Sterol Regulatory Element-Binding Protein 2 (SREBP-2) is a core transcription factor that regulates de novo cholesterol synthesis. Targeting the SREBP pathway is regarded as a potential strategy for treating metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). At present, natural specific and effective modulators of this pathway are still very scarce. We identified a novel nonapeptide ST2b from the vine of the medicinal sweet potato Ipomoea batatas L. cv. Simon 1, and its amino acid sequence is GSFKMEGKR. In vitro experiments have shown that ST2b can significantly promote glucose uptake in insulin-resistant HepG2 cells and improve disorders of glycolipid metabolism. In a mouse model of T2DM induced by streptozotocin and a high-fat, high-sugar diet, intragastric ST2b reduced fasting blood glucose and serum insulin levels, improved glucose tolerance and insulin sensitivity, normalized lipid metabolism, and protected metabolic organs. ST2b binds to INSIG-1, stabilizing it by inhibiting degradation, enhancing INSIG-1 interaction with SCAP, blocking SREBP-2 activation, reducing cholesterol synthesis gene transcription. ST2b from sweet potatoes shows promise as a T2DM treatment by inhibiting the SREBP-2 pathway, suggesting its potential as a therapeutic agent or functional food for T2DM.
Adipose tissues not only store and release energy but also function as endocrine organs and maintaining adipose stem cells (ASCs) and functional adipocytes is essential for systemic metabolic health. Astaxanthin (Ast), an oxygenated carotenoid enriched in seafood, is recognized as a bioactive compound known for its anti-inflammatory and antioxidative properties. However, limited information is available regarding the roles of Ast in human ASCs (hASCs). This study examined the capacity of Ast to counteract TNF-α actions in the inflammatory signaling pathways and proliferation of hASCs. The effects of Ast on hASC adipogenesis and the underlying mechanisms were also determined. Proliferation rates were measured with an MTT assay, and adipogenesis was determined by measuring the expression levels of adipogenic markers and lipid accumulation. Ast (0.01-10 μM) had no effect under basal conditions but attenuated TNFα-mediated suppression of cell viability, as well as activation of canonical proinflammatory signaling pathways in hASCs. Lower concentrations of Ast (0.01 and 0.1 μM) increased adipogenesis, while higher concentrations (2 and 10 μM) inhibited adipogenesis. Ast (0.01 and 0.1 μM) induced adipogenesis by suppressing the anti-adipogenic Wnt/β-catenin pathway and upregulating the adipogenic transcription factors, C/EBPα and PPARγ, during the early periods of adipogenesis. Our results suggest that Ast has beneficial impacts on adipose tissue by suppressing inflammation, thereby maintaining the pool of adipose progenitors and promoting their adipogenesis.
Progression of liver fibrosis is a critical determinant of the prognosis of chronic inflammatory liver disease. We previously reported that platelet-type 12S-lipoxygenase localized in hepatic stellate cells (HSCs), which are primary fibrogenic cells in the injured liver, was upregulated in a methionine-choline deficiency (MCD) diet-induced mouse liver fibrosis model. In this study, the functional contribution of platelet-type 12S-lipoxygenase to the pathological process was investigated. After feeding with an MCD diet for 8 weeks, platelet-type 12S-lipoxygenase-deficient (Alox12-/-) mice exhibited significantly greater Sirius Red-positive areas and higher expression of type I collagen genes (Col1a1 and Col1a2) than wild-type (WT) mice, indicating aggravated fibrosis. Similar results were obtained in a model induced by neonatal streptozotocin injection followed by a high-fat diet (HFD) feeding. Conversely, a human HSC line (TWNT-1) stably overexpressing human platelet-type 12S-lipoxygenase exhibited significantly reduced COL1A1 and COL1A2 expression compared to the parental and mock cells. Analysis of fibrosis-related genes revealed downregulation of platelet-derived growth factor receptors (PDGFR) α and β in platelet-type 12S-lipoxygenase-expressing TWNT-1 cells. Consistently, the hepatic expression of Pdgfra and Pdgfrb was significantly elevated in MCD diet-fed Alox12-/- mice compared to that in MCD diet-fed WT mice. The knockdown of PDGFRs in parental TWNT-1 cells using siRNAs significantly suppressed the expression of type I collagen genes. Collectively, these findings indicate that platelet-type 12S-lipoxygenase expressed in HSCs attenuates liver fibrosis, at least in part, by modulating PDGFR expression.
