In order to investigate the relationship between oxidation and sheep lipids and flavor, this study used hydroxyl radical system, headspace solid phase microextraction and gas-phase coupled methods to analyze the effects of different oxidation times (0, 2, 4, 8 and 12 h) on sheep meat lipids and volatile flavor compounds. Results indicate that conjugated diene increased from 2.89 to 7.93 mmol/kg, and thiobarbituric acid reactive substances increased from 0.31 to 1.26 mg MDA/kg within 12 h. Moreover, the levels of volatile compounds such as pentanal, hexanal, benzaldehyde, octanal, nonanal, 1-octen-3-ol, and 2,3-octanedione increased with the increased levels of hexanal, nonanal, and benzaldehyde associated with rancid odor or acidification. Furthermore, 213 differential lipids were identified, primarily enriched in glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, sphingolipid signaling, and ether lipid metabolism. These lipids and metabolic pathways may play a role in flavor formation during sheep meat oxidation.

The liver is considered a target organ for the accumulation and toxic effects of nanomaterials exposed to the body, especially after oral exposure, but the key toxic pathways have not been fully defined. This study focused on the hepatotoxicity of titanium dioxide nanoparticles (TiO2 NPs) in vivo and in vitro, and tried to identify key toxic pathways using the concept of systems biology and multi-omics methods. In vivo, protein and metabolomic sequencing were performed on the liver of SD rats (0, 50 mg/kg, 90 days), and 386 differential proteins and 29 differential metabolites were screened out, respectively, and the joint analysis found that they were significantly enriched in alanine, aspartate and glutamate metabolism, and butanoate metabolism. In vitro, exposure to TiO2 NPs could induce cytotoxicity and omics changes at different molecular levels in human hepatocellular carcinoma cells. Single omic analysis showed that differentially expressed proteins and metabolites were 80 and 222, respectively. The enriched pathways related to steroid biosynthesis, cholesterol metabolism at the combine levels of proteome and metabolome. KEGG enrichment analysis showed that PI3K-Akt signaling pathway and PPAR signaling pathway were both significantly affected in vitro and in vivo. Through multi-omics analysis, this work offered fresh perspectives and avenues for research on the toxicity mechanism of TiO2 NPs.

In recent years, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) has attracted significant attention in environmental science, yet its behavior in biological systems remains poorly understood. This study involved a 28-day zebrafish exposure experiment at three concentrations (2, 20, and 200 μg/L), to investigate its physiologically based toxicokinetic (PBTK) properties, the formation of biotransformation products, and the metabolic characteristics of liver tissue. The results indicated that the liver and intestines are key organs for 6PPD accumulation, with tissue-specific distribution patterns. The biotransformation of 6PPD in the liver involves various phase I and phase II metabolic reactions, including hydroxylation, N-dealkylation, and sulfation processes. Furthermore, Metabolomics analysis revealed substantial changes in both the diversity and abundance of liver metabolites with increasing 6PPD concentrations, particularly in key biological processes such as lipid metabolism, amino acid metabolism, and redox balance. Notably, significant disruptions in sphingolipid and glycerophospholipid pathways suggest 6PPD may impair membrane fluidity and stability, potentially leading to membrane damage and dysfunction. Overall, this study provides crucial insights into the biological behavior of 6PPD in zebrafish, contributing essential knowledge for its ecotoxicological evaluation.

Amiodarone is an effective therapy for arrhythmias, its prolonged management may lead to significant adverse drug reactions. Amiodarone-induced hepatotoxicity is described by phospholipidosis, hepatic steatosis, cholestatic hepatitis, and cirrhosis. However, the systemic and hepatic lipidome disturbances and underlying toxicological mechanisms remain comprehensively elucidated. Untargeted lipidomics were utilized to analyze serum and liver samples from the rats orally administered a daily dose of amiodarone of either 100 or 300 mg/kg for one week. Changes in the expression of hepatic lipid-related genes were also examined utilizing transcriptomics. We found a higher magnitude of lipidome alterations in the 300 mg/kg than those in the 100 mg/kg groups. Treated animals showed elevated abundances of phosphatidylcholines, ether-linked phosphatidylcholines, sphingomyelins, and ceramides, and decreased levels of triacylglycerols, ether-linked triacylglycerols, and fatty acids. We also found 199 lipid-related differentially expressed hepatic genes between the 300 mg/kg group versus controls, implying lipid metabolism and signaling pathways disturbances. Specifically, elevation of serum phosphatidylcholines and ether-linked phosphatidylcholines, as well as hepatic bismonoacylglycerophosphates might be associated with reduced expression of phospholipase genes and elevated expression of glycerophospholipid biosynthesis genes, possibly driving phospholipidosis. Perturbations of sphingolipid metabolism might also be the key events for amiodarone-induced toxicity. Alterations in gene expression levels related to lipid storage and metabolism, mitochondria functions, and energy homeostasis were also found. Collectively, our study characterized the sophisticated perturbations in the lipidome and transcriptome of amiodarone-treated rats and suggested potential mechanisms responsible for amiodarone-induced hepatotoxicity.

Osteonecrosis of the femoral head (ONFH) is a severe disease characterized by bone tissue necrosis due to vascular impairment, often leading to joint collapse and requiring surgical intervention. Extracellular vesicles (EVs) serve as crucial mediators of intercellular communication, influencing osteogenesis, angiogenesis, and immune regulation. This review summarizes the dual role of EVs in both the pathogenesis of ONFH and post-necrosis bone repair, highlighting the impact of various EV-mediated signaling pathways on bone regeneration and the potential crosstalk among these pathways. Additionally, EVs hold promise as diagnostic biomarkers or contrast agents to complement conventional imaging techniques for ONFH detection. By elucidating the role of EVs in osteonecrosis and addressing the current challenges, we aspire to establish a foundation for the timely identification and treatment of ONFH. The translational potential of this article: This review comprehensively discusses the role of EVs in ONFH, providing innovative and promising insights for its diagnosis and treatment, which also establishes a theoretical foundation for the future clinical application of EVs in ONFH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.

