Lipid-related Genes Research Articles

ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis.

The strongest genetic risk factor for sporadic Alzheimer's disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography-mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD.

Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid genes. Notably, we observe rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for blood lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

THE COMPLEX RELATIONSHIP OF PARAOXONASE GENE POLYMORPHISMS WITH CORONARY ARTERY DISEASE AND LIPID METABOLISM

Cardiovascular disorder (CVD) is one of the major reasons for mortality in developing and developed countries. According to the World Health Organization (WHO), non-communicable diseases (NCDs) are responsible for 50% of the overall disease burden in Pakistan. And among the NCDs, the most prevalent disease is CVD, as approximately every 1 out of 4 adults suffered from coronary artery disease (CAD). Coronary artery disease mainly causes ischemia or hypoxia of the heart due to coronary vessels stenosis or atherosclerosis.1 The key risk factors include smoking, dyslipidemia, hypertension, obesity, family history, and type 2 diabetes mellitus. The genetic contribution to CAD is an independent factor that includes genetic polymorphisms such as single nucleotide polymorphisms (SNPs). Genome-wide association studies (GWAS) suggest many genes SNPs involved in the pathogenesis of coronary artery disease.2 Although many studies identified the genes and single nucleotide polymorphisms but still, the role of these genetic factors is not clearly understood. Paraoxonase (PON) gene cluster is one of the most widely studied genes that consist of three genes PON1, PON2, and PON3, and located on chromosome 7. The PON2 is the oldest gene among this cluster however, all the 3 genes have a high structural homology. The International Union of Biochemistry and Molecular Biology classified the paraoxonases as aryldialkyl phosphatases. The enzymes coded by these gene clusters exhibit the antiatherosclerotic properties that play an essential role in high-density lipoproteins (HDL) or antioxidant properties. The PON1 activity is highly influenced by both genetic (non-modifiable) and environmental factors (modifiable).3 It involves a complex interaction between both genetic and modifiable factors. The human PON1 is a calcium-dependent glycoprotein that is first identified by its ability to hydrolyze various organophosphates. Through lipid peroxides hydrolysis, it reduces the low-density lipoprotein (LDL). Low enzyme levels are associated with cardiac disorders, familial hypercholesterolemia, and diabetes mellitus. To date, approximately 184 SNPs reported, and some coding region SNPs i.e. rs662 and rs854560 are the most widely studied single nucleotide polymorphisms.4 The most commonly studied Q192R polymorphism is associated with poor patient outcomes. The risk allele or R allele is associated with abnormal HDL and triglycerides levels and the worst CVD outcome. Furthermore, the levels of paraoxonase levels are also decreased in CVD patients and there is a complex relationship between different variables particularly genetic markers, lipid profile, or environmental factors with PON activity.5 The PON2 and PON3 similarly play a crucial role in lipid metabolism and inhibit atherosclerosis due to their protective role against the formation of atherosclerotic plaques in coronary arteries. In PON2 rs12704796 is significantly associated with coronary heart disease risk.6 Robertson et al. first reported single nucleotide polymorphism in PON3 at positions number 107 and 99 but the exact mechanism of these SNPs in the pathophysiology of CAD remains to be understood.7 The multi-locus model also revealed a gene to gene interaction between PON2 and PON3 and gene-environment in the Pakistani cardiac patients.8 The single nucleotide polymorphisms in this gene cluster are significantly important in CAD patients. These SNPs may exert their effect by modulating the lipid metabolism and enzyme concentrations in CAD patients, which can be varied according to certain environmental factors and ethnic groups. Thus, in the future, it is suggested to perform a study with more sample size in different populations that can help us in better understanding disease pathophysiology and prevention.

Association of cluster determinant 36, scavenger receptor class B type 1, and major facilitator superfamily domain containing the 2a genetic polymorphism with serum lipid profile in aging population with type 2 diabetes mellitus.

