated genes to clinical phenotypes. METHODS: EvORanker utilizes clinical data, multi-scale phylogenetic profiling, and other omics data to prioritize disease-associated genes. It was evaluated on solved exomes and simulated genomes, compared with existing methods, and applied to 6260 knockout genes with mouse phenotypes lacking human associations. Additionally, EvORanker was made accessible as a user-friendly web tool. RESULTS: In the analyzed exomic cohort, EvORanker accurately identified the "true" disease gene as the top candidate in 69% of cases and within the top 5 candidates in 95% of cases, consistent with results from the simulated dataset. Notably, EvORanker outperformed existing methods, particularly for poorly annotated genes. In the case of the 6260 knockout genes with mouse phenotypes, EvORanker linked 41% of these genes to observed human disease phenotypes. Furthermore, in two unsolved cases, EvORanker successfully identified DLGAP2 and LPCAT3 as disease candidates for previously uncharacterized genetic syndromes. CONCLUSIONS: We highlight clade-based phylogenetic profiling as a powerful systematic approach for prioritizing potential disease genes. Our study showcases the efficacy of EvORanker in associating poorly annotated genes to disease phenotypes observed in patients. The EvORanker server is freely available at https://ccanavati.shinyapps.io/EvORanker/ .

Overexpression of lysophospholipid acyltransferase, LPLAT10/LPCAT4/LPEAT2, in the mouse liver increases glucose-stimulated insulin secretion.

Postprandial hyperglycemia is an early indicator of impaired glucose tolerance that leads to type 2 diabetes mellitus (T2DM). Alterations in the fatty acid composition of phospholipids have been implicated in diseases such as T2DM and nonalcoholic fatty liver disease. Lysophospholipid acyltransferase 10 (LPLAT10, also called LPCAT4 and LPEAT2) plays a role in remodeling fatty acyl chains of phospholipids; however, its relationship with metabolic diseases has not been fully elucidated. LPLAT10 expression is low in the liver, the main organ that regulates metabolism, under normal conditions. Here, we investigated whether overexpression of LPLAT10 in the liver leads to improved glucose metabolism. For overexpression, we generated an LPLAT10-expressing adenovirus (Ad) vector (Ad-LPLAT10) using an improved Ad vector. Postprandial hyperglycemia was suppressed by the induction of glucose-stimulated insulin secretion in Ad-LPLAT10-treated mice compared with that in control Ad vector-treated mice. Hepatic and serum levels of phosphatidylcholine 40:7, containing C18:1 and C22:6, were increased in Ad-LPLAT10-treated mice. Serum from Ad-LPLAT10-treated mice showed increased glucose-stimulated insulin secretion in mouse insulinoma MIN6 cells. These results indicate that changes in hepatic phosphatidylcholine species due to liver-specific LPLAT10 overexpression affect the pancreas and increase glucose-stimulated insulin secretion. Our findings highlight LPLAT10 as a potential novel therapeutic target for T2DM.

Molecular cloning, tissue expression pattern, responses to different fatty acids and potential functions of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in large yellow croaker (Larimichthys crocea).

In farmed fish, diets rich in palm oil have been observed to promote abnormal lipid build-up in the liver, subsequently leading to physiological harm and disease onset. Emerging research suggests that integrating phospholipids into the feed could serve as a potent countermeasure against hepatic impairments induced by vegetable oil consumption. Phosphatidylcholine is the most abundant type among phospholipids. In the metabolic processes of mammal, lysophosphatidylcholine acyltransferase 1 (LPCAT1), crucial for phosphatidylcholine remodeling, demonstrates a marked affinity towards palmitic acid (PA). Nonetheless, aspects concerning the cloning, tissue-specific distribution, and affinity of the LPCAT1 gene to diverse oil sources have yet to be elucidated in the large yellow croaker (Larimichthys crocea). Within the scope of this study, we successfully isolated and cloned the cDNA of the LPCAT1 gene from the large yellow croaker. Subsequent analysis revealed distinct gene expression patterns of LPCAT1 across ten different tissues of the species. The fully sequenced coding DNA sequence (CDS) of LPCAT1 spans 1503 bp and encodes a sequence of 500 amino acids. Comparative sequence alignment indicates that LPCAT1 shares a 69.75 % amino acid similarity with its counterparts in other species. Although LPCAT1 manifests across various tissues of the large yellow croaker, its predominance is markedly evident in the liver and gills. Furthermore, post exposure of the large yellow croaker's hepatocytes to varied fatty acids, PA has a strong response to LPCAT1. Upon the addition of appropriate lysolecithin to palm oil feed, the mRNA expression of LPCAT1 in the liver cells of the large yellow croaker showed significant variations compared to other subtypes. Concurrently, the mRNA expression of pro-inflammatory genes il-1ß, il-6, il-8, tnf-α and ifn-γ in the liver tissue of the large yellow croaker decreased. Interestingly, they exhibit the same trend of change. In conclusion, we have cloned the LPCAT1 gene on fish successfully and find the augmented gene response of LPCAT1 in hepatocytes under PA treatment first. The results of this study suggest that LPCAT1 may be associated with liver inflammation in fish and offer new insights into mitigating liver diseases in fish caused by palm oil feed.

