Zhao PJ, Hu QY, Wang SH
… +12 more, Wang CS, Jian XX, Wen XF, Luo YL, Zhang YQ, Xiang CM, Li GH, Liu SQ, Mo MH, Chen YH, Wang X, Zhang KQ
Sci China Life Sci
· 2026 Jun · PMID 42301561
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Fungal pathogens utilize specialized cellular systems to overcome host defenses, yet no dedicated pathogenic organelles have been previously defined in fungi. Here, we describe a transient, membrane-bound vesicle (100-25...Fungal pathogens utilize specialized cellular systems to overcome host defenses, yet no dedicated pathogenic organelles have been previously defined in fungi. Here, we describe a transient, membrane-bound vesicle (100-250 nm in diameter) that forms specifically within the infection structures of a nematode-trapping fungus Dactylellina haptotyla, which we term the virulensome. Density-gradient isolation yielded virulensome-enriched fractions that killed 81.6% of Caenorhabditis elegans larvae within 24 h and perforated the nematode cuticle. Quantitative proteomics revealed 486 core components, including 31 peptidases and 23 glycoside hydrolases. Knockout of each of three representative proteins-an α-mannosidase (DHGH1), a metalloendopeptidase (DHMEPE1), and a WSC-domain protein-reduced virulensome abundance by up to 80% and lowered nematode mortality by 4-fold. Conversely, recombinant DHGH1 or DHMEPE1 killed >90% of nematodes in vitro. Live-cell super-resolution imaging showed virulensomes polarizing toward the host interface, disintegrating within infection bulbs, and releasing toxic effector cargos into the nematode body. These findings define the virulensome that packages and delivers destructive enzymes in a targeted manner, revealing a previously unrecognized mechanism of pathogenesis.
BACKGROUND: Cardiac damage after polytrauma (PT) is associated with increased mortality. The aim of the present study was to investigate histopathological and transcriptomic changes in the right (RV) and left ventricle (...BACKGROUND: Cardiac damage after polytrauma (PT) is associated with increased mortality. The aim of the present study was to investigate histopathological and transcriptomic changes in the right (RV) and left ventricle (LV) following PT. METHODS: A porcine PT model was conducted in an ICU setting with a follow-up period of 72 h. The animals were allocated into three groups: Sham, minor multiple trauma MiMT (femur fracture and blunt chest trauma) and major multiple trauma MaMT (MiMT with a pressure-controlled hemorrhagic shock). Cardiac damage was assessed via plasma levels of Troponin I and NT-proANP. Histomorphological damage was evaluated according to Heart Injury Score, immunohistochemistry for C5aR1, Nitrotyrosine, Caspase 3 and Connexin 43. mRNA/miRNA expression profiles were identified via NGS. RESULTS: TnI concentrations were elevated in MiMT and MaMT. Histological analyses of the LV revealed increased Nitrotyrosine in MiMT and C5aR1 in MaMT, whereas in the RV, no significant changes were detected. Differentially expressed mRNAs were mainly associated with cell death pathways (MiMT vs. MaMT) in the right ventricle, whereas in the LV, they were predominantly associated with cell death (MiMT vs. MaMT), antigen presentation, chemokine (MaMT vs. Sham), and cytokine signaling (MiMT vs. Sham). miRNA profiles differed strongly between ventricles, with extensive miRNA alterations in the LV (267 MiMT vs. Sham; 261 MaMT vs. Sham) and minimal changes in the RV (2 and 9, respectively). CONCLUSION: The study reveals distinct ventricular responses to PT, with the LV showing pronounced histopathological, mRNA/miRNA alterations, whereas the RV showed only minimal reaction to trauma.
