UNASSIGNED: There are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms.
UNASSIGNED: The association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders.
UNASSIGNED: After an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01; p-trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, p <0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific Xdh knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet.
UNASSIGNED: Our study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine.
UNASSIGNED: Using a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport in vivo. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.

METHODS: The prevalence of high-fat diet (HFD) consumption is increasing among middle-aged and older adults, which accelerates the aging process of this population and is more likely to induce lipid metabolism disorders. But the alleviation of ethanolic extract of propolis (EEP) on lipid metabolism disorders during aging remains unclear.
RESULTS: This study assesseed the impact of EEP intervention (200 mg kg-1 bw) on aging and lipid metabolism disorders in HFD-fed senescence accelerate mouse prone 8 (SAMP8) mice. Findings indicate that EEP ameliorates hair luster degradation and weight gain, reduces systemic inflammation and metabolism levels, enhances hepatic antioxidant enzyme activities, and improves the hepatic expression of senescence-associated secretory phenotype and aging-related genes in HFD-fed SAMP8 mice. Histological staining demonstrates that EEP improves hepatic lipid deposition and inflammatory cell infiltration. Transcriptomic and lipidomic analysis reveal that EEP promotes fatty acid β-oxidation by activating PPAR pathway, resulting in reduced hepatic lipid deposition, and attenuates bile acid (BA) accumulation by improving BA metabolism, which were ensured through qPCR validation of key genes and immunoblot validation of key proteins. CONCLUSIONS : EEP can regulate lipid metabolic dysregulation during aging accompanied by an HFD, potentially delaying the onset and progression of age-related diseases. This provides new approach for supporting healthy aging.

Exposed to ubiquitously perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with non-alcoholic fatty liver disease (NAFLD), yet the underlying molecular mechanism remains elusive. The extrapolation of empirical studies correlating per- and polyfluoroalkyl substance (PFAS) exposure with NAFLD occurrence to real-life exposure was hindered by the limited availability of mechanistic data at environmentally relevant concentrations. Herein, a novel pathway mediating hepatocyte lipid accumulation by PFOA and PFOS at human-relevant dose (<10 μM) was identified by integrating CRISPR-Cas9 genome screening, concentration-dependent transcriptional assay in HepG2 cell and epidemiological data mining. 1) At genetic level, nudt7 showed the highest enriched potency among 569 NAFLD-related genes, and the transcription of nudt7 was significantly downregulated by PFOA and PFOS exposure (<7 μM). 2) At molecular pathway, upon exposure to ≤10-4 μM PFOA and PFOS, the downregulation of nudt7 transcriptional expression triggered the reduction of Ace-CoA hydrolase activity. 3) At cellular level, increased lipids were measured in HepG2 cells with PFOA and PFOS (<2 μM). Overall, we identified a novel mechanism mediated by transcriptional downregulation of nudt7 gene in hepatocellular lipid increase treated with PFOA and PFOS, which could potentially explain the NAFLD occurrence associated with exposure to PFASs in humans.

Background: Alterations in the serum lipid profile have been suspected in many psychiatric disorders, such as schizophrenia and depression. However, studies on lipid status in attention-deficit/hyperactivity disorder (ADHD) are sparse and inconsistent. Methods: Using the nationwide, population-based IQVIA Disease Analyzer database, this retrospective cohort study included 5367 outpatients from general practices in Germany aged ≥18 years with a documented first diagnosis of ADHD between January 2005 and December 2021 and 26,835 propensity score-matched individuals without ADHD. Study outcomes were the first diagnosis of lipid metabolism disorders as a function of ADHD within up to 10 years of the index date. The cumulative 10-year incidence was analyzed using Kaplan-Meier curves and compared using the log-rank test. In addition, univariate Cox regression analyses were performed. Results: In the regression analysis, there was no significant association between ADHD and subsequent lipid metabolism disorders in the total population (HR: 0.94; 95% CI: 0.83-1.08), among women (HR: 1.04; 95% CI: 0.84-1.28), and among men (HR: 0.89; 95% CI: 0.74-1.06). In addition, no significant association was observed in the disease-stratified analyses. Conclusions: The findings of this study indicate that ADHD does not exert an influence on lipid metabolism. However, further investigation is warranted, particularly with respect to pharmacological interventions.