BackgroundLipid metabolism disorder commonly happens in subjects with Type 2 diabetes mellitus (T2DM) which may be linked to genetic variants of lipid metabolism-related genes. However, few studies have explored the relationship between lipid metabolism-related gene polymorphism and serum lipid profile in aging subjects with T2DM. The present study was designed to explore the impact of genetic polymorphism of cluster determinant 36 (CD36) (rs1049673, rs1054516, rs2151916), scavenger receptor class B type 1 (SCARB1) (rs5888), and major facilitator superfamily domain containing the 2a (MFSD2A) (rs12083239, rs4233508, rs12072037) on the relationship between circulating lipids in aging subjects with T2DM.Methods205 T2DM patients and 205 age and gender matched control subjects were recruited. Information on demographic characteristics was collected by using a self-administered questionnaire. Fasting venous blood samples were taken for lipid-related gene genotyping and serum lipid profile measurement. The Chi-square test was used to compare percentage differences and to calculate P-value for Hardy-Weinberg equilibrium. Logistic regression and multiple linear regression were used to explore the risk or correlation between variables, and general linear model (GLM) was used to compare the means of serum lipids between the groups.ResultsIn T2DM group, CD36 rs1054516 and MFSD2A rs12072037 were correlated with serum TC level. In control group, CD36 rs1049673 was correlated with serum HDL-C level. Meanwhile, T2DM subjects with MFSD2A rs12083239 (CG), MFSD2A rs4233508 (TT), and MFSD2A rs12072037 (AA) had higher TG level than control subjects. T2DM subjects with CD36 rs1049673 (CG, GG), CD36 rs1054516 (CT), CD36 rs2151916 (TT, CT), SCARB1 rs5888 (GG), MFSD2A rs12083239 (GG, CG), MFSD2A rs4233508 (TT), and MFSD2A rs12072037 (CA, AA) had lower HDL-C level than control subjects. T2DM subjects with MFSD2A rs12072037 (AA) had lower LDL-C level than control subjects. In dominant model, major genotype (GG) of SCARB1 gene was associated with the risk of T2DM (OR = 0.636, P = 0.032).ConclusionThe genetic polymorphism of CD36 (rs1049673, rs1054516, rs2151916), SCARB1 (rs5888), and MFSD2A (rs12083239, rs4233508, rs12072037) were associated with serum lipids in T2DM subjects. The SCARB1 rs5888 major genotype (GG) was a protective factor for T2DM. Large scale cohort study is required to determine the relationship between lipid metabolism-related gene polymorphism, serum lipid profile and T2DM in aging subjects.

Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate experimental non-alcoholic steatohepatitis via Nrf2/NQO-1 pathway

BackgroundNo approved effective therapy for non-alcoholic steatohepatitis (NASH) is currently available. Exosomes derived from mesenchymal stem cells (MSCs) perform the functions such as inhibiting inflammation, anti-oxidative stress, regulating immunity, but it is not clear whether human umbilical cord mesenchymal stem cells (hUC-MSCs) exosomes protect against NASH through Nrf2/NQO-1 pathway. Therefore, this study was conducted to investigate the effects of hUC-MSCs exosomes on NASH through Nrf2/NQO-1 pathway in vivo and in vitro. MethodsC57BL/6J male mice were fed with high fat and high cholesterol diet (HFHC) and methionine choline deficiency diet (MCD). Mice were treated with or without hUC-MSCs exosomes by tail intravenous injection. The liver histology, lipid metabolism and oxidative stress were evaluated. HepG2 and AML12 cells were incubated with palmitic acid (PA) and MCD conditioned medium, respectively. Then the therapeutic effect of hUC-MSCs exosomes in steatotic cells was evaluated. To elucidate the signaling pathways, the Nrf2-specific blocker ML385 was applied to intervene in vitro. ResultsIn NASH models, hUC-MSCs exosomes attenuated steatosis in hepatocytes, altered the abnormal expression of lipid-related genes including SREBP-1c, PPAR-α, Fabp5, CPT1α, ACOX and FAS, suppressed the hepatic inflammatory responses by decreasing the expression of F4/80+ macrophages, CD11c+ macrophages as well as the content of TNF-α and IL-6. hUC-MSCs exosomes also inhibited oxidative stress by reducing the level of MDA, CYP2E1 and ROS, increasing the activity of SOD and GSH in hepatocytes. Notably, hUC-MSCs exosomes enhanced the protein ratio of p-Nrf2/Nrf2 and the protein expression of NQO-1. Moreover, in vitro, the therapeutic effects of hUC-MSCs exosomes on lipid deposition and ROS were reversed by ML385. Also, ML385 reduced the protein expression of p-Nrf2 and NQO-1 in vitro. ConclusionNrf2/NQO-1 antioxidant signaling pathway may play a key role in the treatment of NASH by hUC-MSCs exosomes.