Recent insights into the function and composition of cell membranes have transformed our understanding from primarily viewing these structures as passive barriers to recognizing them as dynamic entities actively involved in many cellular functions. This review highlights advances in the photopharmacology of phospholipids, emphasizing in particular the role of diacylglycerophospholipids and the impact of their polymorphic nature on synthetic and cellular membrane properties and metabolic processes. We explore photoswitchable diacylglycerophospholipids, termed 'photolipids', which permit precise, reversible modifications of membrane properties via light-induced isomerization. The ability to optically switch phospholipid properties has potential applications in controlling membrane dynamics, protein function, and cellular signaling pathways, and offers promising strategies for drug delivery and treatment of diseases. Developments in azobenzene and hemithioindigo based photolipids are discussed, underscoring their utility in biomedical and biomaterial science applications due to their unique photophysical properties.

Obesity-related kidney disease (ORKD) has recently become a global health issue. Metformin is widely used in patients with type 2 diabetes with concomitant obesity, but its effects on ORKD are insufficiently understood. Accumulation of lipid species including sphingolipids has been reported to disrupt glomerular functions and drive progression of chronic kidney disease. The present study aimed to test the hypothesis that metformin could exert beneficial effects on ORKD, which may be associated with changes in renal lipidomics. Male Sprague-Dawley rats were divided into normal chow diet (ND) group or high-fat diet (HFD)-fed group. After 8 weeks, HFD-fed group was subdivided into metformin treatment (HFD-Met) group and control (HFD-C) group for an additional 8 weeks. Sphingolipids and phospholipids in renal cortex were measured by targeted lipidomics. Compared with ND group, HFD-C group developed histopathological features of ORKD. Metformin alleviated dyslipidemia, renal dysfunction, proteinuria, glomerular hypertrophy, podocyte damage, and renal fibrosis in HFD-fed rats. Renal sphingolipid analysis showed elevations of total ceramide, sphingosine, glucosylceramide, and galactosylceramide levels in HFD-C versus ND group. Specific species, such as ceramide d18:1/22:0, glucosylceramide d18:1/20:0, and galactosylceramide d18:1/16:0, which were positively associated with oxidative stress and insulin resistance, were reduced in HFD-Met versus HFD-C group. Renal phospholipid analysis showed increased levels of total phosphatidylcholine and lysophosphatidylcholine (LPC) in HFD-C rats versus ND rats. The ratio of saturated and monounsaturated LPCs to polyunsaturated LPCs was significantly reduced in HFD-Met rats. These results suggest that metformin alleviates sphingolipids dysregulation and improves ORKD in HFD-fed rats. SIGNIFICANCE STATEMENT: To date, this is the first report to explore effects of metformin on renal lipidomics. These findings reveal specific changes of renal lipid species, which are crucial for deeper understanding the underlying mechanisms of obesity-related kidney disease and effects of metformin on it. The associated signature sphingolipids and phospholipids in the study may have significant implications for developing targeted therapeutic strategies for obesity-related kidney disease.

The microbiota-gut-brain axis plays a pivotal role in neuropsychiatric disorders, particularly in depression. Escitalopram (ESC) is a first-line antidepressant, however, its regulatory mechanisms on the microbiota-gut-brain axis in the treatment of depression remain unclear. The antidepressant effects of ESC were evaluated using the forced swim test in Wistar-Kyoto (WKY) rats, while damage in the gut and brain regions was assessed through H&E staining and immunohistochemistry. The therapeutic mechanisms in WKY rats with depression-like behavior were investigated through 16S rRNA sequencing of the gut microbiota, serum untargeted metabolomics, and hippocampal proteomics. Results indicated that ESC intervention improved depressive-like behaviors, as evidenced by increased swimming times in WKY rats, and also restored intestinal permeability and brain tissue integrity. Significant changes in the gut microbiota composition, particularly an increase in Bacteroides barnesiae, as well as increases in serum sphingolipid metabolites (Sphinganine 1-phosphate, Sphingosine, and Sphingosine-1-phosphate) and hippocampal proteins (Sptlc1, Enpp5, Enpp2), were strongly correlated. These robust correlations suggest that ESC may exert its antidepressant effects by modulating sphingolipid metabolism through the influence of gut microbiota. Accordingly, this research elucidates novel mechanisms underlying the antidepressant efficacy of ESC and highlights the pivotal importance of the microbiota-gut-brain axis in mediating these effects.

Preeclampsia (PE) is a serious pregnancy complication that contributes to maternal and perinatal morbidity and mortality. Understanding its pathogenesis and revealing predictive biomarkers are essential for guiding treatment decisions. In order to explore the global changes of serum metabolites in PE patients and identify potential predictive biomarkers for suspected PE patients (pregnant women who had already shown PE-related symptoms in the middle to late stages of pregnancy, but were not yet confirmatively diagnosed as PE.), a large-scale serum metabolomic analysis was conducted in this study with a prospective cohort of 328 suspected PE patients in the middle or late pregnancy stages, as well as a retrospective cohort of 30 healthy pregnant women and 30 PE patients. Using liquid chromatography mass spectrometry (LC - MS), serum metabolomic profiling revealed that the development of PE was closely associated with disturbed amino acid metabolism. Moreover, a panel of seven predictive biomarkers including 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, gamma-glutamyl-leucine, 2-hydroxyvaleric acid, LysoPC(16:1(9Z)/0:0), PC(DiMe(13,5)/MonoMe(13,5)), ADP-D-glycero-beta-D-manno-heptose and phenylalanyl-tryptophan were identified for PE development by performing multiple statistical analysis and LASSO regression analysis. The combination of these biomarkers showed promise in the prediction of PE development for suspected PE patients, with an AUC of 0.753 and 0.885 for the discovery and validation cohorts, respectively. These findings highlight the potential of large-scale prospective metabolomic studies combined with machine learning algorithms in identifying key biomarkers for predicting PE development, while retrospective metabolomics studies provide insights into the pathogenesis of PE.