BACKGROUND: White matter lesions (WMLs) are increasingly linked to the pathological process of chronic vascular dementia (VaD). An effective crocins fraction extracted from Gardenia Fructus, GJ-4, has been shown to improve cognitive function in several Alzheimer\'s disease models and VaD models.
OBJECTIVE: To explore the potential mechanisms of GJ-4 on WMLs in a chronic VaD mouse model.
METHODS: The chronic VaD mouse model was established, and WMLs were characterized by cerebral blood flow (CBF), behavioral tests, LFB staining, and immunohistochemistry. The anti-oxidative effect of GJ-4 was validated by examining biochemical parameters (SOD, MDA, and GSH) and the Keap1-Nrf2/HO-1 pathway. The impact of GJ-4 on lipid metabolism in WM was further investigated through lipidomic analysis.
RESULTS: GJ-4 significantly attenuated cognitive impairments and improved the CBF of BCAS (bilateral common carotid artery stenosis)-induced mice. Mechanism research showed that GJ-4 could enhance cognition by promoting the repair of WMLs by inhibiting oxidative stress. Furthermore, GJ-4 treatment significantly reduced chronic cerebral hypoperfusion (CCH)-induced WMLs via improving lipid metabolism disorder in the WM.
CONCLUSIONS: This research has provided valuable insights into the significance of WMLs in CCH-induced VaD and underscored the potential of GJ-4 as a therapeutic agent for improving cognitive function by targeting WMLs. These findings suggest that GJ-4 is a promising candidate for the treatment of VaD.

Objective: To investigate the mechanism of Sulfo-N-succinimidyloleate (SSO) regulating lipid metabolism disorder induced by silicon dioxide (SiO(2)) . Methods: In March 2023, Rat alveolar macrophages NR8383 were cultured in vitro and randomly divided into control group (C), SSO exposure group (SSO), SiO(2) exposure group (SiO(2)) and SiO(2)+SSO exposure group (SiO(2)+SSO). NR8383 cells were exposure separately or jointly by SSO and SiO(2) for 36 h to construct cell models. Immunofluorescence and BODIPY 493/ 503 staining were used to detect cluster of differentiation (CD36) and intracellular lipid levels, the protein expression levels of CD36, liver X receptors (LXR), P-mammalian target of rapamycin (P-mTOR) and cholinephosphotransferase 1 (CHPT1) were detected by Western blot, respectively, and lipid metabolomics was used to screen for different lipid metabolites and enrichment pathways. Single-factor ANOVA was used for multi-group comparison, and LSD test was used for pair-to-group comparison. Results: SiO(2) caused the expression of CD36 and P-mTOR to increase (P=0.012, 0.020), the expression of LXR to decrease (P=0.005), and the intracellular lipid level to increase. After SSO treatment, CD36 expression decreased (P=0.023) and LXR expression increased (P=0.000) in SiO(2)+SSO exposure group compared with SiO(2) exposure group. Metabolomics identified 87 different metabolites in the C group and SiO(2) exposure group, 19 different metabolites in the SiO(2) exposure group and SiO(2)+SSO group, and 5 overlaps of different metabolites in the two comparison groups, they are PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), and Sphinganine. In addition, the differential metabolites of the two comparison groups were mainly concentrated in the glycerophospholipid metabolism and sphingolipid metabolism pathways. The differential gene CHPT1 in glycerophospholipid metabolic pathway was verified, and the expression of CHPT1 decreased after SiO(2) exposure. Conclusion: SSO may improve SiO(2)-induced lipid metabolism disorders by regulating PS (22∶1/14∶0), DG (O-16∶0/18∶0/0∶0), PGP (i-13∶0/i-20∶0), PC (18∶3/16∶0), SPA, glycerophospholipid metabolism and sphingolipid metabolism pathways.
目的： 探讨磺基-N-琥珀酰亚胺油酸酯（sulfo-N-succinimidyloleate，SSO）调控二氧化硅（silicon dioxide，SiO(2)）诱导的巨噬细胞脂质代谢紊乱的机制。 方法： 于2023年3月，以常规体外培养大鼠肺泡巨噬细胞NR8383，随机分为对照组（C组）、SSO染毒组、SiO(2)染毒组和SiO(2)+SSO染毒组，使用SSO和SiO(2)分别单独或联合染毒NR8383细胞36 h构建细胞模型。免疫荧光和BODIPY 493/503染色分别检测白细胞分化抗原36（cluster of differentiation，CD36）和细胞内脂质的水平，Western blot检测细胞内CD36、肝脏X受体（liver X receptors，LXR）、磷酸化哺乳动物雷帕霉素靶蛋白（P-mammalian target of rapamycin，P-mTOR）、胆碱磷酸转移酶1（cholinephosphotransferase 1，CHPT1）的蛋白表达水平，脂质代谢组学筛选差异脂质代谢物及富集的途径。多组比较采用单因素方差分析，组内两两比较用LSD检验。 结果： SiO(2)染毒导致巨噬细胞CD36、P-mTOR表达增加（P=0.012、0.020），LXR表达降低（P=0.005），细胞内脂质水平升高，给予SSO干预后，与SiO(2)染毒组比较，SiO(2)+SSO染毒组巨噬细胞CD36表达降低（P=0.023），LXR表达升高（P=0.000）。代谢组学筛选出C组和SiO(2)染毒组中有87个差异代谢物，SiO(2)染毒组和SiO(2)+SSO染毒组中有19个差异代谢物，两个组中差异代谢物存在5个交集，分别为PS（22∶1/14∶0）、DG（O-16∶0/18∶0/0∶0）、PGP（i-13∶0/i-20∶0）、PC（18∶3/16∶0）、鞘氨酸（SPA）。两个比较组差异代谢物均主要富集在甘油磷脂代谢和鞘脂代谢通路。对甘油磷脂代谢通路中的差异基因CHPT1进行验证，SiO(2)染毒后导致巨噬细胞CHPT1表达降低（P=0.041）。 结论： SSO可能通过调控PS（22∶1/14∶0）、DG（O-16∶0/18∶0/0∶0）、PGP（i-13∶0/i-20∶0）、PC（18∶3/16∶0）、SPA以及甘油磷脂代谢和鞘脂代谢通路改善SiO(2)诱导的巨噬细胞脂质代谢紊乱。.