Peripheral nerve injury (PNI) remains a significant clinical challenge due to the difficulty in achieving complete structural and functional recovery after injury. Recent studies have demonstrated that cholesterol metabolism serves not only as an essential substrate for myelin formation and maintenance, but also exerts critical regulatory roles in axonal regeneration, Schwann cell reprogramming, inflammatory modulation, and remyelination following injury. However, the complex mechanisms linking cholesterol metabolism to peripheral nerve regeneration remain insufficiently elucidated. Existing evidence suggests that injured Schwann cells, macrophages, and neurons can establish a dynamic lipid transport network through apolipoproteins, lipoprotein receptors, and cholesterol-sensing signaling pathways, thereby coordinating metabolic homeostasis and immune responses within the regenerative microenvironment. This review systematically summarizes the dynamic alterations in cholesterol metabolism following peripheral nerve injury and its mechanistic roles in the nerve repair process, with particular emphasis on the regulatory molecules and signaling pathways involved in cholesterol synthesis, transport, uptake, efflux, and neurosteroidogenesis. Furthermore, this review outlines current potential therapeutic strategies targeting cholesterol metabolism, including liver X receptor (LXR) agonists, apolipoprotein E (ApoE)-mimetic peptides, and neurosteroid-related interventions, and analyzes their prospective applications in promoting nerve regeneration and functional recovery. Finally, this review discusses the major challenges and pressing scientific questions facing this field, and presents future perspectives on the construction of cell-type-specific metabolic atlases, the application of multi-omics technologies, and the direction of clinical translational research, providing theoretical foundations and novel research insights for the development of peripheral nerve repair strategies targeting cholesterol metabolism.
The global incidence of hypertriglyceridemic pancreatitis (HTGP) is increasing, particularly in China, highlighting the urgent need to understand its pathogenesis. Given the metabolic basis of HTGP, this study aimed to define its specific metabolic profile and identify potential therapeutic targets. We first performed plasma metabolomic analysis in patients with acute pancreatitis of different etiologies, identifying a distinct HTGP signature characterized by significant reduction in 13-hydroxyoctadecadienoic acid (13-HODE) levels, which was validated in an HTGP rat model. Decreased 13-HODE reflects redirected metabolic flux along the ALOX15 lipid peroxidation cascade and metabolic reprogramming. We therefore employed oxidized lipidomics and confirmed the accumulation of oxidized lipids. Notably, specific phosphatidylethanolamine hydroperoxide (PE-OOH) was detected in both systemic circulation and pancreatic tissue, and the levels of PE-OOH were positively correlated with disease severity. Considering the central role of lipid peroxidation, we focused on arachidonate 15-lipoxygenase (ALOX15), a key enzyme in this pathway. Treatment with two different ALOX15 inhibitors, PD146176 and baicalein, effectively alleviated disease phenotype and reduced lipid peroxidation in HTGP. Taken together, our findings establish a correlation between decreased 13-HODE and enhanced lipid peroxidation in HTGP and demonstrate that ALOX15 inhibition represents a promising therapeutic strategy.
Mesenchymal stem cell (MSC) osteodifferentiation involves adaptations of lipid metabolism but the specific regulatory roles of lipid species remain underexplored. We use a global metabolomics approach, comprising LC-MS lipidomics and NMR metabotolomics, to identify mechanistic features of human adipose-derived MSC (hAMSC) osteodifferentiation and new markers of osteogenic progression. Results show that, upon differentiation, cellular metabolism progresses through an early osteocommitment phase (day 7) followed by active osteodifferentiation (day 21), with underlying proliferation contributing towards membrane remodeling, oxidative stress protection and lipid-supported energy/signaling processes. At day 7, differentiating cells exhibit coordinated lipid remodeling and activation of the phosphocreatine (PCr)-creatine (Cr) axis. This leads to accumulation of phosphocholine, PCr and sphingomyelin, in preparation for mineralization and extracellular vesicle formation. Concomitantly, calcium oscillatory signaling and active purinergic metabolism are predicted. Other early features persist until day 21, including increased polyunsaturated fatty acids (PUFAs)-rich plasmalogen levels, enhanced endogenous substrate mobilization and metabolic autonomy. At this later stage, accumulation of storage lipids occurs, likely contributing to ω-3/ω-6 balance. FA regulation seems to be accompanied by a shift from TCA/OXPHOS towards β-oxidation and PCr hydrolysis, as predominant energy sources. Late-stage osteodifferentiation is also characterized by inhibition of pathways associated with undifferentiated state maintenance, while several upstream regulators emerge as pro-osteogenic. The resulting metabolic framework enables actionable monitoring and rational optimization of bone tissue engineering strategies.