Lipid imaging mass spectrometry (LIMS) allows for establishing the bidimensional distribution of lipid species within a tissue section. One of the main advantages is the generation of spatial information on lipid species distribution at a spatial (lateral) resolution bordering on single-cell resolution with no need to isolate cells. Thus, LIMS images demonstrate, with a level of detail never described before, that lipid profiles are highly sensitive to cell type and pathophysiological state. The wealth and relevance of the information conveyed by LIMS makes up for the lack of a separation stage before sample injection into the mass analyzer, which can somehow be circumvented by other means. Hence, the possibility of describing the lipidome at the cellular level while preserving the microenvironment offers an incomparable opportunity to investigate physiological and pathological contexts. However, to fully grasp the biological implications of the lipid profiles, it is essential to contextualize LIMS data within the broader multiscale 'omic' landscape, entailing genomics, epigenomics, and proteomics, each offering a unique window into the regulatory layers of the cell. In this line, the number of techniques that can be combined with LIMS to delve into the molecular mechanisms underlying differential lipid profiles is continuously increasing. Herein, we aim to describe the key features of LIMS analyses, from sample preparation to data interpretation, as well as the current methodologies to enrich and complete the final outcome. While the field is rapidly advancing, we consider there is solid evidence to foresee the incorporation of LIMS into clinical environments.

Plastic pollution has become a global pollution problem that cannot be ignored. As the main destination of human oral intake, the toxic effects of plastic on the digestive system represented by the intestine and liver are the focus of current research. Marine-derived DHA-PS has a variety of biological activities, mainly focusing on improving brain function and regulating lipid metabolism. However, whether it has an improvement effect on PS-NPs-induced hepato-intestinal injury and the underlying mechanism remain unclear.

A murine liver injury model was established by gavage of PS-NPs for six weeks. By integrating approaches from lipidomics, transcriptomics, and gut microbiota analysis, the molecular mechanism by which DHA-PS alleviates PS-NPs-induced murine hepatotoxicity was explored through the "gut-liver axis".

Our findings reveal that prolonged exposure to PS-NPs results in significant murine liver damage and dysfunction, characterized by increased oxidative stress and inflammation, along with exacerbated hepatic lipid accumulation. Mechanistically, PS-NPs disrupt the hepatic SIRT1-AMPK pathway by suppressing the expression of SIRT1, AMPKα, and PPARα, while enhancing the expression of SREBP-1c, ultimately leading to disordered hepatic lipid metabolism. The sphingolipid and glycerophospholipid metabolic pathways were particularly affected. Additionally, in agreement with transcriptomic analyses, PS-NPs activate the hepatic TLR4/NF-κB pathway. At the same time, exposure to PS-NPs decreases the expression of ZO-1, occludin, and claudin-1, diminishes the relative abundance of beneficial gut bacteria (norank_f_Muribaculaceae, Akkermansia, and norank_f_norank_o_Clostridia_UCG-014), and increases the prevalence of pathogenic gut bacteria (Coriobacteriaceae_UCG-002 and Desulfovibrio), exacerbating liver injury through the gut-liver axis. However, administering DHA-PS (50 mg/kg) effectively alleviated these injuries.

This study was the first to employ multi-omics techniques to elucidate the potential mechanisms underlying hepatotoxicity induced by PS-NPs, thereby supporting the use of DHA-PS as a dietary supplement to mitigate the effects of nanoplastic pollutants.

Krabbe disease is a sphingolipidosis characterized by the genetic deficiency of the acid hydrolase β-galactosylceramidase (GALC). Most of the studies concerning the biological role of GALC performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease) indicate that the pathogenesis of this disorder is the consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine), ignoring the possibility that this enzyme may exert a wider biological impact. Indeed, limited information is available about the effect of GALC downregulation on the cell lipidome in adult and developing organisms. The teleost zebrafish (Danio rerio) has emerged as a useful platform to model human genetic diseases, including sphingolipidoses, and two GALC co-orthologs have been identified in zebrafish (galca and galcb). Here, we investigated the effect of the competitive and irreversible GALC inhibitor β-galactose-cyclophellitol (GCP) on the lipid profile of zebrafish embryos. Molecular modelling indicates that GCP can be sequestered in the catalytic site of the enzyme and covalently binds human GALC, and the zebrafish Galca and Galcb proteins in a similar manner. Accordingly, GCP inhibits the β-galactosylceramide hydrolase activity of zebrafish in vitro and in vivo, leading to significant alterations of the lipidome of zebrafish embryos. These results indicate that the lack of GALC activity deeply affects the lipidome during the early stages of embryonic development, and thereby provide insights into the pathogenesis of Krabbe disease.

Obese asthma represents a unique phenotype of asthma characterized by severe symptoms, poor medication controls, increased frequency of exacerbations, and an overall diminished quality of life. Numerous factors, including the complex interactions between environment, mechanical processes, inflammatory responses, and metabolites disturbance, contribute to the onset of obese asthma.

Notably, multiple metabolomics studies in the last several years have revealed the significant abnormalities in lipid metabolism among obese asthmatic patients. Several bioactive lipid messengers participate in the development of obese asthma has also been observed. Here, we present and discuss the latest advances regarding how bioactive lipid molecules contribute to the pathogenic process and mechanisms underlying obese asthma. The key roles of potentially significant effector cells and the pathways by which they respond to diverse lipid metabolites are also described. We finally summarize current lipid-related therapeutic options for the treatment of obese asthma and discuss their application prospects.