Cao Z, Yu Z, Wang X
… +5 more, Jiang D, Yuan Y, Shu Z, Yang Y, Zhang Y
Sci China Life Sci
· 2026 Jun · PMID 42295639
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Emerging evidence highlights the pivotal roles of RNA modifications in affecting male fertility and offspring health. However, the dynamic landscapes of RNA modification during spermatogenesis and sperm maturation are st...Emerging evidence highlights the pivotal roles of RNA modifications in affecting male fertility and offspring health. However, the dynamic landscapes of RNA modification during spermatogenesis and sperm maturation are still incompletely characterized. Here, we profiled 27 RNA modifications across total RNA, tRNA-enriched fractions, and small RNA fractions in developing mouse testes (P7-P56), isolated spermatogenic cells, and epididymal sperm by applying a liquid chromatography-tandem mass spectrometry-based RNA modification quantification platform, deciphered the developmental dynamics of RNA modification signature and coordinative inter-modification cross-talk. Through integrative analyses of RNA modification signatures among spermatogenic cells in the testis and spermatids at different maturation stages in the epididymis, we found that most RNA modifications were gradually reprogrammed from the testis to the epididymis, and finally declined in mature sperm. Specifically, some RNA modifications (e.g., mA and mU) were enriched in meiotic prophase II spermatocytes and round spermatids, while others (e.g., mC and mG) exhibited high abundance in caput sperm. Additionally, using a type 2 diabetes mellitus mouse model, we found that sperm RNA modification signatures are dynamically reprogrammed during epididymal maturation in response to diabetes, leading to a remarkable alteration in sperm RNA modification signatures and inter-modification correlation networks. Collectively, our study delineates the dynamic landscape of RNA modifications during spermatogenesis and maturation, uncovering its origins and trajectory alterations in the type 2 diabetes mellitus mouse model. This provides novel insights into both the underpinned regulatory mechanisms of RNA modification-dependent spermatogenesis and epigenetic remodeling of sperm during epididymal maturation.
He H, Liu Y, Zhang J
… +15 more, Zheng X, Jiang L, Du Z, Zuo J, Cao S, Peng X, Zheng Z, Li K, Shen C, Chen Y, Yin P, Wang C, Xiong L, Dong F, Liu Z
Sci China Life Sci
· 2026 Jun · PMID 42295638
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Phosphorus is essential for plants, absorbed as inorganic phosphate (Pi) and distributed via specialized transporters. The SULTR-like phosphorus distribution transporter (SPDT) preferentially allocates phosphorus to deve...Phosphorus is essential for plants, absorbed as inorganic phosphate (Pi) and distributed via specialized transporters. The SULTR-like phosphorus distribution transporter (SPDT) preferentially allocates phosphorus to developing grains-an energetically costly process that can potentially be attenuated without affecting crop yield and germination, positioning SPDT as a prime target for sustainable agriculture. Here, we report cryo-EM structures of rice SPDT in Pi-bound and apo states, uncovering an elevator-type transport mechanism. The transmembrane region segregates into a mobile Pi-binding core domain and a stationary gate domain. Pi coordination involves specific residues within the core domain, followed by an electropositive vestibule that extends from the binding pocket to the cytoplasm. Integrative structural and smFRET analyses demonstrate a dynamic mechanism regulating the transporter's conformational equilibrium. In this mechanism, the transporter's intracellular STAS domain acts as a bidirectional conformation-switch: (i) membrane-proximal binding stabilizes the inward-facing state via interactions with the core/gate domains, while (ii) dissociation enables reset to the outward-facing state. This dynamic coupling elucidates the regulatory mechanism of the STAS domain, highlighting its universally conserved function across the SulP, SULTR, and SLC26 families. Our findings provide a mechanistic blueprint for engineering phosphorus allocation in crops to enhance nutrient-use efficiency.
Glioblastoma (GBM) is a grade IV glioma, which is the most malignant astrocytoma and originates from astrocytic glial cells. GBM tumors consist of a complex mixture of heterogeneous cells, complicating the search for the...Glioblastoma (GBM) is a grade IV glioma, which is the most malignant astrocytoma and originates from astrocytic glial cells. GBM tumors consist of a complex mixture of heterogeneous cells, complicating the search for the cell of origin. The acquisition and maintenance of the hallmarks of cancer depend, to various degrees, on the contributions from the tumor microenvironment (TME). This reliance on the TME offers an opportunity for therapeutic intervention by targeting TME elements or the signaling pathways. There is a significant therapeutic advantage in targeting the TME compared with directly targeting cancer cells, because cancer cells are prone to drug resistance due to their genomic instability. As an alternative approach, targeted therapies may limit unwanted toxicity, associated with conventional therapies and more effectively block the tumor proliferation. Although immunotherapy achieved some notable successes in the treatment of several malignancies such as melanoma and lung cancer, its efficacy in GBM remains limited due to BBB, low tumor mutational burden, an immunosuppressive TME, and profound intratumoral heterogeneity, contributing to therapeutic resistance. There are several modes of immunotherapy including restorative, adoptive cell transfer, passive, active, modulatory and immunogenic cell death (ICD) immunotherapies. The successful development of immunotherapeutics for GBM requires generating a robust antitumor immune response while overcoming T-cell anergy and tolerance. The immune system has various checkpoint pathways; thus, targeting multiple checkpoints simultaneously will have potential survival benefits.