Lipids, which possess a variety of physiological functions, have been demonstrated to be involved in the development of CVB3-induced viral myocarditis (VM). Nevertheless, the dynamic changes of lipid in VM, along with the underlying mechanisms, still require clarification. In our study, the serum and heart lipidomics in both the NC and VM groups was performed by LC-MS/MS. Univariate and multivariate statistical analyses were employed to identify the differential lipids between groups. The heart samples were further tested by the transcriptomic analysis to find the expression profile changes of genes involved in lipid metabolism. Totally, 628 differential lipids in the heart and 666 in the serum were selected based on the criteria of VIP > 1.0, P < 0.05, and fold change >1 or < 1, respectively. Glycerophospholipids (GP) and sphingolipids (SP) were identified as the primary differential lipids, suggesting a marked imbalance in the corresponding lipid metabolic pathways that may be involved in the progression of VM. Simultaneously, the transcriptional profile proved that differentially expressed genes (DEGs) were significantly enriched in GP and SP metabolism pathways. In the serum, the GP category members DLCL (20:5/22:6) and CL (23:1/18:0/22:4/22:6), as well as the SP category members Hex2Cer (d18:2/24:0) and SPHP (d20:1), exhibited a two-fold change. Collectively, combined with transcriptomics and lipidomics data suggest that CVB3 exert its destructive effect on heart possibly by regulating GP and SP metabolism pathways. Several lipids in serum may serve as potential indicators for the progression of VM.
Recent studies have demonstrated that annelids possess front-end desaturases and elongases involved in the biosynthesis of physiologically important long-chain polyunsaturated fatty acids (LC-PUFA). However, methyl-end desaturases (ωx desaturases), enzymes that play a central role in the de novo biosynthesis of polyunsaturated fatty acids and their subsequent conversion into LC-PUFA, have so far been reported in only a limited number of polychaete species. To advance our understanding of ωx desaturases across the phylum Annelida, this study performed a comprehensive molecular and functional characterisation of these enzymes in the major annelid taxa Polychaeta, Clitellata and Sipuncula, encompassing species from diverse taxonomic groups and ecological niches. A total of 110 ωx desaturase sequences were retrieved from available genomes and transcriptomes. The number of ωx desaturase genes varied among species, ranging from zero to four copies. Phylogenetic analyses revealed that annelid ωx desaturases are classified into two major clades, designated Cluster A and Cluster B. Analyses of histidine-box motifs and exon-intron organisation revealed conserved patterns within each clade. Functional characterisation of ωx desaturases from Eisenia fetida (Clitellata) and Sipunculus nudus (Sipuncula), together with previously published data from polychaetes, demonstrated that annelids generally possess two ωx desaturases, one with Δ12 desaturase activity and another with ω3 desaturase activity. Collectively, these results demonstrate that annelids possess a phylogenetically and functionally diverse ωx desaturase repertoire that underpins their LC-PUFA biosynthetic capacity and may reflect adaptation to different ecological and nutritional environments.
Futile cycles (FCs), also known as substrate cycles, are a pair of opposing biochemical reactions that continually convert a substrate into a product and back. In doing so, FCs waste ATP without producing a tangible metabolic output (thus termed 'futile'). Because ATP hydrolysis is exothermic, recent studies have extensively focused on the thermogenic function of various FCs, particularly in adipose tissue. However, the function of FCs on other target organs and their primary biological functions remain poorly defined. In this forward-looking minireview/perspective, we discuss a few underexplored functions of FCs that underpin metabolic flexibility and systemic metabolic health. We propose an integrative model in which discrete FCs across metabolic organs act in concert to regulate cellular energetics and organismal metabolic physiology. We postulate that FCs sense and integrate metabolic status, redox balance, and metabolite signaling, with mitochondria serving as the central hub where energetic and signaling cues converge to generate a calibrated cellular response. Given the broad regulatory role of FCs, including in metabolic flexibility, future studies should aim to define the wider functions vis-à-vis metabolic homeostasis in health and disease.