This review underscores the impacts of abnormal lipid metabolism in the etiopathogenesis of obese asthma and asks for further investigation to elucidate the intricate correlations among lipids, obesity, and asthma.

Lead is a common environmental pollutant which can accumulate in the kidney and cause renal injury. However, regulatory effects and mechanisms of Sparassis latifolia polysaccharide (SLP) on lipid metabolism abnormality in kidney exposed to lead are not clarified. In this study, mice were used to construct an animal model to observe the histopathological changes in kidney, measure lead content, damage indicators, differentially expressed metabolites (DEMs) and genes (DEGs) in key signaling pathways that cause lipid metabolism abnormalities based on lipidomics and transcriptomics, which were later validated using qPCR and western blotting. Co-treatment of Pb and N-acetylcysteine (NAC) were used to verify the link between SLP and oxidative stress. Our results indicated that treatment with SLP identified 276 DEMs (including metabolism of glycerophospholipid, sphingolipid, glycerolipid and fatty acid) and 177 DEGs (including genes related to oxidative stress, inflammation, autophagy and lipid metabolism). Notably, regulatory effects of SLP on abnormal lipid metabolism in kidney were mainly associated with oxidative stress, inflammation and autophagy; SLP could regulate abnormal lipid metabolism in kidney by reducing oxidative stress and affecting its downstream-regulated autophagy and inflammatory to alleviate renal injury caused by lead exposure. This study provides a theoretical basis for SLP intervention in lead injury.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

Deoxynivalenol (DON), 3-acetyldeoxynivalenol (3-ADON) and 15-acetyldeoxynivalenol (15-ADON) belong to type B trichothecenes that are widely detected in agricultural products as one of the most common classes of mycotoxins. In the present study, we aimed to characterize the alteration of lipid metabolism in normal human hepatocytes by poisoning with DON and its acetylated derivatives. After verifying the hepatotoxicity of the three toxins, DON, 15-ADON, and 3-ADON, the mRNA expression was determined by transcriptomics, and the results showed that DON and 15-ADON had a significant regulatory effect on the transcriptome, in which glycerophospholipid metabolism pathway and phospholipase D signaling pathways have not been reported in studies of DON and its acetylated derivatives. For further validation, we explored lipid metabolism in depth and found that PC (15:0/16:0), PC (16:1/18:3), PC (18:1/22:6), PC (16:0/16:0), PC (16:0/16:1), PC (16:1/18:1), PC (14:0/18:2), PE (14:0/16:0) and PE (18:1/18:3) were downregulated for all nine lipids. Combined with the transcriptome results, we found that hepatic steatosis induced by the three toxins, DON, 15-ADON and 3-ADON, was associated with altered expression of genes related to lipid oxidation, lipogenesis and lipolysis, and their effects on lipid metabolism in L-02 cells were mainly realized through the PC-PE cycle.

The mechanisms occur in children with obesity after lifestyle intervention remain poorly explained. Here, we investigated the serum proteomes and metabolomes of children with obesity who had undergone 30 days of weight loss intervention.

Serum samples and clinical parameters were collected before and after lifestyle alteration interventions. Proteomic and metabolomic profiling was used to identify the differentially expressed proteins and differentially abundant metabolites in response to weight loss intervention. Lifestyle alteration interventions significantly decreased BMI, waist circumference, hip circumference and body fat, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL) and high non-HDL cholesterol, but not TG and high-density lipoprotein cholesterol (HDL), in children with obesity. By comparing the multiomics data, we identified 43 proteins and 165 metabolites that were significantly differentially expressed in children with obesity before and after lifestyle alteration interventions. Using integrated -omics analysis, we obtained 7 KEGG pathways that were organically integrated based on the correlations between differentially expressed proteins (DEPs) and metabolites (DMs). Further interaction analysis identified 7 proteins as candidate DEPs and 9 metabolites as candidate DMs. Interestingly, we found that some of these candidate DEPs and candidate DMs were significantly correlated with clinical parameters.

Our results provide valuable proteome and metabolome data resources for better understanding weight loss-associated responses in children with obesity. In addition, we analyzed the number of significantly differentially expressed proteins and metabolites, shed new light on weight loss pathogenesis in children with obesity, and added potential therapeutic agents for obese children.

Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer's disease. The role of gut microbiota in Alzheimer's disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer's disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer's disease based on existing data.

Calebin-A is a minor phytoconstituent of turmeric known for its activity against inflammation, oxidative stress, cancerous, and metabolic disorders like Non-alcoholic fatty liver disease(NAFLD). Based on bioinformatic tools. Subsequently, the details of the interaction of critical proteins with Calebin-A were investigated using the molecular docking technique.

We first probed the intersection of genes/ proteins between NAFLD and Calebin-A through online databases. Besides, we performed an enrichment analysis using the ClueGO plugin to investigate signaling pathways and gene ontology. Next, we evaluate the possible interaction of Calebin-A with significant hub proteins involved in NAFLD through a molecular docking study.

We identified 87 intersection genes Calebin-A targets associated with NAFLD. PPI network analysis introduced 10 hub genes (TP53, TNF, STAT3, HSP90AA1, PTGS2, HDAC6, ABCB1, CCT2, NR1I2, and GUSB). In KEGG enrichment, most were associated with Sphingolipid, vascular endothelial growth factor A (VEGFA), C-type lectin receptor, and mitogen-activated protein kinase (MAPK) signaling pathways. The biological processes described in 87 intersection genes are mostly concerned with regulating the apoptotic process, cytokine production, and intracellular signal transduction. Molecular docking results also directed that Calebin-A had a high affinity to bind hub proteins linked to NAFLD.

Here, we showed that Calebin-A, through its effect on several critical genes/ proteins and pathways, might repress the progression of NAFLD.