Temporal Alterations of Sphingolipids in Optic Nerves After Indirect Traumatic Optic Neuropathy

PurposeTo identify optic nerve (ON) lipid alterations associated with sonication-induced traumatic optic neuropathy (TON).DesignExperimental study.SubjectsA mouse model of indirect TON was generated using sound energy concentrated focally at the entrance of the optic canal using a laboratory sonifier with a microtip probe.MethodsAnalyses of datasets generated from high-performance liquid chromatography-electrospray tandem mass spectrometry of ONs dissected from the head of the ON to the optic chiasm at 1 day, 7 days, and 14 days postsonication compared with that in nonsonicated controls.Main Outcome MeasuresLipid abundance alterations in postsonicated ONs were evaluated using 1-way analysis of variance (false discovery rate-adjusted significant P value < 0.01), lipid-related gene sets, biochemical properties, and receiver operating characteristic to identify lipids associated with optic neuropathy.ResultsThere were 28 lipid species with significantly different abundances across the control and postsonication groups. The 2 most significantly upregulated lipids included a sphingomyelin (SM) species, SM(d40:7), and a hexosylceramide (CerG1) species, CerG1(d18:1/24:2). Hexosylceramide (d18:1/24:2) was noted to have a stepwise increasing trend from day 1 to day 14 after sonication-induced optic neuropathy. Investigation of biophysical properties showed notable enrichment of lipids with high and above-average transition temperatures at day 14 after sonication. Lipid-related gene set analysis revealed enrichment in sphingolipid and glycosphingolipid metabolic processes. The best classifier to differentiate day 14 postsonication from controls, based on area under the receiver operating characteristic curve, was CerG1(d18:1/24:2) (area under the receiver operating characteristic curve: 1).ConclusionsTemporal alterations in sphingolipid metabolism and biochemical properties were observed in the ON of mice after sonication-induced optic neuropathy, with notable elevations in sphingomyelin and hexosylceramide species. Hexosylceramide (d18:1/24:2) may be associated with damage after indirect trauma, indicating that lipid membrane abnormalities may be a mediator of pathology due to trauma.

Integration of clinical and transcriptomics reveals programming of the lipid metabolism in gastric cancer

Lipid metabolism has a profound impact on gastric cancer (GC) progression and is a newly targetable vulnerability for cancer therapy. Given the importance of lipids in cancer cellular processes, in this study we employed lipidomic clinical and transcriptomic data to connect the variations of lipid metabolism changes of GC. We constructed a clinical nomogram based on the lipid factors and other clinical items. Then by using multi-omics techniques, we established a lipid-related gene signature for individualized prognosis prediction in patients with GC. Moreover, a total of 1357 GC cases were then applied to evaluate the robustness of this model. WGCNA was used to identify co-expression modules and enriched genes associated with GC lipid metabolism. The role of key genes ACLY in GC was further investigated. The prognostic value of the lipgenesis signature was analyzed using Cox regression model, and clinical nomogram was established. Among them, we observed overexpression of ACLY significantly increased the levels of intracellular free fatty acid and triglyceride, and activated AKT/mTOR pathway to promote cancer development. In conclusion, our findings revealed that GC exhibited a reprogramming of lipid metabolism in association with an altered expression of associated genes. Among them, ACLY significantly promoted GC lipid metabolism and increased cancer cell proliferation, suggesting that this pathway can be targetable as a metabolic vulnerability in future GC therapy.

Increased Lipids in Chlamydomonas reinhardtii by Multiple Regulations of DOF, LACS2, and CIS1.

Microalgal lipids are essential for biofuel and dietary supplement production. Lipid engineering for higher production has been studied for years. However, due to the complexity of lipid metabolism, single-gene engineering gradually encounters bottlenecks. Multiple gene regulation is more beneficial to boosting lipid accumulation and further clarifying the complex regulatory mechanism of lipid biosynthesis in the homeostasis of lipids, carbohydrates, and protein metabolism. Here, three lipid-related genes, DOF, LACS2, and CIS, were co-regulated in Chlamydomonas reinhartii by two circles of transformation to overexpress DOF and knock down LACS2 and CIS simultaneously. With the multiple regulations of these genes, the intracellular lipids and FA content increased by 142% and 52%, respectively, compared with CC849, whereas the starch and protein contents decreased by 45% and 24%. Transcriptomic analysis showed that genes in TAG and FA biosynthesis were up-regulated, and genes in starch and protein metabolism were down-regulated. This revealed that more carbon precursor fluxes from starch and protein metabolism were redirected towards lipid synthesis pathways. These results showed that regulating genes in various metabolisms contributed to carbon flux redirection and significantly improved intracellular lipids, demonstrating the potential of multiple gene regulation strategies and providing possible candidates for lipid overproduction in microalgae.