Wu Q, Li W, Chen Y
… +26 more, Zhang H, Li D, Li Z, Xiong F, Guo G, Dong L, Cui X, Xie J, Lu P, Wang G, Zhang P, Zhu K, Li B, Lou H, Li Y, Zhu J, Fan M, Zhang P, Li Z, Yuan C, Liu Y, Li H, Hua W, Dong L, Liu Z, Li M
Sci China Life Sci
· 2026 Jun · PMID 42287594
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Haghighi A, Demeter ZO, Zsidai A
… +11 more, Lengyel L, Haghighi S, Ostorházi E, Jakab A, Kökény G, Görbe A, Szabó D, Magierowski M, Gyires K, Wachtl G, Zádori ZS
BACKGROUND AND AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause small intestinal injury, which largely depends on the presence of gut bacteria and the immune responses triggered by them. While previous studi...BACKGROUND AND AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause small intestinal injury, which largely depends on the presence of gut bacteria and the immune responses triggered by them. While previous studies have emphasised the role of Toll-like receptor 4 (TLR4) and TLR2 in enteropathy, the functional significance of TLR5, a receptor for bacterial flagellin, remains elusive. Thus, we aimed to assess the impact of TLR5 activation and inhibition on NSAID enteropathy in mice. MATERIALS AND METHODS: Enteropathy was induced using indomethacin (IND). Mucosal injury, inflammation and the mRNA levels of TLR5, TLR4 and TLR2 were assessed after 24 h. The intestinal flagellin load was measured using Western blot, while bacterial counts were assessed using qPCR. Flagellin (10 and 30 μg) and TH1020 (10 μg) were administered intraperitoneally. TLR5 levels were also determined in the ileum of naproxen-treated rats. KEY FINDINGS: NSAID enteropathy was associated with downregulation of TLR5, intestinal inflammation and apoptosis, mucosal histological damage, higher bacterial counts and flagellin load in the intestine, and upregulation of TLR2 and TLR4. IND-induced changes, except the fall in TLR5 expression, were reduced or completely prevented in animals that had been pretreated with flagellin. Importantly, flagellin induced similar robust protection when administered four hours after IND. In contrast to flagellin, treatment with the potent and selective TLR5 antagonist TH1020 exacerbated the intestinal inflammation caused by IND. SIGNIFICANCE: Our findings reveal that TLR5 activation protects against NSAID-induced enteropathy and may therefore be a new therapeutic avenue.
AIMS: To investigate the role of G protein pathway suppressor 2 (GPS2) nuclear translocation in hepatic stellate cell (HSC) activation and its underlying mechanisms in liver fibrosis. MATERIALS AND METHODS: RNA sequencin...AIMS: To investigate the role of G protein pathway suppressor 2 (GPS2) nuclear translocation in hepatic stellate cell (HSC) activation and its underlying mechanisms in liver fibrosis. MATERIALS AND METHODS: RNA sequencing (RNA-seq) was performed to analyze differential gene expression among experimental groups. Fatty acid oxidation (FAO) was evaluated using FAO Blue staining. Co-immunoprecipitation (Co-IP) assays were conducted to investigate the interaction between GPS2 and its potential binding partners. In addition, HSC activation was induced by PDGF-BB, and cell proliferation, activation markers, and mitochondrial FAO levels were systematically assessed. KEY FINDINGS: GPS2 nuclear translocation was significantly increased during HSC activation. Inhibition of GPS2 nuclear translocation attenuated liver fibrosis and reduced HSC activation. Mechanistically, blocking GPS2 nuclear translocation weakened its interaction with PPARα. PPARα was found to regulate mitochondrial FAO, which in turn promoted HSC proliferation and activation. Suppression of PPARα reduced FAO and alleviated HSC activation. SIGNIFICANCE: This study identifies a novel mechanism whereby GPS2 nuclear translocation promotes HSC activation through interaction with PPARα and regulation of mitochondrial FAO. Targeting GPS2 nuclear translocation may represent a potential therapeutic strategy for liver fibrosis.