Breast cancer is the most prevalent cancer in women. Metabolic abnormalities, particularly increased lipid synthesis and uptake, impact the onset and progression of the disease. However, the influence of lipid metabolism in breast cancer varies according to the disease stage and patient's hormone status. In postmenopausal patients, obesity is associated with a higher risk and poor prognosis of luminal tumors, while in premenopausal individuals, it is correlated to BRCA mutated tumors. In fact, the tumor's lipid profile may be used to distinguish between HER2+, luminal and BRCA-mutated tumors. Moreover, drug resistance was associated with increased fatty acid synthesis and alterations in membrane composition, impacting its fluidity and spatial subdomains such as lipid rafts. Here, we discuss the subtype-specific lipid metabolism alterations found in breast cancer and the potentiality of its modulation in a clinical setting.

Addressing soil salinization and implementing sustainable practices for cultivating cash crops on saline-alkali land is a prominent global challenge. Cynomorium songaricum is an important salt-alkali tolerant medicinal plant capable of adapting to saline-alkali environments. In this study, two typical ecotypes of C. songaricum from the desert-steppe (DS) and saline-alkali land (SAL) habitats were selected. Through the integration of multi-omics with machine learning, the rhizosphere microbial communities, genetic maps, and metabolic profiles of two ecotypes were created and the crucial factors for the adaptation of C. songaricum to saline-alkali stress were identified, including 7 keystone OTUs (i.e. Novosphingobium sp., Sinorhizobium meliloti, and Glycomyces sp.), 5 core genes (cell wall-related genes), and 10 most important metabolites (i.e. cucurbitacin D and 3-Hydroxybutyrate) were identified. Our results indicated that under saline-alkali environments, the microbial competition might become more intense, and the microbial community network had the simple but stable structure, accompanied by the changes in the gene expression related to cell wall for adaptation. However, this regulation led to the reduction in active ingredients, such as the accumulation of flavonoids and organic acid, and enhanced the synthesis of bitter substances (cucurbitacin D), resulting in the decrease in the quality of C. songaricum. Therefore, compared to the SAL ecotype, the DS was more suitable for the subsequent development of medicinal and edible products of C. songaricum. Furthermore, to explore the reasons for this quality variation, we constructed a comprehensive microbial-genetic-metabolic regulatory network, revealing that the metabolism of C. songaricum was primarily influenced by genetic factors. These findings not only offer new insights for future research into plant salt-alkali tolerance strategies but also provide a crucial understanding for cultivating high-quality medicinal plants.

Most previous studies have focused primarily on the adverse effects of environmental chemicals on organisms of good healthy. Although global prevalence of non-alcoholic fatty liver disease (NAFLD) has reached approximately 25%, the impact of environmentally persistent organic chemicals on organisms with NAFLD is substantially unknown. Polyhalogenated carbazoles (PHCZs) as emerging contaminants have been frequently detected in the environment and organisms. In this study, we investigated the impact of the most frequently detected PHCZs, 3,6-dichlorocarbazole (36-CCZ), on zebrafish with high-fat diet (HFD)-induced NAFLD. After 4 weeks exposure to environmentally relevant concentrations of 36-CCZ (0.16-0.45 μg/L), the accumulation of lipid in zebrafish liver dramatically increased, and the transcription of genes involved in lipid synthesis, transport and oxidation was significantly upregulated, demonstrating that 36-CCZ had exacerbated the NAFLD in zebrafish. Lipidomic analysis indicated that 36-CCZ had significantly affected liver lipid metabolic pathways, mainly including glycerolipids and glycerophospholipids. Additionally, fifteen lipids were identified as potential lipid biomarkers for 36-CCZ exacerbation of NAFLD, including diacylglycerols (DGs), triglycerides (TGs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), phosphatidic acid (PA), and phosphatidylinositol (PI). These findings demonstrate that long-term exposure to 36-CCZ can promote the progression of NAFLD, which will contribute to raising awareness of the health risks of PHCZs.

Vitamin K isoforms are known as co-factors for the synthesis of blood-clotting proteins, but several other bioactivities were reported. In this work, we isolated a vitamin K1-analogue (OH-PhQ) from the cyanobacterium Tychonema sp. LEGE 07196 with lipid reducing activity. OH-PhQ reduced neutral lipid reservoirs with an EC50 value of 31 μM after 48 h exposure in zebrafish larvae, while other vitamin K isoforms had EC50 values of 21.1 μM (K2) and 1.2 μM (K3). No lipid reducing activity was observed for K1 up to 50 μM. The presence of vitamin K isoforms was studied in zebrafish after exposure (OH-PhQ, K1, K2 and K3), and a clear preference for bioconversion was observed to retain K1 and OH-PhQ. Untargeted metabolomics revealed different biological effects for vitamin K isoforms on the subclass and metabolite level, but similarities were present on the compound class level, particularly on the regulation of glycerophospholipids. Our data showed for the first time a lipid reducing activity of OH-PhQ and performed a comparative analysis of vitamin K isoforms, which could be important for the development of future nutraceuticals or food supplements.

Flubendiamide (FLU), a widely used diamide insecticide, has been observed to potentiate adipogenesis in 3T3-L1 preadipocytes in vitro. Whether exposure to FLU disrupts hepatic lipid homeostasis in mammals and induces visceral obesity, however, remains unclear. The aim of this study was to assess the effects of FLU when administered orally to male C57BL/6J mice under normal diet (ND) and high-fat diet (HFD) conditions. FLU accumulated at higher levels in the tissues of the HFD group than those of the ND group, indicating that an HFD contributed to the accumulation of lipophilic pesticides in vivo. Notably, FLU (logP = 4.14) is highly lipophilic and easily accumulates in fat. Exposure to FLU had opposing effects on the lipid metabolism of the liver in the ND and HFD groups. Liver triacylglycerol levels in the ND group were reduced, while those in the HFD group were increased, resulting in more severe hepatic steatosis. More lipid accumulation was also observed in HepG2 cells exposed to FLU. Changes in hepatic lipid deposition in vivo occurred as the enhanced transcriptional regulation of the genes involved in lipid uptake, de novo lipogenesis, and fatty acid β-oxidation (FAO). Moreover, an excessive increase in FAO caused oxidative stress, which in turn exacerbated the inflammation of the liver. This study revealed the disruptive effect of FLU exposure on hepatic lipid homeostasis, which may facilitate the triggering of nonalcoholic fatty liver disease in HFD-fed mice.