Consumption of a high-fat diet (HFD) diet is a factor associated with several diseases including obesity and its associated complications, especially liver and kidney dysfunction via promoting derangement of lipid metabolism. It has been reported that fructooligosaccharides (FOS) improve insulin sensitivity and ectopic lipid accumulation. The aim of this study was to investigate the effects of FOS on insulin resistance, liver and renal lipid accumulation, inflammasome formation, oxidative stress and intestinal barrier integrity in an obese rat model. Male Wistar rats were fed a normal (ND) or HFD for 16 weeks. The rats given a HFD were then given FOS at 1 or 2 g/day and metformin at 30 mg/kg/day daily for 8 weeks by oral gavage. The results demonstrated that FOS and metformin improved insulin resistance. FOS showed greater efficacy than metformin in attenuating intestinal barrier leakage. FOS and metformin decreased liver lipid synthesis as evidenced by the downregulation of SREBP1c, FAS and perilipin2. Renal lipid accumulation was restored concomitant with the reduction in renal lipid content and lipotoxicity. Liver and renal inflammation and organ injury were restored to within normal limits. However, FOS had no effect on the antioxidant enzymes via KEAP1/NRF2. Metformin attenuated renal oxidative stress via the suppression of PKCα and the FOXO1 signaling pathway. These suggest that FOS and metformin have the potential to improve gut health and prevent liver and renal complications and could be used as a useful supplement in the obese condition.
Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are central downstream effectors of the Hippo pathway and play key roles in hepatic metabolic regulation. However, the molecular mechanisms by which YAP/TAZ modulate lipid processing in hepatocytes remain incompletely understood. In this study, we investigated a YAP/TAZ-dependent non-coding RNA regulatory network controlling low-density lipoprotein receptor (LDLR) expression and lipid droplet accumulation in human hepatic cells. Using transcriptomic profiling combined with functional validation in human hepatocellular carcinoma cells, we identified the long non-coding RNA Shwachman-Bodian-Diamond Syndrome Pseudogene 1 (SBDSP1) as a YAP/TAZ-downstream transcript that positively regulates LDLR expression. Silencing of YAP/TAZ significantly reduced SBDSP1 levels, accompanied by downregulation of LDLR mRNA and protein, impaired LDL uptake, and reduced intracellular lipid droplet accumulation. Mechanistically, SBDSP1 was predicted to interact with miR-29a-5p, a microRNA putatively targeting the 3' untranslated region of LDLR. Knockdown of SBDSP1 or mimicking of miR-29a-5p decreased LDLR expression and reduced lipid accumulation, while luciferase reporter assays confirmed direct interactions between miR-29a-5p and both SBDSP1 and LDLR. Collectively, these findings describe a potential YAP/TAZ-SBDSP1-miR-29a-5p-LDLR regulatory axis that controls hepatic lipid uptake and accumulation. This study provides molecular insights into the interplay between Hippo pathway signaling and non-coding RNA networks to regulate lipid metabolism, highlighting a potential regulatory mechanism that may be relevant to hepatic lipid accumulation in metabolic dysfunction-associated steatotic liver disease.