Comprehensive lipid and lipid-related gene investigations of host immune responses to characterize metabolism-centric biomarkers for pulmonary tuberculosis

Despite remarkable success in the prevention and treatment of tuberculosis (TB), it remains one of the most devastating infectious diseases worldwide. Management of TB requires an efficient and timely diagnostic strategy. In this study, we comprehensively characterized the plasma lipidome of TB patients, then selected candidate lipid and lipid-related gene biomarkers using a data-driven, knowledge-based framework. Among 93 lipids that were identified as potential biomarker candidates, ether-linked phosphatidylcholine (PC O–) and phosphatidylcholine (PC) were generally upregulated, while free fatty acids and triglycerides with longer fatty acyl chains were downregulated in the TB group. Lipid-related gene enrichment analysis revealed significantly altered metabolic pathways (e.g., ether lipid, linolenic acid, and cholesterol) and immune response signaling pathways. Based on these potential biomarkers, TB patients could be differentiated from controls in the internal validation (random forest model, area under the curve [AUC] 0.936, 95% confidence interval [CI] 0.865–0.992). PC(O-40:4), PC(O-42:5), PC(36:0), and PC(34:4) were robust biomarkers able to distinguish TB patients from individuals with latent infection and healthy controls, as shown in the external validation. Small changes in expression were identified for 162 significant lipid-related genes in the comparison of TB patients vs. controls; in the random forest model, their utilities were demonstrated by AUCs that ranged from 0.829 to 0.956 in three cohorts. In conclusion, this study introduced a potential framework that can be used to identify and validate metabolism-centric biomarkers.

Differential distribution of gene polymorphisms associated with hypercholesterolemia, hypertriglyceridemia, and hypoalphalipoproteinemia among Native American and Mestizo Mexicans

BACKGROUNDDyslipidemias are metabolic abnormalities associated with chronic diseases caused by genetic and environmental factors. The Mexican population displays regional differences according to ethnicity with an impact on the type of dyslipidemia. AIMTo define the main dyslipidemias, the frequency of lipid-related risk alleles, and their association with hyperlipidemic states among different ethnic groups in West Mexico. METHODSIn a retrospective study, 1324 adults were selected to compare dyslipidemias and lipid-related gene polymorphisms. Demographic, clinical, and laboratory data were collected. A subgroup of 196 normal weight subjects without impaired glucose was selected for the association analyses. Genotyping was determined by allelic discrimination assay. RESULTSHypercholesterolemia was the most prevalent dyslipidemia (42.3%). The frequency of the risk alleles associated with hypoalphalipoproteinemia (ABCA1) and hypercholesterolemia (APOE, LDLR) was higher in the Native Americans (P = 0.047). In contrast, the Mestizos with European ancestry showed a higher frequency of the risk alleles for hypertriglyceridemia (APOE2, MTTP) (P = 0.045). In normal weight Mestizo subjects, the APOB TT and LDLR GG genotypes were associated risk factors for hypercholesterolemia (OR = 5.33, 95%CI: 1.537-18.502, P = 0.008 and OR = 3.90, 95%CI: 1.042-14.583, P = 0.043, respectively), and displayed an increase in low-density lipoprotein cholesterol levels (APOB: β = 40.39, 95%CI: 14.415-66.366, P = 0.004; LDLR: β = 20.77, 95%CI: 5.763-35.784, P = 0.007).CONCLUSIONGene polymorphisms and dyslipidemias showed a differential distribution. Regional primary health care strategies are required to mitigate their prevalence considering the genetic and environmental features which could have important implications for personalized medicine within the new era of precision medicine.

Coix Seed-Based Milk Fermented With Limosilactobacillus reuteri Improves Lipid Metabolism and Gut Microbiota in Mice Fed With a High-Fat Diet.

The aim of this study was to investigate the effects of coix seed-based milk (CSM) fermented with Limosilactobacillus reuteri (L. reuteri) on dyslipidemia and the composition of the intestinal microbiota in high fat diet (HFD)-fed mice. Changes in the body weight, serum lipid levels, activities of hepatic oxidative stress factors, expression of lipid-related genes, and composition of the intestinal microbiota of HFD-fed mice after supplementation with CSM were determined. The results showed that intake of CSM reduced the body weight gain as well as serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels, and increased the high-density lipoprotein cholesterol (HDL-C) levels in the mice. Meanwhile, supplementation with CSM could relieve liver oxidative stress, down-regulate the expression of genes related to lipid synthesis, and prevent liver fat accumulation in mice fed with HFD. The 16S rRNA sequencing of the intestinal microbiota showed that CSM regulated the gut microbiota community structure at different taxonomic levels, and reversed gut dysbiosis induced by HFD. The relative abundance of Muribaculaceae, Lachnospiraceae, Dubosiella and Akkermansia which are negatively correlated with blood lipid levels were significantly increased by the intervention of CSM, while the relative abundance of Desulfovibrionaceae, Ruminococca-ceae_UCG-014, Psychrobacter, and Staphylococcus which have positive correlation with blood lipid levels were significantly decreased. These results indicated that CSM might serve as a novel and promising dietary supplement for ameliorating hyperlipidemia and intestinal microbiota disorders caused by HFDs.