This study investigated the potential benefits of the administration of red ginseng (RG) on lipid metabolism and the profiles of individual free fatty acids (FFAs) in healthy horses. Eight healthy horses, raised under similar conditions, were randomly divided into two groups, each comprising four horses. The experimental group received powdered RG (600 mg/kg/day) mixed with a carrier, and the control group received only the carrier. The parameters associated with lipid metabolism and probable adverse effects were evaluated in both groups after 3 weeks. The computational molecular networking (MN) approach was applied to analyze the FFA profiles. The results indicated that RG administration significantly reduced blood triglyceride levels in the experimental group. Analysis of the FFAs using MN revealed significant decreases in specific types of FFAs (C12:0, dodecanoic acid; C14:0, myristric acid; C18:1, oleic acid; C18:2, linoleic acid). RG consumption did not produce significant adverse effects on the renal, hepatic, and immune functions. Thus, RG was found to effectively modulate lipid metabolism and the levels of individual FFAs. The application of the MN for the analysis of FFAs represents a novel approach and can be considered for future research.

Baicalin has various neuroprotective effects in models of nervous system disease. Our study has shown baicalin could alleviate depressive-like behaviors in a neuroendocrine mouse model. But the systematic metabolic characteristic and particular targets of baicalin in regulating depressive behaviors have never been investigated. Therefore, this study aims to reveal the hippocampal metabolic profiling of chronic unpredictable mild stress (CUMS) induced depressive rats and the potential metabolic variations after baicalin treatment. We first used the sucrose preference test and open field test to access the antidepressant effects of baicalin. Then, metabolites of the hippocampus after baicalin therapy were monitored by widely-targeted metabolomics based on ultra-performance liquid chromatography-tandem mass spectrometry technology. Finally, the potential mechanism associated with neurogenesis obtained from metabolomics was verified by immunohistochemistry. The results showed that baicalin(40,80 mg/kg) could significantly alleviate depressive behaviors induced by CUMS as demonstrated by an increase in sucrose preference and movement distance and stand-up times in open field test. In the metabolomic analysis, a total of 733 metabolites were identified after baicalin treatment including 15 differential metabolites such as organic acid and its derivatives, heterocyclic compounds, fatty acid, bile acids, amino acid and its metabolites, and so on. Enrichment for differential metabolites showed that the differential metabolites might be involved in the process of folate and cofactor biosynthesis, cholesterol metabolism, primary bile acid biosynthesis, tyrosine metabolism and dopaminergic synapse. Moreover, immunohistochemical analysis confirmed baicalin could facilitate hippocampal neurogenesis of depressive rats in CUMS model. These results suggested baicalin might exert antidepressant effects through regulating the differential metabolites which might play a crucial role in inhibiting oxidative stress and improving neurogenesis. Our findings wish to discover the potential mechanism of baicalin on depression from the metabolomics perspective and promote its clinical application.

Nonylphenol (NP), a widely recognized endocrine disruptor, exhibits lipophobic properties that drive its accumulation in adipose tissue, leading to various physiological disruptions. Using Caenorhabditis elegans, this study investigated the effects of NP exposure on lipid homeostasis and physiological indicators. NP exposure increased lipid storage, hindered reproduction and growth, and altered phospholipid composition. Transcriptional analysis revealed NP's promotion of lipogenesis and inhibition of lipolysis. Metabolites related to lipid metabolism like citrate, amino acids, and neurotransmitters, along with lipids, collectively influenced physiological processes. This work elucidates the complex link between lipid metabolism disturbances and NP-induced physiological disruptions, enhancing our understanding of NP's multifaceted toxicity.

The level of carbon black (CB) pollution in the environment is rapidly increasing, owing to the increase in natural and industrial emissions. The water environment has become an important sink for CB. However, studies on CB mainly focused on its impact on air pollution and phytoremediation applications, and the toxicity mechanism of CB in aquatic organisms is relatively limited. Thus, Daphnia magna was used as a model organism to explore the developmental toxicity of environmentally relevant concentrations of CB under a full life-cycle exposure. The toxicity mechanism of CB in aquatic organisms was investigated based on metabolomic and symbiotic microbial analyses. It was found that compared with the control group, the body length of exposed D. magna decreased, while the mortality and intestinal inflammation increased with increasing concentration of CB. The normal reproductive regularity of D. magna was disturbed, and the deformity and body length of the offspring increased and decreased, respectively, after CB exposure. Metabolomic analysis showed that the urea cycle metabolic pathway of exposed D. magna was increased significantly, suggesting a perturbation of N metabolism. In addition, two eicosanoids were increased, suggesting possible inflammation in D. magna. The levels of seven phospholipid metabolites decreased that might be responsible for offspring malformations. Microbiological analysis showed that the composition of the symbiotic microbial community of D. magna was disturbed, including microorganisms involved in carbon cycling, nitrogen cycling, and biodegradation of pollutants, as well as pathogenic microorganisms. Overall, this study found that the inflammatory related metabolites and symbiotic bacterial, as well as reproductive related metabolites, were disrupted after D. magna exposed to different concentrations of CB, which revealed a possible developmental toxicity mechanism of CB in D. magna. These findings provide a scientific basis for analyzing the risks of CB in aquatic environments.

