Life metabolism最新文献

Perivascular adipose tissue (PVAT) is a critical regulator of vascular homeostasis, and sympathetic nerves play a fundamental role in vascular function. However, the function of PVAT as an intermediary in neurovascular communication remains poorly understood. Due to the limitations of conventional two-dimensional (2D) imaging and the low tyrosine hydroxylase signal observed at room temperature, we reevaluated the sympathetic neuroanatomy of aortic PVAT (aPVAT) using volume fluorescence imaging under cold conditions. This approach enabled whole-mount three-dimensional (3D) visualization of the sympathetic network in murine aPVAT. Retrograde tracing was performed to identify neural origins. Cold-exposed mice were assessed for sympathetic activity, plasma norepinephrine levels, and blood pressure fluctuations. The function of aPVAT sympathetic nerves was further examined via local ablation with 6-hydroxydopamine. Our results revealed an undescribed, hierarchically organized sympathetic network, characterized by a primary nerve trunk along the aortic arch that branches into secondary fibers penetrating into the adipose tissue. This innervation exhibited a significant increase in density under cold exposure. Retrograde tracing confirmed the left stellate ganglion as the predominant source, which was shared by major thoracic organs such as the heart and lung. Importantly, local ablation of sympathetic nerves within aPVAT abolished the cold-induced hypertensive response, while ablation of sympathetic nerves within inguinal white adipose tissue had no such effect on hypertension. These findings established sympathetic nerves within aPVAT as a critical source of perivascular innervation and identified this localized neuro-adipovascular circuit as a potential therapeutic target for neurogenic hypertension.

Type 2 diabetes (T2D) is characterized by pancreatic islet β-cell dysfunction and systemic insulin resistance, with meta-inflammation playing a critical role in disease progression. As the major type of immune cell population in islets, both resident and recruited macrophages are important regulators of the islet immune microenvironment under physiological and T2D conditions. Exercise is an effective strategy for treating T2D, yet its impacts on islet inflammation and β-cell dysfunction remain elusive. Here, we established a mouse model of exercise intervention in obesity-associated T2D by combining high-fat diet (HFD) feeding with treadmill running. Notably, exercise markedly improves glucose tolerance and insulin sensitivity, accompanied by substantial mitigation of HFD-induced β-cell dysfunction, islet hypertrophy, and alterations in β-cell subpopulations. Exercise also reduces intra-islet infiltration of CD45⁺ immune cells and dampens pro-inflammatory gene expression, indicating robust attenuation of islet inflammation. Using untargeted plasma proteomics, we identified the secreted protein acidic and rich in cysteine (SPARC) as a circulating factor, whose suppression is associated with exercise-linked islet protection under HFD conditions. Mechanistically, our data support a model in which SPARC contributes to β-cell dysfunction, at least in part, through macrophage inflammasome-related signaling. Further analysis of a human cohort demonstrates that circulating SPARC protein levels are markedly elevated in patients with T2D, exhibiting a significant negative correlation with parameters indicative of insulin sensitivity and β-cell function, and a positive correlation with insulin resistance. Together, this work provides a systemic characterization of the effects of exercise intervention on islet homeostasis and β-cell function, and highlights SPARC as a candidate immuno-metabolic node for T2D intervention.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in regulating low-density lipoprotein cholesterol (LDL-C) levels and has emerged as an attractive target for atherosclerotic cardiovascular disease (ASCVD) therapy. While mono-clonal antibodies targeting PCSK9 have demonstrated clinical efficacy, their high cost and need for repeated administration limit widespread use. In this study, we developed a peptide-based vaccine by identifying B-cell epitopes from PCSK9-antibody complexes using the Protein Data Bank (PDB) structural data and AlphaFold3 prediction, and fusing them with a heterologous T-helper epitope. The vaccine induced strong and durable anti-PCSK9 antibody responses in mice, guinea pigs, and rhesus macaques when formulated with the CpG plus alum adjuvant. The vaccine significantly reduced LDL-C levels and attenuated hepatic lipid accumulation in both prophylactic and therapeutic mouse models. Moreover, it mitigated the progression of atherosclerotic plaques. The vaccine also demonstrated no signs of systemic toxicity or autoimmunity in animal models. These findings indicate that the vaccine is a safe, effective, and scalable approach for controlling hypercholesterolemia and preventing ASCVD through active immunization against PCSK9.

The plasma membrane dynamically organizes into specialized lipid domains to sustain cell proliferative signaling, yet the regu-latory mechanisms driving this process, especially during tumor progression, remain poorly understood. Here, we uncover cleft lip and palate transmembrane protein 1-like protein (CLPTM1L), an endoplasmic reticulum-localized lipid scramblase, as a critical regulator of membrane raft formation and the epidermal growth factor receptor (EGFR)-mediated proliferative signaling in cancer. High CLPTM1L expression was significantly associated with poor patient survival in glioblastoma (GBM), the most aggressive brain cancer. Depletion of CLPTM1L disrupts cellular lipid homeostasis and results in a substantial loss of membrane raft components, including glycosphingolipids and glycosylphosphatidylinositol (GPI)-anchored proteins. The cell-surface level of EGFR, which colocalizes with raft marker GM1, is markedly reduced upon CLPTM1L loss. We show that CLPTM1L-mediated raft remodeling promotes EGFR signaling and drives cell proliferation in both cancer and non-cancer cells. In GBM mouse models, CLPTM1L depletion inhibits EGFR signaling and profoundly impairs orthotopic tumor growth. Our work establishes CLPTM1L as a key regulator of membrane raft domain formation and highlights its critical role in cancer proliferative signaling.

[This corrects the article DOI: 10.1093/lifemeta/loae026.].

Sphingolipids regulate hepatic lipid homeostasis, cell survival, inflammation, and tissue repair. In the healthy liver, balanced de novo sphingolipid synthesis, salvage pathways, and sphingosine-1-phosphate (S1P)-related signals maintain metabolic flexibility, endothelial integrity, and immune quiescence. Dysregulation of sphingolipid metabolism drives the initiation and progression of chronic liver diseases. In metabolic dysfunction-associated steatohepatitis, the acyl chain length-specific remodeling of dihydroceramides and ceramides, together with increased neutral sphingomyelinase activity, triggers lipotoxic stress, abnormal anabolic signal transduction, and hepatic lobule inflammation. Liver fibrosis involves reprogramming of the hepatic stellate cell S1P receptor signaling from regenerative toward profibrotic pathways. In hepatocellular carcinoma, tumor cells utilize sphingolipid metabolism to promote angiogenesis, evade immune surveillance, and develop therapeutic resistance. Sphingolipid remodeling in viral hepatitis links viral persistence to distinct circulating lipid signatures that correlate with disease severity and prognosis. Importantly, multiple nodes in the sphingolipid network and their downstream effectors are emerging as therapeutic targets. Promising preclinical strategies include liver-targeted small interfering RNA against key biosynthetic enzymes, selective modulation of sphingolipid receptors, and nanoliposomal formulations of bioactive ceramides. To enable clinical translation, innovative approaches are being developed to overcome key challenges in delivery, specificity, and safety. Overall, this review integrates recent mechanistic insights, emphasizing that sphingolipids act as central regulators of liver pathophysiology and are also important biomarkers and therapeutic targets in chronic liver diseases.

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