AIMS: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Epigenetic regulation by p300 histone acetyltransferase plays a central role in fibroblast activation and f...AIMS: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Epigenetic regulation by p300 histone acetyltransferase plays a central role in fibroblast activation and fibrotic gene transcription. This study aimed to identify novel p300 inhibitors from an FDA-regulated compound library using integrated computational approaches and to evaluate their anti-fibrotic potential. MATERIALS AND METHODS: Candidate compounds were screened via p300 HAT activity assay. Bronopol was validated as a p300 inhibitor using Autodock vina, DiffDock AI-based blind docking, and molecular dynamics simulations. Anti-fibrotic efficacy was assessed in TGF-β-stimulated mouse (Mlg) and human (WI-38) lung fibroblasts and in a bleomycin-induced mouse model of pulmonary fibrosis. KEY FINDINGS: Bronopol stably occupied the Acetyl-CoA-binding pocket of p300, forming persistent interactions with Arg1410 and Thr1411, and inhibited p300 enzymatic activity with greater potency than canonical inhibitor C646. In vivo, Bronopol inhibited endogenous p300 enzymatic activity in lung tissue, markedly reduced collagen deposition, myofibroblast activation, and overall fibrotic severity, accompanied by decreased histone H3 acetylation. Bronopol also inhibited p300 enzymatic activity and suppressed TGF-β-induced histone H3 acetylation, fibrotic gene expression, and fibroblast-to-myofibroblast activation in lung fibroblast cell lines. SIGNIFICANCE: Bronopol, an FDA-regulated antimicrobial agent, exhibits potent anti-fibrotic effects through epigenetic inhibition of p300, highlighting its potential as a repurposed therapeutic candidate for IPF and other fibrotic diseases.
Extravillous trophoblasts (EVT) are essential for placental invasion into the maternal decidua and spiral artery remodeling, ensuring a successful pregnancy. It is well-established that early placental development occurs...Extravillous trophoblasts (EVT) are essential for placental invasion into the maternal decidua and spiral artery remodeling, ensuring a successful pregnancy. It is well-established that early placental development occurs under physiologically hypoxic conditions (~2% O), while the later stages proceed under increased physiological oxygen levels (~8% O). However, the heterogeneity of EVT across these distinct developmental conditions remains poorly characterized. Moreover, the molecular mechanisms governing EVT lineage development and function under low oxygen conditions remain largely elusive. Herein, we systematically characterize the transcriptome dynamics underlying the differentiation of cytotrophoblasts (VCT) and human trophoblast stem cells (hTSC) into EVT at single-cell resolution. Our analysis reveals pronounced functional and phenotypic heterogeneity among EVT from early versus late gestational stages, as well as between in vivo and in vitro models. We demonstrate that oxygen tension is a pivotal factor driving EVT heterogeneity, giving rise to distinct subtypes with invasive/migratory and secretory potentials. Furthermore, we elucidate that hypoxia impairs EVT lineage development from hTSC in vitro. Hypoxia reduces intracellular UDP-N-acetyl-d-glucosamine (UDP-GlcNAc) level, thereby possibly disrupting protein N-glycosylation. We further demonstrate that N-glycosylation pathway activity is significantly elevated during the differentiation of hTSC into EVT, as pharmacological inhibition with tunicamycin (TM) completely blocks this process. UDP-GlcNAc supplementation rescues the EVT differentiation defect under hypoxia, demonstrating that protein N-glycosylation is essential for EVT lineage commitment under low oxygen conditions. Our findings uncover a hypoxia-sensitive glycosylation in EVT development and provide new insights into early placental development.
Nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoic acid and thyroid hormone (SMRT) are critical regulators that mediate transcriptional repression through histone deacetylation. Despite high struct...Nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoic acid and thyroid hormone (SMRT) are critical regulators that mediate transcriptional repression through histone deacetylation. Despite high structural homology, their distinct roles in the central nervous system remain poorly understood. To elucidate these roles, we generated neuronal-specific NCoR1 or SMRT knockout mice using Snap25-IRES2-Cre mice. Behavioral assessments revealed that while both NCoR1 and SMRT deficiency led to hypoactivity, social deficits, and mild anxiety, NCoR1-deficient mice uniquely exhibited enhanced learning abilities in a visual discrimination task, indicating functional separation in cognitive regulation. This divergence was supported by RNA-sequencing in the amygdala at postnatal day 21 (PND 21), where SMRT deletion upregulated 449 genes, whereas NCoR1 deletion upregulated only 8 genes. Furthermore, we investigated the protein stability of HDAC3, the primary enzymatic partner of these corepressors. At PND 21, HDAC3 levels were significantly reduced in the NCoR1-deficient hippocampus but significantly increased in the SMRT-deficient amygdala. In contrast, HDAC3 levels remained stable in the adult cerebellum and PND 3 cerebrum regardless of corepressor status. Notably, while mice with deletion of both NCoR1 and SMRT exhibit early postnatal lethality, their HDAC3 levels were unchanged compared to controls at PND 3, suggesting that the lethal phenotype is not primarily driven by a systemic loss of HDAC3 protein. Collectively, our findings demonstrate that NCoR1 and SMRT function through independent transcriptional networks and context-dependent regulatory mechanisms. This study highlights the specialized, non-redundant roles of these homologous corepressors in the brain according to developmental stage and region.
Resistin, an adipokine secreted by adipocytes and immune cells, and NF-κB, a pro-inflammatory transcription factor involved in immune regulation, have been implicated in obesity-induced asthma. C57BL/6 mice were assigned...Resistin, an adipokine secreted by adipocytes and immune cells, and NF-κB, a pro-inflammatory transcription factor involved in immune regulation, have been implicated in obesity-induced asthma. C57BL/6 mice were assigned to either an ovalbumin-induced asthma model or an obesity group. The mice were treated with CDN1163 (SERCA activator; administered 12 times over 3 weeks), resistin recombinant protein (4 times over 2 weeks), resistin blocking antibody (3 times per week), and/or an NF-κB inhibitor (MG132; 3 times per week). For in vitro experiments, Beas-2B bronchial epithelial cells were treated with lipopolysaccharide (LPS), insulin, siRNAs targeting resistin, Retnlα, and Retnlβ, and NF-κB inhibitor. In murine model, CDN1163 ameliorated both obesity-induced and -aggravated asthma by improving airway hyper-responsiveness, airway inflammation, tissue remodeling, and fibrosis, and decreasing inflammatory cytokines, including NF-κB. Exogenous resistin stimulation via administration of recombinant resistin protein significantly increased NF-κB expression, whereas the resistin-neutralizing antibody reversed this effect and ameliorated features of asthma. Notably, NF-κB inhibition significantly alleviated airway hyper-responsiveness, inflammation, and fibrosis, but did not alter resistin levels. In vitro experiments showed that resistin-targeting siRNAs significantly decreased LPS- and insulin-induced pro-inflammatory cytokine production. NF-κB inhibitor decreased the levels of inflammatory cytokines, but not resistin. In human cohort study, resistin expression was significantly higher in obese asthma compared to asthma patients with normal BMI. Resistin signaling via the NF-κB pathway may contribute to obesity-induced and -aggravated asthma and may represent a potential therapeutic target.
The excessive expansion of white adipose tissue (WAT) that characterizes obesity is a major global health concern. N6-methyladenosine (mA) modification and its readers regulate metabolic homeostasis, but how mA-dependent...The excessive expansion of white adipose tissue (WAT) that characterizes obesity is a major global health concern. N6-methyladenosine (mA) modification and its readers regulate metabolic homeostasis, but how mA-dependent translational control shapes mitochondrial remodeling in white adipocytes during obesity remains unclear. In this study, we examined the function of the mA reader YTHDF1 in diet-induced adiposity using whole-body and adipocyte-specific Ythdf1 knockout mice, together with primary adipocyte models. Under high-fat diet (HFD) feeding, both Ythdf1 and Ythdf1 mice developed greater obesity with WAT hypertrophy and metabolic dysfunction. YTHDF1 was enriched in adipocyte precursor cells and downregulated during adipogenesis and in WAT from obese mice. RNA sequencing of differentiating adipocytes revealed that Ythdf1 deficiency rewired energy metabolism, with enrichment of tricarboxylic acid cycle and oxidative phosphorylation pathways, increased mitochondrial remodeling, and enhanced lipid accumulation. Mechanistically, functional studies combined with RIP-qPCR, reporter assays and polysome profiling supported Nod1 as an mA-responsive translational target of YTHDF1 in adipocytes, sustaining NOD1 protein abundance in WAT. Ythdf1 deletion reduced NOD1 protein abundance and enhanced mitochondrial- and lipid-associated readouts, whereas NOD1 overexpression attenuated these phenotypes in Ythdf1-deficient adipocytes. SERCA1 protein abundance was also altered upon Ythdf1/Nod1 perturbation, suggesting a possible association between the YTHDF1-NOD1 pathway and SERCA1-related calcium handling in adipocytes. Together, these findings identify YTHDF1 as an mA reader that limits diet-induced adiposity and adipocyte mitochondrial remodeling, at least partly through maintaining NOD1 protein abundance, with SERCA1 emerging as a candidate molecule associated with Ythdf1/Nod1 perturbation.