Biological membranes, primarily composed of lipids, envelop each living cell. The intricate composition and organization of membrane lipids, including the variety of fatty acids they encompass, serve a dynamic role in sustaining cellular structural integrity and functionality. Typically, modifications in lipid composition coincide with consequential alterations in universally significant signaling pathways. Exploring the various fatty acids, which serve as the foundational building blocks of membrane lipids, provides crucial insights into the underlying mechanisms governing a myriad of cellular processes, such as membrane fluidity, protein trafficking, signal transduction, intercellular communication, and the etiology of certain metabolic disorders. Furthermore, comprehending how alterations in the lipid composition, especially concerning the fatty acid profile, either contribute to or prevent the onset of pathological conditions stands as a compelling area of research. Hence, this review aims to meticulously introduce the intricacies of membrane lipids and their constituent fatty acids in a healthy organism, thereby illuminating their remarkable diversity and profound influence on cellular function. Furthermore, this review aspires to highlight some potential therapeutic targets for various pathological conditions that may be ameliorated through dietary fatty acid supplements. The initial section of this review expounds on the eukaryotic biomembranes and their complex lipids. Subsequent sections provide insights into the synthesis, membrane incorporation, and distribution of fatty acids across various fractions of membrane lipids. The last section highlights the functional significance of membrane-associated fatty acids and their innate capacity to shape the various cellular physiological responses.

Extracellular vesicles (EVs) are messengers that carry information in the form of proteins, lipids, and nucleic acids and are not only essential for intercellular communication but also play a critical role in the progression of various pathologies, including ovarian cancer. There has been recent substantial research characterising EV cargo, specifically, the lipid profile of EVs. Lipids are involved in formation and cargo sorting of EVs, their release and cellular uptake. Numerous lipidomic studies demonstrated the enrichment of specific classes of lipids in EVs derived from cancer cells suggesting that the EV associated lipids can potentially be employed as minimally invasive biomarkers for early diagnosis of various malignancies, including ovarian cancer. In this review, we aim to provide a general overview of the heterogeneity of EV, biogenesis, their lipid content, and function in cancer progression focussing on ovarian cancer.

Metabolomics, proteomics and DNA methylome assays, when done in tandem from the same blood sample and analyzed together, offer an opportunity to evaluate the molecular basis of post-traumatic stress disorder (PTSD) course and pathogenesis. We performed separate metabolomics, proteomics, and DNA methylome assays on blood samples from two well-characterized cohorts of 159 active duty male participants with relatively recent onset PTSD (<1.5 years) and 300 male veterans with chronic PTSD (>7 years). Analyses of the multi-omics datasets from these two independent cohorts were used to identify convergent and distinct molecular profiles that might constitute potential signatures of severity and progression of PTSD and its comorbid conditions. Molecular signatures indicative of homeostatic processes such as signaling and metabolic pathways involved in cellular remodeling, neurogenesis, molecular safeguards against oxidative stress, metabolism of polyunsaturated fatty acids, regulation of normal immune response, post-transcriptional regulation, cellular maintenance and markers of longevity were significantly activated in the active duty participants with recent PTSD. In contrast, we observed significantly altered multimodal molecular signatures associated with chronic inflammation, neurodegeneration, cardiovascular and metabolic disorders, and cellular attritions in the veterans with chronic PTSD. Activation status of signaling and metabolic pathways at the early and late timepoints of PTSD demonstrated the differential molecular changes related to homeostatic processes at its recent and multi-system syndromes at its chronic phase. Molecular alterations in the recent PTSD seem to indicate some sort of recalibration or compensatory response, possibly directed in mitigating the pathological trajectory of the disorder.

COVID-19 is a highly infectious respiratory disease that can manifest in various clinical presentations. Although many studies have reported the lipidomic signature of COVID-19, the molecular changes in asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals remain elusive.

This study combined a comprehensive lipidomic analysis of 220 plasma samples from 166 subjects: 62 healthy controls, 16 asymptomatic infections, and 88 COVID-19 patients. We quantified 732 lipids separately in this cohort. We performed a difference analysis, validated with machine learning models, and also performed GO and KEGG pathway enrichment analysis using differential lipids from different control groups.

We found 175 differentially expressed lipids associated with SASR-CoV-2 infection, disease severity, and viral persistence in patients with COVID-19. PC (O-20:1/20:1), PC (O-20:1/20:0), and PC (O-18:0/18:1) better distinguished asymptomatic infected individuals from normal individuals. Furthermore, some patients tested positive for SARS-CoV-2 nucleic acid by RT-PCR but did not become negative for a longer period of time (≥60 days, designated here as long-term nucleic acid test positive, LTNP), whereas other patients became negative for viral nucleic acid in a shorter period of time (≤45 days, designated as short-term nucleic acid test positive, STNP). We have found that TG (14:1/14:1/18:2) and FFA (4:0) were differentially expressed in LTNP and STNP.

In summary, the integration of lipid information can help us discover novel biomarkers to identify asymptomatic individuals and further deepen our understanding of the molecular pathogenesis of COVID-19.

Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be explored. Previous studies found that pioglitazone and metformin therapy could partly ameliorate NAFLD, but their combination therapy effects have not been researched. In the present study, we assessed the protective effects of metformin and pioglitazone combination therapy on liver lipid metabolism in high-fat diet (HFD)-fed mice and investigated the molecular mechanism.

Male C57BL/6 mice were divided into five groups: normal control; HFD control; metformin monotherapy; pioglitazone monotherapy and combined therapy. After 8 weeks of pharmacological intervention, glucose and lipid metabolism characteristics, hepatic histology, lipidomics profiling and RNA-seq analysis were performed.

The combination of pioglitazone and metformin significantly ameliorated HFD-induced metabolic disturbance and the hepatic oil red O area. A lipidomics analysis showed that combined therapy could significantly reduce the high levels of free fatty acids (FFA), diacylglycerol and triglycerides, while a set of glycerophospholipids and sphingolipids were increased in the combined therapy group. Consistently, an RNA-seq analysis also showed a remarkable reduction in genes associated with FFA uptake and de novo lipogenesis, including Cd36, Fads1, Fads2, Fasn, Scd1, Elovl5 and Pklr in the combined therapy group.