Abstract 2374: Early metabolic rewiring of prostate cancer cells triggered by bone progenitors defines survival of metastatic prostate cancer

Abstract Bone hosts the 88% of Prostate Cancer (PCa) metastases and no curative therapy is currently available for this stage. Arrival of PCa cells to the bone homing organ is accompanied by a metabolic adaptation, which may be mediated by bone secreted factors. Herein, we sought to identify key metabolic genes fueling PCa bone metastasis and soluble factors secreted by bone cells leading to the metabolic rewiring of tumoral cells. By an indirect transwell co-culture system of PCa (PC3) and bone progenitor cells (MC3T3, pre-osteoblasts; or Raw264.7, pre-osteoclasts) we analyzed the transcriptome (RNA-seq) of PC3 cells modulated by soluble factors released from bone precursors. GSEA showed a strong activation of lipid metabolism, including PPAR and PI3K-Akt pathways, fat absorption and digestion. We then performed a Principal Component Analysis using transcriptomic data from human PCa and bone metastasis samples (GSE74685), showcasing that those metabolic genes that appeared significantly dysregulated in the co-culture model could accurately cluster samples by their tissue of origin in two defined groups: primary PCa and bone metastasis. This result was confirmed by an unsupervised clustering analysis, highlighting that the transcriptional metabolic profile triggered in the in vitro model has a clinical correlate in human bone metastasis samples. Interestingly, when performing a survival analysis for those genes in the SU2C-PCF dataset, we observed that 4 lipid-associated genes, PPARA, VDR, SLC16A1 and GPX1, correlated with a shorter overall survival time, and appeared as independent risk-predictors of death (HR: 4.96, 2.85, 3.93 and 3.67, respectively; P&amp;lt;0.05). These results prompted us to evaluate the communication axis by which the expression of the lipid transcriptomic signature is regulated in PC3 cells co-cultured with bone progenitor cells. We performed an Ingenuity Pathway Analysis (QIAGEN) showing that the tumoral Protein Kinase A (PKA) appears as a master regulator of this signature. Accordingly, when we treated PC3 cells with the conditioned media (CM) of PC3 grown alone or the co-culture, we observed a decreased ATP content in the latter compared with controls, which is restored upon PKA inhibition, confirming the role of this kinase in the metabolic phenotype of co-cultured cells. Finally, secretome analysis (ESI-MS/MS) of CM from the co-cultures displayed relevant soluble factors secreted by bone progenitors (Col1a1, Fn1) which are directly linked to PKA activity. Overall, we identified an early lipid-related gene signature in PCa cells triggered by the dialogue with bone cells, enough to discriminate metastatic human PCa from primary tumors and critical for PCa survival. This signature may respond to released soluble bone factors through tumoral cell PKA activation. Our findings pinpoint new attractive metabolic druggable targets to halt disease progression. Citation Format: Pablo Sanchis, Nicolas Anselmino, Rosario Lavignolle, Agustina Sabater, Estefania Labanca, Juan Bizzotto, Sofia Lage-Vickers, Gaston Pascual, Rocio Seniuk, Ayelen Toro, Nora Navone, Javier Cotignla, Elba Vazquez, Geraldine Gueron. Early metabolic rewiring of prostate cancer cells triggered by bone progenitors defines survival of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2374.

Inhibitory Effects of Mongolian Medicine Yihe-Tang on Continuous Darkness Induced Liver Steatosis in Zebrafish.