Targeting phospholipid remodeling pathway improves insulin resistance in diabetic mouse models.

Previous studies have revealed that membrane phospholipid composition controlled by lysophosphatidylcholine acyltransferase 3 (LPCAT3) is involved in the development of insulin resistance in type 2 diabetes. In this study, we aimed to investigate the therapeutic potential of targeting Lpcat3 in the treatment of insulin resistance in diabetic mouse models. Lpcat3 expression was suppressed in the whole body by antisense oligonucleotides (ASO) injection or in the liver by adeno-associated virus (AAV)-encoded Cre in high-fat diet (HFD)-induced and genetic ob/ob type 2 diabetic mouse models. Glucose tolerance test (GTT), insulin tolerance test (ITT), fasting blood glucose, and insulin levels were used to assess insulin sensitivity. Lipid levels in the liver and serum were measured. The expression of genes involved in de novo lipogenesis was analyzed by real-time RT-PCR. Metabolic rates were measured by indirect calorimetry using the Comprehensive Lab Animal Monitoring System (CLAMS). Our data demonstrate that acute knockout of hepatic Lpcat3 by AAV-Cre improves both hyperglycemia and hypertriglyceridemia in HFD-fed mice. Similarly, whole-body ablation of Lpcat3 by ASO administration improves obesity and insulin resistance in both HFD-fed and ob/ob mice. These findings demonstrate that targeting LPCAT3 could be a novel therapy for insulin resistance.

Lysophospholipid acyltransferases orchestrate the compositional diversity of phospholipids.

Lysophospholipid acyltransferases (LPLATs), in concert with glycerol-3-phosphate acyltransferases (GPATs) and phospholipase A1/2s, orchestrate the compositional diversity of the fatty chains in membrane phospholipids. Fourteen LPLAT enzymes which come from two distinct families, AGPAT and MBOAT, have been identified, and in this mini-review we provide an overview of their roles in de novo and remodeling pathways of membrane phospholipid biosynthesis. Recently new nomenclature for LPLATs has been introduced (LPLATx, where x is a number 1-14), and we also give an overview of key biological functions that have been discovered for LPLAT1-14, revealed primarily through studies of LPLAT-gene-deficient mice as well as by linkages to various human diseases.

Pan-cancer analysis identifies LPCATs family as a prognostic biomarker and validation of LPCAT4/WNT/ß-catenin/c-JUN/ACSL3 in hepatocellular carcinoma.

Lipid remodeling regulators are now being investigated as potential therapeutic targets for cancer therapy as a result of their involvement, which includes promoting cancer cells' adaptation to the restricted environment. Lysophosphatidylcholine acyltransferases (LPCATs, LPCAT1-4) are enzymes that regulate the remodeling of bio-membranes. The functions of these enzymes in cancer are largely unknown. In the current study, we found that genes belonging to the LPCAT family participated in tumor advancement and were strongly linked to dismal prognosis in many different malignancies. We constructed the LPCATs scores model and explored this model in pan-cancer. Malignant pathways in pan-cancer were positively related to LPCATs scores, and all pathways had strong links to the tumor microenvironment (TME). Multiple immune-associated features of the TME in pan-cancer were likewise associated with higher LPCATs scores. In addition, the LPCATs score functioned as a prognostic marker for immune checkpoint inhibitor (ICI) therapies in patients with cancer. LPCAT4 enhanced cell growth and cholesterol biosynthesis by up-regulating ACSL3 in hepatocellular carcinoma (HCC). WNT/ß-catenin/c-JUN signaling pathway mediated LPCAT4's regulation on ACSL3. These findings demonstrated that genes in the LPCAT family might be used as cancer immunotherapy and prognosis-related biomarkers. Specifically, LPCAT4 could be a treatment target of HCC.

LPCAT1 enhances the invasion and migration in gastric cancer: Based on computational biology methods and in vitro experiments.