Cartilage acidic protein 1 (CRTAC1) has recently emerged as a molecule of interest across multiple pathological contexts, particularly in degenerative diseases such as osteoarthritis (OA), as well as in selected pulmonar...Cartilage acidic protein 1 (CRTAC1) has recently emerged as a molecule of interest across multiple pathological contexts, particularly in degenerative diseases such as osteoarthritis (OA), as well as in selected pulmonary and malignant conditions. Originally described as a cartilage-associated extracellular matrix (ECM) protein, CRTAC1 is also expressed in other tissues, including lung and bladder, suggesting broader biological functions. Two major isoforms have been identified, with CRTAC1-A predominating in peripheral tissues. Accumulating evidence indicates that CRTAC1 is associated with ECM remodeling and may influence cell-matrix interactions through integrin binding and modulation of calcium-dependent signaling pathways. Experimental studies suggest that CRTAC1 can affect intracellular calcium flux, oxidative stress responses, and stress kinase activation, including p38 MAPK and JNK pathways, contributing to context-dependent regulation of cell survival and apoptosis. However, the extent to which these mechanisms directly translate into in vivo disease processes remains unclear. Clinically, CRTAC1 shows the strongest evidence as a biomarker in OA, where large-scale proteomic studies consistently associate elevated plasma levels with disease severity, progression, and risk of joint replacement. In contrast, findings in pulmonary diseases and cancer are more heterogeneous and appear to be context-dependent. Overall, CRTAC1 represents a promising biomarker candidate, particularly in degenerative joint disease, while its mechanistic roles and broader clinical applicability require further validation through standardized and large-scale studies.
Feeding timing has recently been recognized as important for cardiometabolic health. However, it remains unknown how abnormal feeding timing influences lipid metabolism, which may be relevant to cardiovascular disease ri...Feeding timing has recently been recognized as important for cardiometabolic health. However, it remains unknown how abnormal feeding timing influences lipid metabolism, which may be relevant to cardiovascular disease risk. Here, we investigated how breakfast skipping (BS) combined with a Western diet (WD), which is a typical unhealthy feeding behavior combination in humans, affects lipid metabolism in rats. Wistar male rats were fed a WD (sucrose 52%, casein 20%, lard 15%, corn oil 2%, and cholesterol 1%) during zeitgeber time (ZT) 12-0 in the control group and ZT16-4 in the BS group. This experiment was conducted for 14 days. The BS rats showed massive rhythmic hyper-remnant-like particle (RLP)-cholesterolemia. Circadian oscillations of almost clock genes and cholesterol synthesis-related sterol regulatory element-binding protein 2 and 3-hydroxy-3-methylglutaryl-CoA synthase was delayed due to BS. The average mRNA level of cholesterol degradation-related genes, including sterol 12 α-hydroxylase and ATP binding cassette subfamily G member 5, was decreased in response to BS. In adipose tissue, circadian oscillation of clock genes was also delayed by BS, and the average mRNA level of adipose triglyceride lipase and lipoprotein lipase was enhanced. These data suggest that the combination of BS and WD is associated with massive rhythmic hypercholesterolemia, which may involve altered circadian oscillation of hepatic and adipose clock genes and changes in lipid metabolism. Although lipid metabolism differs between rodents and humans, particularly in lipoprotein profiles, these findings may provide insight into mechanisms linking feeding timing and altered lipid metabolism.