The constant dark induction (DD) causes lipid degeneration and nonalcoholic fatty liver disease (NAFLD) in zebrafish, which might be closely related to the imbalance of gut microbiota and require in-depth study. In this study, a total of 144 zebrafish were divided into four groups, including the control group, Yihe-Tang group, constant dark group, and constant dark + Yihe-Tang group, and were treated with constant darkness (except control and Yihe-Tang groups) for 21 days. The bodyweights of zebrafish were recorded after 8 d, 15 d, and 22 d. The sequencing analysis of gut microbiota, detection of liver histopathological changes, and comparison of lipid metabolism-related gene expression levels were performed on the 22nd day of the experiment. The results showed that the Yihe-Tang could inhibit the constant dark-induced increase in zebrafish weight and liver steatosis. As compared to the control group, the dark treatment could alter the composition of gut microbiota in zebrafish, increase the relative abundance of harmful bacteria, and decrease the Cetobacterium and Bacteroides to Firmicutes ratio in the intestines. The abundance of Proteobacteria in the constant dark + Yihe-Tang group was close to that in the control group and that of Fusobacteria and Cetobacterium increased, especially the Cetobacterium, which increased significantly. The constant dark treatment caused an abnormal expression of liver lipid-related genes, inhibited lipid metabolism, and promoted fat accumulation. However, the Yihe-Tang could restore these changes to the level of the control group. This study indicated that Yihe-Tang could restore the constant dark-induced liver lipid degeneration. We hypothesized that Cetobacterium could significantly inhibit steatosis.

A Novel Human Heterozygous SCP2 Mutation Leads to Alterations in Lipid Metabolism

Peroxisomal β‐oxidation plays a critical role in the detoxification of fatty acids and in cholesterol metabolism to form bile acids. The sterol carrier protein‐x (SCPx) is a lipid transfer protein with thiolase activity catalyzing the final step of the peroxisomal β‐oxidation process. SCPx deficiency has been previously reported in only two patients. Here, we report the third patient with SCPx deficiency and the first resulting from a heterozygous mutation in the SCP2gene encoding SCPx. The patient presented with azoospermia, cardiac dysrhythmia, muscle wasting, and progressive brainstem neurodegeneration. The objective of this work was to investigate the link between the patient’s SCP2mutation and his clinical presentations. We hypothesized that, because SCPx plays a critical role in the transport and metabolism of many lipids, the patient’s SCP2 mutation could lead to widespread alterations in lipid‐related genes and their target pathways. Patient fibroblasts (WESP) and normal human dermal fibroblasts (NHDF) were used to investigate the effects of the SCP2 mutation. RNA sequencing was used to identify lipid‐related differentially expressed genes, which led to the identification of metabolic pathways affected by the patient’s SCP2 mutation including cholesterol metabolism, peroxisome proliferator‐activated receptor (PPAR) signaling, and serotonergic synapse signaling. Lipidomic analyses were used to identify changes in the levels of various lipids including several sterols, free fatty acids, phospholipids, and acylcarnitines. This led to the identification of other affected metabolic pathways including steroid biosynthesis, bile acid metabolism, and fatty acid degradation. Collectively, these findings show that the patient’s heterozygous mutation in SCP2 led to alterations in several lipid metabolic pathways, which may explain certain clinical consequences of SCPx deficiency.

Sex-dependent host-microbiome dynamics in zebrafish: Implications for toxicology and gastrointestinal physiology

The physiology of males and females can be vastly different, complicating interpretation of toxicological and physiological data. The objectives of this study were to elucidate the sex differences in the microbiome-gastrointestinal (GI) transcriptome of adult zebrafish. We compared microbial composition and diversity in both males and females fed the same diet and housed in the same environment. There were no sex-specific differences in weight gain nor gastrointestinal morphology based on histopathology. There was no difference in gut microbial diversity, richness (Shannon and Chao1 index) nor predicted functional composition of the microbiome between males and females. Prior to post-hoc correction, male zebrafish showed higher abundance for the bacterial families Erythrobacteraceae and Lamiaceae, both belonging to the phyla Actinobacteria and Proteobacteria. At the genus level, Lamia and Altererythrobacter were more dominant in males and an unidentified genus in Bacteroidetes was more abundant in females. There were 16 unique differentially expressed transcripts in the gastrointestinal tissue between male and female zebrafish (FDR corrected, p < 0.05). Relative to males, the mRNA expression for trim35–9, slc25a48, chchd3b, csad, and hsd17b3 were lower in female GI while cyp2k6, adra2c, and bckdk were higher in the female GI. Immune and lipid-related gene network expression differed between the sexes (i.e., cholesterol export and metabolism) as well as networks related to gastric motility, gastrointestinal system absorption and digestion. Such data provide clues as to putative differences in gastrointestinal physiology between male and female zebrafish. This study identifies host-transcriptome differences that can be considered when interpreting the microgenderome of zebrafish in studies investigating GI physiology and toxicology of fishes.