OBJECTIVES:GPR183, a G protein-coupled receptor activated by oxysterols, regulates immune and metabolic signaling in a sex-dependent manner. Lauroyl tryptamine (LT), a lipid-modified microbial metabolite, was recently identified as a GPR183 antagonist. We hypothesized that LT disrupts oxysterol-driven metabolic regulation by antagonizing GPR183 activity. METHODS:LT's antagonistic properties were assessed using BRET-based assays for GPR183-mediated arrestin recruitment and G protein signaling. LT absorption was quantified in isolated perfused rat colon. Metabolic outcomes were evaluated in wild-type (WT) and Gpr183 knockout (Gpr183-/-) mice treated with LT or the synthetic antagonist NIBR189. To examine microbiota contributions, cecal contents from WT and Gpr183-/- mice were transplanted into germ-free recipients, and metabolic phenotypes were analyzed. RESULTS:LT selectively inhibited oxysterol (7α,25-OHC)-induced arrestin recruitment via human and mouse GPR183 without altering Gαi signaling. LT was absorbed across the colonic epithelium in a dose-dependent manner. Female mice treated with NIBR189 but not LT exhibited differences in body weight change and glucose homeostasis. Microbiota transfer did not reproduce the phenotype. LT induced weight loss in male WT mice, but not in Gpr183-/- males. CONCLUSION:LT functions as a pathway-specific antagonist of oxysterol signaling via GPR183, modulating lipid-sensitive metabolic pathways in a sex-dependent manner.
Chronic mild hypoxia at moderate altitude (2260 m) has been linked to improved systemic metabolism, but its liver-specific associations under high-energy diets remain incompletely defined. In this study, age-matched male C57BL/6 J mice were maintained for 15 weeks at simulated low altitude (50 m) or moderate altitude (2260 m) while fed a normal diet (ND), high-fat diet (HFD), or HFD with 30% fructose (HFD + HFr). Hepatic outcomes were assessed using ultrasonography, histology, electron microscopy, serum biochemistry, targeted energy metabolomics, lipidomics, and immunoblotting. Compared with the corresponding low-altitude high-energy diet groups, mice at 2260 m showed lower diet-associated weight gain, hepatic steatosis, and ALT/AST elevations. Structural analyses showed reduced lipid-droplet accumulation and qualitatively improved mitochondrial ultrastructural appearance. Metabolomics showed coordinated decreases in steady-state intermediates across glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle relative to the 50 m HFD group, together with enzyme changes consistent with reduced lipogenic capacity and altered fatty-acid uptake/oxidation. Lipidomic profiling further showed lower accumulation of neutral lipids, including triglycerides and diacylglycerols, as well as sphingolipids, while phospholipid class-level composition appeared less disturbed. Overall, moderate-altitude exposure was associated with attenuation of high-energy-diet-related hepatic metabolic dysfunction and with coordinated metabolic remodeling. These findings identify chronic mild hypoxia as an important contextual factor associated with hepatic metabolic responses, while direct causal mechanisms require further validation.
Lens fibers undergo organelle degradation during lens terminal differentiation. Defects in organelle degradation of lens fibers lead to congenital cataract. As a member of heat shock factor family, HSF4 governs lens development by regulating the expression of key factors. HSF4 transcriptionally regulates ATG9a to induce organelle degradation via the autophagic pathway during lens terminal differentiation. HSF4 is also required for the organelle membrane translocation of phospholipases PLAATs, which were suggested to promote organelle degradation independent of autophagy in lens fibers. However, the detailed mechanism how HSF4 induces organelle degradation in lens fibers still remains unknown. In this study, we found that lipid peroxidation was extensively suppressed in HSF4del42 mouse lens fibers. HSF4 likely transcriptionally regulated the expression of lipoxygenase ALOX15 in lens. ALOX15 is uniquely expressed in lens fibers and colocalized with organelles in differentiating lens fibers. Knockout of ALOX15 had little effect on the organelle degradation in lens fibers. Unlike the total inhibition in HSF4del42 lens fibers, lipid peroxidation was only partially disturbed in ALOX15-/- lens fibers, possibly due to the compensatory role of ALOX12. Our findings demonstrate that HSF4 promotes lipid peroxidation by transcriptionally regulating ALOX15 expression in lens fibers, thus may contribute to the organelle degradation during lens OFZ formation. These findings expand our understanding of the molecular mechanisms underlying lens terminal differentiation.