BACKGROUND AND AIM: The biological functions and clinical implications of lysophosphatidylcholine acyltransferase 1 (LPCAT1) remain unclarified in gastric cancer (GC). The aim of the current study was to explore the possible clinicopathological significance of LPCAT1 and its perspective mechanism in GC tissues. MATERIALS AND METHODS: The protein expression and mRNA levels of LPCAT1 were detected from in-house immunohistochemistry and public high-throughput RNA arrays and RNA sequencing. To have a comprehensive understanding of the clinical value of LPCAT1 in GC, all enrolled data were integrated to calculate the expression difference and standard mean difference (SMD). The biological mechanism of LPCAT1 in GC was confirmed by computational biology and in vitro experiments. Migration and invasion assays were also conducted to confirm the effect of LPCAT1 in GC. RESULTS: Both protein and mRNA expression levels of LPCAT1 in GC were remarkably higher than those in noncancerous controls. Comprehensively, the SMD of LPCAT1 mRNA was 1.11 (95% CI = 0.86-1.36) in GC, and the summarized AUC was 0.85 based on 15 datasets containing 1727 cases of GC and 940 cases of non-GC controls. Moreover, LPCAT1 could accelerate the invasion and migration of GC by boosting the neutrophil degranulation pathway and disturbing the immune microenvironment. CONCLUSION: An increased level of LPCAT1 may promote the progression of GC.

The validation and clinical significance of LPCAT1 down-regulation in acute myeloid leukemia.

BACKGROUND: Overexpression of lysophosphatidylcholine acyltransferase 1 (LPCAT1) has been found in various solid cancers and is associated with disease progression, metastasis, and recurrence. However, the expression pattern of LPCAT1 in acute myeloid leukemia (AML) bone marrow remains unknown. The present study aimed to compare LPCAT1 expression differences in bone marrow samples from AML patients and healthy controls and assess the clinical relevance of LPCAT1 in AML. METHODS AND RESULTS: LPCAT1 expression in bone marrow was significantly lower in AML than in healthy controls predicted by public databases. Furthermore, real-time quantitative PCR (RQ-PCR) validated that LPCAT1 expression in bone marrow was significantly down-regulated in AML compared to healthy controls [0.056 (0.000-0.846) vs 0.253 (0.031-1.000)]. The DiseaseMeth version 2.0 and The Cancer Genome Atlas analysis revealed that the LPCAT1 promoter was hypermethylated in AML, and there was a strong negative correlation between LPCAT1 expression and methylation (R = - 0.610, P < 0.001). RQ-PCR revealed that the frequency of LPCAT1 low expression was lower in the FAB-M4/M5 subtype than in the other subtypes (P = 0.018). The ROC curve revealed that LPCAT1 expression could serve as a potential diagnostic marker for differentiating AML from controls with an area under the ROC curve of 0.819 (95% CI 0.743-0.894, P < 0.001). In cytogenetically normal AML, patients with LPCAT1 low expression had significantly longer overall survival than those without LPCAT1 low expression (median 19 versus 5.5 months, P = 0.036). CONCLUSIONS: LPCAT1 is down-regulated in AML bone marrow, and LPCAT1 down-regulation could be used as a potential biomarker for AML diagnosis and prognosis.

Dietary omega-3 fatty acid does not improve male infertility caused by lysophospholipid acyltransferase 3 (LPLAT3/AGPAT3) deficiency.

Docosahexaenoic acid (DHA), an omega-3 fatty acid, usually presents as a constituent of phospholipids in the cellular membrane. Lysophospholipid acyltransferase 3 (LPLAT3; AGPAT3) is the primary enzyme that incorporates DHA into phospholipids. LPLAT3-KO mice show male infertility and visual dysfunction accompanied by decreased phospholipids (PLs) containing DHA (PL-DHA) in the testis and retina, respectively. In this study, we evaluated the effect of diets consisting mainly of triacylglycerol-bound DHA (fish oil) and PL-bound DHA (salmon roe oil) on the amount of PL-DHA in a broad range of tissues and on reproductive functions. Both diets elevated phosphatidylcholines (PCs)-containing DHA in most tissues of wild type (WT) mice. Although LPLAT3-KO mice acquired a minimal amount of PC-DHA in the testes and sperm by eating either of the diets, reproductive function did not improve. The present study suggests that DHA-rich diets do not restore sufficient PL-DHA to improve male infertility in LPLAT3-KO mice. Alternatively, PL-DHA can be biosynthesized by LPLAT3 but not by external supplementation, which may be necessary for normal reproductive function.

Knockdown of LPCAT1 Repressed Hepatocellular Carcinoma Growth and Invasion by Targeting S100A11.