Experimental study on the influence of different aperture connectors on nanofat

Nanofat, as a derivative of adipose tissue, has gradually become a research hotspot in beauty and regenerative medicine. However, the nanofat preparation method has not yet been standardized; it remains unknown whether the aperture of the connector has any influence on the transplantation effect. Adipose tissue was mechanically emulsified into nanofat tissue through different connector apertures (1.0, 1.5, and 2.0mm). Cell survival and apoptosis were measured using the volume of oil droplets, glucose transportation test, flow cytometry, cell counting kit-8 (CCK-8), wound healing assay, transwell migration assay, and fluorescence staining. The expression of adiponectin, GluT4, and PPAR-γ in nanofat-derived stem cells (NFSCs) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The fineness of nanofat tissue texture decreased with an increase in the aperture connector. The amounts of glucose transferred in the three groups (1, 1.5, and 2mm) were 4.7±0.894, 6.1±1.026, and 6.9±0.868mmol/L, respectively. Flow cytometric analysis showed that the proportion of NFSCs in the 2.0mm group was the highest (91.267±1.210%). Cell proliferation and migration abilities were stronger in the 1.5 and 2.0mm groups. The numbers of late apoptotic and dead cells in the 2.0mm group were significantly fewer than those in the two other groups. Expression levels of lipid-related genes were as follows: adiponectin > GluT4 > PPAR-γ in each component. As nanofat is emulsified, the use of larger aperture connectors (2.0mm) appeared to decrease the degree of adipocyte lysis and increase the biological activity of adipose tissue.

Stanniocalcin 1 promotes metastasis, lipid metabolism and cisplatin chemoresistance via the FOXC2/ITGB6 signaling axis in ovarian cancer

BackgroundStanniocalcin 1 (STC1) plays an integral role in ovarian cancer (OC). However, the functional role of STC1 in metastasis, lipid metabolism and cisplatin (DDP) chemoresistance in OC is not fully understood.MethodsSingle-cell sequencing and IHC analysis were performed to reveal STC1 expression profiles in patient tissues. Metastasis, lipid metabolism and DDP chemoresistance were subsequently assessed. Cell-based in vitro and in vivo assays were subsequently conducted to gain insight into the underlying mechanism of STC1 in OC.ResultsSingle-cell sequencing assays and IHC analysis verified that STC1 expression was significantly enhanced in OC tissues compared with para-carcinoma tissues, and it was further up-regulated in peritoneal metastasis tissues compared with OC tissues. In vitro and in vivo experiments demonstrated that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance in OC. Simultaneously, STC1 promoted lipid metabolism by up-regulating lipid-related genes such as UCP1, TOM20 and perilipin1. Mechanistically, STC1 directly bound to integrin β6 (ITGB6) to activate the PI3K signaling pathway. Moreover, STC1 was directly regulated by Forkhead box C2 (FOXC2) in OC. Notably, targeting STC1 and the FOXC2/ITGB6 signaling axis was related to DDP chemoresistance in vitro.ConclusionsOverall, these findings revealed that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance via the FOXC2/ITGB6 signaling axis in OC. Thus, STC1 may be used as a prognostic indicator in patients with metastatic OC. Meanwhile, STC1 could be a therapeutic target in OC patients, especially those who have developed chemoresistance to DDP.

An integrated omics analysis reveals the gene expression profiles of maize, castor bean, and rapeseed for seed oil biosynthesis

BackgroundSeed storage lipids are valuable for human diet and for the sustainable development of mankind. In recent decades, many lipid metabolism genes and pathways have been identified, but the molecular mechanisms that underlie differences in seed oil biosynthesis in species with developed embryo and endosperm are not fully understood.ResultsWe performed comparative genome and transcriptome analyses of castor bean and rapeseed, which have high seed oil contents, and maize, which has a low seed oil content. These results revealed the molecular underpinnings of the low seed oil content in maize. First of all, transcriptome analyses showed that more than 61% of the lipid- and carbohydrate-related genes were regulated in castor bean and rapeseed, but only 20.1% of the lipid-related genes and 22.5% of the carbohydrate-related genes were regulated in maize. Then, compared to castor bean and rapeseed, fewer lipid biosynthesis genes but more lipid metabolism genes were regulated in the maize embryo. More importantly, most maize genes encoding lipid-related transcription factors, triacylglycerol (TAG) biosynthetic enzymes, pentose phosphate pathway (PPP) and Calvin Cycle proteins were not regulated during seed oil synthesis, despite the presence of many homologs in the maize genome. Additionally, we observed differential regulation of vital oil biosynthetic enzymes and extremely high expression levels of oil biosynthetic genes in castor bean, which were consistent with the rapid accumulation of oil in castor bean developing seeds.ConclusionsCompared to high-oil seeds (castor bean and rapeseed), less oil biosynthetic genes were regulated during the seed development in low-oil seed (maize). These results shed light on molecular mechanisms of lipid biosynthesis in maize, castor bean, and rapeseed. They can provide information on key target genes that may be useful for future experimental manipulation of oil production in oil plants.