BACKGROUND:Caveolin-2 (CAV2) is a lipid droplet (LD)-associated protein. Its role in oral leukoplakia (OLK), an oral potentially malignant disorder, and the underlying lipid metabolism mechanisms remain unclear. METHODS:CAV2 conditional knockout (cKO; CAV2flox/flox; K14-Cre) and control (Flox) C57BL/6 mice were used to establish OLK models via 4-nitroquinoline-N-oxide (4NQO). A subset received a high-fat diet (HFD). Oil red O staining, RNA sequencing, multiplex immunofluorescence (Ki-67, E-cadherin, Perilipin-1, FABP5), ELISA (acetyl-CoA), serum biochemistry (ALT, TG), and targeted GC-MS/MS fatty acid profiling were performed. RESULTS:CAV2 knockout significantly suppressed OLK progression, evidenced by reduced lesion diameter/number and attenuated pathological severity. HFD failed to rescue OLK progression. RNA-seq confirmed dysregulation of lipid transport, lipolysis, and fatty acid metabolism/biosynthesis. Targeted metabolomics revealed markedly attenuated carcinogen-induced fatty acid accumulation in cKO mice, with C18:2n6c (linoleic acid, LA) identified as the sole metabolite showing significant genotype-dependent reduction under 4NQO challenge. cKO mice exhibited downregulated Perilipin-1 and Ki-67, and upregulated FABP5 and E-cadherin. CAV2 knockout also induced lesion acetyl-CoA accumulation and systemic lipid metabolism abnormalities. CONCLUSIONS:CAV2 knockout inhibits OLK formation and progression by disrupting lipid metabolism homeostasis, including restriction of LA bioavailability. Exogenous fatty acid supplementation failed to rescue OLK progression or restore metabolic homeostasis, highlighting CAV2 as a potential therapeutic target.
Visceral hypersensitivity (VH) is regarded as a core pathophysiological mechanism in irritable bowel syndrome (IBS). Although maternal vitamin A deficiency (VAD) during pregnancy has been linked to gastrointestinal dysfunction in offspring, its specific role in VH and the underlying mechanisms are not yet fully understood. This study aimed to explore the effects of maternal VAD on the development of VH in offspring and to assess the potential therapeutic role of postnatal vitamin A supplementation (VAS). Using a maternal VAD rat model, we observed that maternal VAD was associated with the development of VH in offspring, along with downregulated intestinal retinoic acid receptor β (RARβ) and activation of the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2)/prostaglandin E2 receptor EP2 (EP2) axis in enteric glial cells (EGCs). These changes could be partially reversed by postnatal VAS. In a NaB-induced IBS model, VA intervention appeared to alleviate VH, gastrointestinal dysmotility, and diarrhea-like symptoms, possibly through suppression of the TLR4/MyD88/NF-κB pathway. In vitro experiments indicated that retinoic acid (RA), the active metabolite of VA, may inhibit TLR4/MyD88/NF-κB activation in EGCs, leading to reduced COX-2 expression and PGE2 synthesis. These findings suggest a nutritionally regulated mechanism linking maternal VA status to offspring VH and raise the possibility that the RA-RARβ axis may serve as a potential target for early nutritional interventions in IBS.
Inositol is an essential metabolite required for membrane biogenesis, cell signaling and trafficking, and gene expression. Its importance is underscored by the fact that inositol depletion leads to death in eukaryotic cells ranging from yeast to human. Perturbation of inositol homeostasis is implicated in numerous human disorders. In yeast, inositol is synthesized de novo from glucose-6-phosphate (G-6-P) through a two-step pathway controlled by the rate-limiting enzyme myo-inositol phosphate synthase (MIPS), encoded by INO1. INO1 expression is tightly controlled by the Henry regulatory circuit in response to inositol and by the Reg1-Snf1 pathway in response to glucose. As both inositol synthesis and glycolysis utilize the same precursor, G-6-P, the current study tested the hypothesis that inositol synthesis is regulated by glycolytic activity. Genetic and pharmacological approaches were used to alter glycolysis. Inositol synthesis was determined by liquid chromatography mass spectrometry analysis of [U-13C]-glucose incorporation into inositol and by assaying INO1 mRNA and MIPS protein expression. In rho0 cells and wild type cells treated with the electron transport inhibitor potassium cyanide, both of which exhibit increased glycolytic activity, inositol levels were reduced by 47.5% and 57.9%, respectively, compared to controls. INO1 mRNA and MIPS protein levels were also decreased in these cells. The effect of downregulation of glycolysis was determined using the humanized yeast strain HHK2, which expresses a decreased rate of glycolysis due to the less active human hexokinase. Consistent with our hypothesis, HHK2 cells exhibited a 41.5% increase in inositol synthesis. Dysregulation of inositol synthesis did not affect glycolysis. These results identify altered glycolytic activity as a mechanism of inositol regulation and demonstrate the role of metabolic crosstalk in controlling these biochemical pathways.
