Biology subjects

Letian, A.

Publications and source records attributed to Letian, A..

5 recordsLinked to original sources

bioRxiv2025

PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation

Cerebral small vessel disease (CSVD) is strongly linked to metabolic risk factors and represents a major cause of vascular cognitive impairment and dementia. The interactions of genetic and environmental risk factors driving cerebrovascular pathology in metabolic syndrome are poorly understood. Here, we characterize neuroinflammatory and neurodegenerative phenotypes in a mouse model of metabolic syndrome with atherosclerosis induced by hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression combined with high-fat diet (HFD). PCSK9+HFD mice exhibit hallmark features of CSVD including vascular rarefaction, impaired neurovascular coupling, blood-brain barrier disruption, white matter injury, neuronal loss, and cognitive deficits. Notably, we identify lipid-droplet accumulating microglia (LDAM) as a distinct cellular phenotype that emerges in response to metabolic stress and correlates with cerebrovascular dysfunction. Three-dimensional light sheet microscopy reveals widespread vascular network disruption. Immunophenotyping demonstrates that microglia in PCSK9+HFD group exhibit enhanced phagocytic activation and ramification complexity yet accumulate perivascular amyloid-{beta}, suggesting impaired clearance capacity. Importantly, we observed vascular amyloid-{beta} deposition in wild-type mice without genetic Alzheimers disease mutations, suggesting that metabolic stress contributes to cerebrovascular amyloid pathology. PCSK9+HFD mice displayed recognition memory deficits and increased anxiety-like behavior. Our findings establish that severe hypercholesterolemia accelerates CSVD pathogenesis, and identify LDAM as a distinct pathological feature linking systemic metabolic syndrome to cerebrovascular dysfunction and cognitive impairment.

neuroscience↗

bioRxiv2025

Neutrophil TLR2 signaling promotes lipid accumulation and vascular plaque growth

Neutrophils are short-lived cells that are produced by the billions every day to circulate throughout the body and surveil all tissues. They are a key component of the innate immune system that play essential roles in antimicrobial immunity, but can also instigate sterile inflammatory diseases like gout and cancer. Immunometabolic paradigms that were developed by studying T cells and macrophages establish that cellular metabolic programming dictates immune function. Neutrophils have long been known as glucose-reliant and highly glycolytic. But surprising neutrophil heterogeneity has recently been described, and roles for lipids have been reported in both granulopoiesis and mature neutrophil effector function. Therefore, we set out to uncover how neutrophils acquire lipids from their environment and how this influences their functionality in the context of lipotoxicity. We found that neutrophils take up both free fatty acids and complex lipoproteins, but that their uptake is regulated through different signaling pathways. Neutrophil lipoprotein uptake is inducible by certain TLR2 signals, and this causes neutrophils to depolymerize their actin fibers and stop moving. Using a mouse model of atherosclerosis, we show that neutrophils in the plaque are lipid-laden and that neutrophil-deficient mice are protected from atherosclerotic plaque growth. Lipoprotein uptake causes neutrophils to recruit macrophages, conditional ablation of TLR2 on neutrophils prevents their lipid uptake and storage, and these mice are also protected against atherosclerosis. Our work highlights an important understudied role for lipids in neutrophil biology, and the importance of studying different lipid classes and different signaling pathways in neutrophils as compared to other myeloid populations.

immunology↗

bioRxiv2024

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance

{beta}-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.

biochemistry↗

bioRxiv2022

Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation

Aging is accompanied by chronic low-grade inflammation, but the mechanisms that allow this to persist are not well understood. Ketone bodies are alternative fuels produced when glucose is limited and improve indicators of healthspan in aging mouse models. Moreover, the most abundant ketone body, {beta}-hydroxybutyrate (BHB), inhibits the NLRP3 inflammasome in myeloid cells, a key potentiator of age-related inflammation. Given that myeloid cells express ketogenic machinery, we hypothesized this pathway may serve as a metabolic checkpoint of inflammation. To test this hypothesis, we conditionally ablated ketogenesis by disrupting expression of the terminal enzyme required for ketogenesis, 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL). By deleting HMGCL in the liver, we validated the functional targeting and establish that the liver is the only organ that can produce the life-sustaining quantities of ketone bodies required for survival during fasting or ketogenic diet feeding. Conditional ablation of HMGCL in neutrophils and macrophages had modest effects on body weight and glucose tolerance in agin, but worsened glucose homeostasis in myeloid cell specific Hmgcl deficient mice fed a high-fat diet. Our results suggest that during aging, liver derived circulating ketone bodies might be more important for deactivating NLRP3 inflammasome and controlling organismal metabolism.

immunology↗

bioRxiv2021

Therapeutic anti-PD-L1 antibody affects ESCRT-mediated functions in cells expressing oncogenic EGFR.

PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy. Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1s proximal proteome in human lung epithelial cells. Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells. These specific effects in mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors.

cell biology↗