Influence of Dietary Inositol Supplementation on Growth, Liver Histology, Lipid Metabolism, and Related Genes Expression on Juvenile Hybrid Grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatu) Fed High-Lipid Diets

An 8-week feeding trial was conducted to investigate the effects of dietary inositol on growth performance, lipid metabolism, and expression of lipid related genes of hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatu) (initial body weight 6.76 ± 0.34 g). Six isonitrogenous and isolipidic (16.35%) diets were formulated to contain graded levels of inositol (0.17 g/kg (J1), 0.62 g/kg (J2), 1.03 g/kg (J3), 1.78 g/kg (J4), 3.43 g/kg (J5), and 6.59 g/kg (J6)). The results indicated that (a) weight gain rate appeared gradually increasing trend and significant increase in four inositol treatments (J3, J4, J5, and J6) ( P &lt; 0.05 ). Protein efficiency ratio was slightly improved in the J4 group ( P &lt; 0.05 ), but there was no significant difference exhibiting in survival rate between the inositol-treated groups and the control group ( P &gt; 0.05 ). (b) In serum, dietary inositol significantly reduced the contents of triglyceride (TG), total cholesterol (TC), low-density lipoprotein, and clearly increased the content of high-density lipoprotein ( P &lt; 0.05 ). In the liver, dietary inositol significantly decreased contents of TG, TC, and very low-density lipoprotein ( P &lt; 0.05 ). The activities of lipoprotein lipase, hepatic lipase, and adipose triglyceride lipase were slightly improved in the inositol-treated groups ( P &lt; 0.05 ). (c) With increasing of inositol supplement, decreasing of lipid droplet could be observed in hepatocyte. (d) In the liver, dietary inositol significantly downregulated the mRNA levels of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), 6-phosphogluconate dehydrogenase (6PGD), and sterol regulatory element-binding protein-1 (SREBP1) ( P &lt; 0.05 ), while it remarkably upregulated the mRNA levels of lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), and carnitine palmitoyl transferase1 (CPT1) ( P &lt; 0.05 ). In summary, dietary inositol improved growth and reduced lipid composition in the liver of hybrid grouper through decreasing of fatty acid synthesis and increasing of lipid catabolism. Under the experimental conditions, broken-line regression analysis showed that 1.23~1.67 g/kg dietary inositol was recommended in juvenile grouper high-lipid diets.

Exploring Camelina sativa lipid metabolism regulation by combining gene co‐expression and DNA affinity purification analyses

SUMMARYCamelina (Camelina sativa) is an annual oilseed plant that is gaining momentum as a biofuel cover crop. Understanding gene regulatory networks is essential to deciphering plant metabolic pathways, including lipid metabolism. Here, we take advantage of a growing collection of gene expression datasets to predict transcription factors (TFs) associated with the control of Camelina lipid metabolism. We identified approximately 350 TFs highly co‐expressed with lipid‐related genes (LRGs). These TFs are highly represented in the MYB, AP2/ERF, bZIP, and bHLH families, including a significant number of homologs of well‐known Arabidopsis lipid and seed developmental regulators. After prioritizing the top 22 TFs for further validation, we identified DNA‐binding sites and predicted target genes for 16 out of the 22 TFs tested using DNA affinity purification followed by sequencing (DAP‐seq). Enrichment analyses of targets supported the co‐expression prediction for most TF candidates, and the comparison to Arabidopsis revealed some common themes, but also aspects unique to Camelina. Within the top potential lipid regulators, we identified CsaMYB1, CsaABI3AVP1‐2, CsaHB1, CsaNAC2, CsaMYB3, and CsaNAC1 as likely involved in the control of seed fatty acid elongation and CsaABI3AVP1‐2 and CsabZIP1 as potential regulators of the synthesis and degradation of triacylglycerols (TAGs), respectively. Altogether, the integration of co‐expression data and DNA‐binding assays permitted us to generate a high‐confidence and short list of Camelina TFs involved in the control of lipid metabolism during seed development.