OBJECTIVE: To explore the function of LPCAT1 in hepatocellular carcinoma progression. METHODS: Bioinformatics analysis was utilized to the data from TCGA to explore the level of LPCAT1 between normal and tumor tissues, as well as the relationship between LPCAT1 level and tumor grade and prognosis of HCC. Subsequently, we used siRNA to silence LPCAT1 in HCC cells to detect cell proliferation, migration, and invasion ability. RESULTS: The expression of LPCAT1 was significantly increased in HCC tissues. High LPCAT1 expression was correlated with high histologic grade and poor prognosis of HCC. In addition, silencing of LPCAT1 inhibited the proliferation, migration and invasion of liver cancer cells. Moreover, LPCAT1 knockdown suppressed S100A11 and Snail both at mRNA and protein level. CONCLUSION: LPCAT1 promoted the growth, invasion and migration of HCC cells by regulating S100A11 and Snail. Therefore, LPCAT1 may serve as a potential molecular target for the diagnosis and treatment of HCC.

Integrative Analysis of Transcriptome and Metabolome to Illuminate the Protective Effects of Didymin against Acute Hepatic Injury.

Based on the multiomics analysis, this study is aimed at investigating the underlying mechanism of didymin against acute liver injury (ALI). The mice were administrated with didymin for 2 weeks, followed by injection with lipopolysaccharide (LPS) plus D-galactosamine (D-Gal) to induce ALI. The pathological examination revealed that didymin significantly ameliorated LPS/D-Gal-induced hepatic damage. Also, it markedly reduced proinflammatory cytokines release by inhibiting the TLR4/NF-κB pathway activation, alleviating inflammatory injury. A transcriptome analysis proved 2680 differently expressed genes (DEGs) between the model and didymin groups and suggested that the PI3K/Akt and metabolic pathways might be the most relevant targets. Meanwhile, the metabolome analysis revealed 67 differently expressed metabolites (DEMs) between the didymin and model groups that were mainly clustered into the glycerophospholipid metabolism, which was consistent with the transcriptome study. Importantly, a comprehensive analysis of both the omics indicated a strong correlation between the DEGs and DEMs, and an in-depth study demonstrated that didymin alleviated metabolic disorder and hepatocyte injury likely by inhibiting the glycerophospholipid metabolism pathway through the regulation of PLA2G4B, LPCAT3, and CEPT1 expression. In conclusion, this study demonstrates that didymin can ameliorate LPS/D-Gal-induced ALI by inhibiting the glycerophospholipid metabolism and PI3K/Akt and TLR4/NF-κB pathways.

LPCAT1 acts as an independent prognostic biomarker correlated with immune infiltration in hepatocellular carcinoma.

BACKGROUND: Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is overexpressed in multiple human tumors. However, the role of LPCAT1 in hepatocellular carcinoma (HCC) has not been understood. We aim to explore the relationships between LPCAT1 expression and prognosis, clinicopathological features, tumor microenvironment (TME), immune cell infiltration, immune checkpoint gene expression, and related signaling pathways in HCC. Furthermore, we also explored the relationship between LPCAT1 expression and drug sensitivity to HCC treatment. METHODS: The expression profiles were acquired from the Cancer Genome Atlas (TCGA) and the Human Protein Atlas (THPA). Immune status and infiltration in cancer tissues were explored using the single sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithm. RESULTS: LPCAT1 was overexpressed in HCC, and its expression was related to poor prognosis, LPCAT1 was an independent prognostic biomarker in HCC. Expression of LPCAT1 increased statistically with the increase of clinical stage and grade of HCC patients. GO and KEGG network analysis revealed that LPCAT1 positively associated molecules were mostly enriched in functions related to cell adhesion. The TME score of high-LPCAT1 group was significantly higher than that of low-LPCAT1 group. Immune infiltrating cells positively correlated with LPCAT1 expression were Macrophages M0, B cells memory, Dendritic cells activated, T cells regulatory and T cells gamma delta in HCC. We found a positive correlation between LPCAT1 and most immune checkpoint gene expression. The IC50 of 5-Fluorouracil, Gemcitabine, Mitomycin C, Sorafenib and Cabozantinib in patients with high-LPCAT1 expression was lower than that in patients with low-LPCAT1 expression. Our findings provide a wealth of information for further understanding of the biological functions and signaling pathways of LPCAT1 in HCC. CONCLUSIONS: LPCAT1 is an independent prognostic biomarker and associated with tumor microenvironment, immune cell infiltration, immune checkpoint expression and drug sensitivity in hepatocellular carcinoma.