OBJECTIVE:Trans-10, cis-12 conjugated linoleic acid (t10c12-CLA) can affect lipid metabolism, leading to weight loss and attracting widespread attention. However, its suitability for use in lactating mothers remains unclear. A transgenic mouse, named Pai (homozygous) and Pai/wt (heterozygous), capable of producing endogenous t10c12-CLA was successfully established. METHODS:In this study, embryo transfer technology was utilized to transplant embryos of wild-type (wt) mice into the transgenic mice, in order to investigate the effects of t10c12-CLA on biometric and reproductive parameters. RESULTS:Embryo transfer efficiency remained unchanged following the procedure. The male-to-female ratio of offspring in Pai/wt group was significantly higher than that in wt and Pai groups. Additionally, the birth weight, 21-day body weight, serum glucose level and triglyceride level of pups in Pai group were significantly lower than those in wt group. Simultaneously, the Pai pups exhibited modulated gut microbiota composition and regulated metabolic profiles in white adipose tissue and liver. Further investigations in liver tissue and HepG2 cells revealed that these effects featured suppressed lipogenesis (FASN, ChREBP), enhanced fatty acid oxidation (CPT1A) through activation of AMPK pathway in liver. CONCLUSIONS:Maternal t10c12-CLA could suppress lipogenesis and lower lipid levels by activating the AMPK pathway, and alter the composition of gut microbiota, thereby impacting offspring lipid metabolism.
Dysregulated lipid metabolism drives atherosclerosis (AS). Yacon, an Andean lipid-modulating tuber, exerts anti-AS potential, but mechanisms remain unclear. We integrated network pharmacology, machine learning, single-cell RNA sequencing (scRNA-seq), and in vivo validation to explore its anti-AS effects and targets. Active constituents and targets were curated from literature, TCMSP, and SwissTargetPrediction; lipid/AS genes from GeneCards, OMIM, and GEO were filtered via limma, WGCNA, LASSO, randomForest, and SVM-RFE. Immune infiltration and external validation confirmed hub gene relevance. scRNA-seq prioritized FABP5; docking and dynamics quantified compound-FABP5 interactions. In vivo efficacy was tested in high-fat diet (HFD)-fed ApoE-/- mice via histology (Oil Red O, H&E, and Masson) and molecular assays (RT-qPCR, Western blot, and immunofluorescence). We identified 12 constituents, 384 targets, and seven core targets (AURKA, MMP9, FABP5, etc.), with FABP5 top-ranked. Docking and dynamics identified Enhydrin as the strongest FABP5 binder. Enhydrin administration was associated with reduced hepatic lipid accumulation, decreased serum triacylglycerol (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, and increased high-density lipoprotein cholesterol (HDLC) levels. Histopathological analysis of arterial tissues revealed attenuated vascular lipid deposition and delayed atherosclerotic lesion progression. Across assays, Enhydrin downregulated FABP5, reduced abnormal fatty acid trafficking, and upregulated PPARγ and ABCA1, with markedly reduced vascular lipid deposition and improved serum lipid profiles, reflecting enhanced cholesterol efflux. Conclusion: Our integrative multi-omics analysis pinpointed FABP5 as a promising novel target for yacon-derived Enhydrin in atherosclerosis. In vivo, Enhydrin markedly downregulated FABP5 and upregulated PPARγ and ABCA1, suggesting this axis mediates its anti-atherosclerotic activity. SIGNIFICANCE STATEMENT: 1: This study identified FABP5 as a candidate target for atherosclerosis through integrative multi-omics, and its association with the anti-atherosclerotic effects of Enhydrin suggests therapeutic potential. 2: The anti-atherosclerotic effects of yacon's active components and their underlying molecular pathways were systematically screened and preliminarily characterized by integrating bioinformatic prediction with in vivo validation, laying a preliminary theoretical foundation for further pharmacological investigation and clinical translation.