Bisphenol G (BPG), bisphenol M (BPM) and bisphenol TMC (BPTMC), are newly recognized analogues of bisphenol A (BPA), which have been detected in multiple environmental media. However, the understanding of their negative impacts on environmental health is limited. In this study, zebrafish embryos were exposed to BPA and the three analogues (0.1, 10, and 1000 μg/L) to identify their developmental toxic effects. According to our results, all of the three analogues induced significant developmental disorders on zebrafish embryos including inhibited yolk sac absorption, altered heart rate, and teratogenic effects. Oil Red O staining indicated lipid accumulation in the yolk sac region of zebrafish after bisphenol analogues exposure, which was consistent with the delayed yolk uptake. Untargeted lipidomic analysis indicated the abundance of triacylglycerols, ceramides and fatty acids was significantly altered by the three analogues. The combined analysis of lipidomics and transcriptomics results indicated BPG and BPM affected lipid metabolism by disrupting peroxisome proliferator-activated receptor pathway and interfering with lipid homeostasis and transport. This partly explained the morphological changes of embryos after bisphenol exposure. In conclusion, our study reveals that BPG, BPM and BPTMC possess acute and developmental toxicity toward zebrafish, and the developmental abnormalities are associated with the disturbances in lipid metabolism.

Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders affecting the health of the organism and inducing the occurrence of diseases. Saponins, as biologically active substances present in plants, have lipid-lowering, inflammation-reducing, and anti-atherosclerotic effects. Saponins are thought to be involved in the regulation of lipid metabolism in the body; it suppresses the appetite and, thus, reduces energy intake by modulating pro-opiomelanocortin/Cocaine amphetamine regulated transcript (POMC/CART) neurons and neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus, the appetite control center. Saponins directly activate the AMP-activated protein kinase (AMPK) signaling pathway and related transcriptional regulators such as peroxisome-proliferator-activated-receptors (PPAR), CCAAT/enhancer-binding proteins (C/EBP), and sterol-regulatory element binding proteins (SREBP) increase fatty acid oxidation and inhibit lipid synthesis. It also modulates gut-liver interactions to improve lipid metabolism by regulating gut microbes and their metabolites and derivatives-short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine (TMA), lipopolysaccharide (LPS), et al. This paper reviews the positive effects of different saponins on lipid metabolism disorders, suggesting that the gut-liver axis plays a crucial role in improving lipid metabolism processes and may be used as a therapeutic target to provide new strategies for treating lipid metabolism disorders.