Pioglitazone and metformin might have a synergistic protective effect on NAFLD by improving hepatic lipid profiles in HFD-induced mice. Further studies are needed to verify the clinical effects.

The objective is to assess the circulating lipidome of children with obesity before and after lifestyle intervention and to compare the data to the circulating lipidome of adults with obesity before and after bariatric surgery. Ten pediatric (PE) and thirty adult (AD) patients with obesity were prospectively recruited at a referral single center. The PE cohort received lifestyle recommendations. The AD cohort underwent bariatric surgery. Clinical parameters and lipidome were analyzed in serum before and after six months of metabolic intervention. The abundance of phosphatidylinositols in the PE cohort and phosphatidylcholines in the AD significantly increased, while O-phosphatidylserines in the PE cohort and diacyl/triacylglycerols in the AD decreased. Fifteen lipid species were coincident in both groups after lifestyle intervention and bariatric surgery. Five species of phosphatidylinositols, sphingomyelins, and cholesteryl esters were upregulated. Eight species of diacylglycerols, glycerophosphoglycerols, glycerophosphoethanolamines, and phosphatidylcholines were downregulated. Most matching species were regulated in the same direction except for two phosphatidylinositols: PI(O-36:2) and PI(O-34:0). A specific set of lipid species regulated after bariatric surgery in adult individuals was also modulated in children undergoing lifestyle intervention, suggesting they may constitute a core circulating lipid profile signature indicative of early development of obesity and improvement after clinical interventions regardless of individual age.

Molybdenum disulfide (MoS₂) nanosheets are increasingly applied in several fields, but effective and accurate strategies to fully characterize potential risks to soil ecosystems are lacking. We introduce a coelomocyte-based in vivo exposure strategy to identify novel adverse outcome pathways (AOPs) and molecular endpoints from nontransformed (NTMoS₂) and ultraviolet-transformed (UTMoS₂) MoS₂ nanosheets (10 and 100 mg Mo/L) on the earthworm Eisenia fetida using nontargeted lipidomics integrated with transcriptomics. Machine learning-based digital pathology analysis coupled with phenotypic monitoring was further used to establish the correlation between lipid profiling and whole organism effects. As an ionic control, Na₂MoO₄ exposure significantly reduced (61.2-79.5%) the cellular contents of membrane-associated lipids (glycerophospholipids) in earthworm coelomocytes. Downregulation of the unsaturated fatty acid synthesis pathway and leakage of lactate dehydrogenase (LDH) verified the Na₂MoO₄-induced membrane stress. Compared to conventional molybdate, NTMoS₂ inhibited genes related to transmembrane transport and caused the differential upregulation of phospholipid content. Unlike NTMoS₂, UTMoS₂ specifically upregulated the glyceride metabolism (10.3-179%) and lipid peroxidation degree (50.4-69.4%). Consequently, lipolytic pathways were activated to compensate for the potential energy deprivation. With pathology image quantification, we report that UTMoS₂ caused more severe epithelial damage and intestinal steatosis than NTMoS₂, which is attributed to the edge effect and higher Mo release upon UV irradiation. Our results reveal differential AOPs involving soil sentinel organisms exposed to different Mo forms, demonstrating the potential of liposome analysis to identify novel AOPs and furthermore accurate soil risk assessment strategies for emerging contaminants.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.

Phospholipase D1 (PLD1), a phosphatidylcholine-hydrolysing enzyme, is involved in cellular lipid metabolism. However, its involvement in hepatocyte lipid metabolism and consequently non-alcoholic fatty liver disease (NAFLD) has not been explicitly explored.

NAFLD was induced in hepatocyte-specific Pld1 knockout (Pld1(H)-KO) and littermate Pld1 ^flox/flox (Pld1-Flox) control mice feeding a high-fat diet (HFD) for 20 wk. Changes of the lipid composition in the liver were compared. Alpha mouse liver 12 (AML12) cells and mouse primary hepatocytes were incubated with oleic acid or sodium palmitate in vitro to explore the role of PLD1 in the development of hepatic steatosis. Hepatic PLD1 expression was evaluated in liver biopsy samples in patients with NAFLD.

PLD1 expression levels were increased in the hepatocytes of patients with NAFLD and HFD-fed mice. Compared with Pld1-Flox mice, Pld1(H)-KO mice exhibited decreased plasma glucose and lipid levels as well as lipid accumulation in liver tissues after HFD feeding. Transcriptomic analysis showed that hepatocyte-specific deficiency of PLD1 decreased Cd36 expression in steatosis liver tissues, which was confirmed at the protein and gene levels. In vitro, specific inhibition of PLD1 with VU0155069 or VU0359595 decreased CD36 expression and lipid accumulation in oleic acid- or sodium palmitate-treated AML12 cells or primary hepatocytes. Inhibition of hepatocyte PLD1 significantly altered lipid composition, especially phosphatidic acid and lysophosphatidic acid levels in liver tissues with hepatic steatosis. Furthermore, phosphatidic acid, the downstream product of PLD1, increased the expression levels of CD36 in AML12 cells, which was reversed by a PPARγ antagonist.

Hepatocyte-specific Pld1 deficiency ameliorates lipid accumulation and NAFLD development by inhibiting the PPARγ/CD36 pathway. PLD1 may be a new target for the treatment of NAFLD.

The involvement of PLD1 in hepatocyte lipid metabolism and NAFLD has not been explicitly explored. In this study, we found that the inhibition of hepatocyte PLD1 exerted potent protective effects against HFD-induced NAFLD, which were attributable to a reduction in PPARγ/CD36 pathway-mediated lipid accumulation in hepatocytes. Targeting hepatocyte PLD1 may be a new target for the treatment of NAFLD.