UNASSIGNED: Epidemiological research has demonstrated that there is a connection between lipid metabolism disorder and an increased risk of developing arteriosclerosis (AS) and abdominal aortic aneurysm (AAA). However, the precise relationship between lipid metabolism, AS, and AAA is still not fully understood. The objective of this study was to examine the pathways and potential fatty acid metabolism-related genes (FRGs) that are shared between AS and AAA.
UNASSIGNED: AS- and AAA-associated datasets were retrieved from the Gene Expression Omnibus (GEO) database, and the limma package was utilized to identify differentially expressed FRGs (DFRGs) common to both AS and AAA patients. Functional enrichment analysis was conducted on the (DFRGs), and a protein-protein interaction (PPI) network was established. The selection of signature genes was performed through the utilization of least absolute shrinkage and selection operator (LASSO) regression and random forest (RF). Subsequently, a nomogram was developed using the results of the screening process, and the crucial genes were validated in two separate external datasets (GSE28829 and GSE17901) as well as clinical samples. In the end, single-sample gene set enrichment analysis (ssGSEA) was utilized to assess the immune cell patterns in both AS and AAA. Additionally, the correlation between key crosstalk genes and immune cell was evaluated.
UNASSIGNED: In comparison to control group, both AS and AAA patients exhibited a decrease in fatty acid metabolism score. We found 40 DFRGs overlapping in AS and AAA, with lipid and amino acid metabolism critical in their pathogenesis. PCBD1, ACADL, MGLL, BCKDHB, and IDH3G were identified as signature genes connecting AS and AAA. Their expression levels were confirmed in validation datasets and clinical samples. The analysis of immune infiltration showed that neutrophils, NK CD56dim cells, and Tem cells are important in AS and AAA development. Correlation analysis suggested that these signature genes may be involved in immune cell infiltration.
UNASSIGNED: The fatty acid metabolism pathway appears to be linked to the development of both AS and AAA. Furthermore, PCBD1, ACADL, MGLL, BCKDHB, and IDH3G have the potential to serve as diagnostic markers for patients with AS complicated by AAA.

BACKGROUND: Gualou is derived from the fruit of Trichosanthes kirilowii Maxim, while Xiebai from the bulbs of Allium macrostemon Bunge. Gualou and Xiebai herb pair (2:1) is widely used in clinical practice to treat atherosclerotic cardiovascular diseases. However, the mechanism underlying its potential activity on atherosclerosis (AS) has not been fully elucidated.
METHODS: The extract of Gualou-Xiebai herb pair (GXE) was prepared from Gualou (80 g) and Xiebai (40 g) by continuous refluxing with 50% ethanol for 2 h at 80°C. In vivo, ApoE-/- mice were fed a high-fat diet (HFD) for 10 weeks to induce an AS model, and then the mice were treated with GXE (3, 6, 12 g/kg) or atorvastatin (10 mg/kg) via oral gavage. Besides, RAW264.7 macrophages were stimulated by ox-LDL to establish a foam cell model in vitro.
RESULTS: GXE suppressed plaque formation, regulated plasma lipids, and promoted liver lipid clearance in AS mice. In addition, 0.5, 1, and 2 mg/mL GXE significantly reduced the TC and FC levels in ox-LDL (50 μg/mL)-stimulated foam cells. GXE increased cholesterol efflux from the foam cells to ApoA-1 and HDL, and enhanced the protein expressions of ABCA1, ABCG1, and SR-BI, which were reversed by the PPARγ inhibitor. Meanwhile, GXE increased the LCAT levels, decreased the lipid levels and increased the TBA levels in the liver of AS mice. Molecular docking indicated that some compounds in GXE showed favorable binding energy with PPARγ, LCAT and CYP7A1 proteins, especially apigenin-7-O-β-D-glucoside and quercetin.
CONCLUSIONS: In summary, our results suggested that GXE improved lipid metabolism disorders by enhancing RCT, providing a scientific basis for the clinical use of GXE in AS treatment.