Biology subjects

Choi, M. K.

Publications and source records attributed to Choi, M. K..

4 recordsLinked to original sources

bioRxiv2026

ApoE-Dependent Lipid Handling by Median Eminence Microglia Preserves Myelin Integrity and Metabolic Function

Microglia regulate hypothalamic control of systemic metabolism, but the mechanisms underlying their contribution remain unclear. Here, we identify a distinct apolipoprotein E (ApoE) microglial population enriched in the median eminence (ME), a brain region involved in sensing peripheral cues and metabolic regulation. These microglia engage multiple functional programs related to lipid handling, interferon signaling, and stress responses that are differentially regulated within the ME. Consumption of a Western diet (WD) increased interferon signaling and lipid accumulation in ME microglia. Expression of the human APOE4 isoform in mice exacerbated microglial lipid dysregulation, interferon signaling, and impaired ME myelin organization. Deleting APOE in microglia attenuated their ability to couple lipid accumulation to interferon signaling, identifying microglial APOE as a cell-intrinsic determinant of interferon responses. Finally, selective activation of liver X receptor signaling using synthetic HDL nanoparticles restored microglial lipid homeostasis, improved hypothalamic leptin responsiveness, and limited weight gain in WD-fed mice. Together, these findings define an Apoe-dependent regulatory program in ME microglia that is therapeutically targetable and clarify how nutritional stress disrupts hypothalamic control of metabolic homeostasis.

neuroscience↗

bioRxiv2025

The protein phosphatase 2C domain contributes to the pathobiological function of adenylyl cyclase in Cryptococcus neoformans

Adenylyl cyclase produces cyclic adenosine monophosphate, a signalling molecule that controls fungal development and virulence. Fungal adenylyl cyclases are distinguished by the presence of a conserved protein phosphatase 2C domain, whose function remains unknown. Here we show that the protein phosphatase 2C domain of Cac1, the adenylyl cyclase of the human pathogen Cryptococcus neoformans, has an unusual structure but functions as a metal-dependent serine/threonine phosphatase. Deletion of this domain or the adenylyl cyclase catalytic domain demonstrated that the protein phosphatase 2C domain is required for full Cac1 activity, influencing melanin and capsule synthesis, sexual differentiation, titan cell formation, and cell wall integrity. Notably, loss of the protein phosphatase 2C domain induces type 2 helper T-cell-biased immunity and extensive pulmonary damage yet does not cause mortality in mice. Integrated transcriptomic and phosphoproteomic analyses further revealed shared and domain-specific signalling outputs. Together, these findings define a pivotal role for the adenylyl cyclase-linked protein phosphatase 2C domain in C. neoformans pathobiology.

microbiology↗

bioRxiv2023

Elevated Glucocorticoid alters the trajectory of hypothalamic development and function

Exposure to excess glucocorticoid (GC) during early development is implicated in adult dysfunctions. Reduced adult hippocampal neurogenesis is a well-known consequence of exposure to early life stress or elevated GC, however the effects on neurogenesis during development and effects on other brain regions are not well understood. Using an optogenetic zebrafish model, here we analysed the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development. This is followed by failed maturation and early decline accompanied by impaired feeding, growth, and longevity. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such as rx3 by GC. Our data provide cellular and molecular level insight into GC-induced alteration of the hypothalamic development trajectory, a process crucial for health across the life-course.

neuroscience↗

bioRxiv2020

Engineered Red Blood Cells Carrying PCSK9 Inhibitors Persistently Lower LDL and Prevent Obesity

Low plasma levels of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) are associated with decreased low-density lipoprotein (LDL) cholesterol and a reduced risk of cardiovascular disease. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of LDL receptors (LDLR), very low-density lipoprotein receptors (VLDLR), apolipoprotein E receptor 2 (ApoER2), and lipoprotein receptor-related protein 1 (LRP1) and accelerates their degradation, thus acting as a key regulator of lipid metabolism. Antibody and RNAi - based PCSK9 inhibitor treatments lower cholesterol and prevent cardiovascular incidents in patients, but their high cost hampers market penetration. We sought to develop a safe, long-term and one-time solution to treat hyperlipidemia. We created a cDNA encoding a chimeric protein in which the extracellular N-terminus of glycophorin A was fused to the LDLR EGFA domain and introduced this gene into mouse bone marrow hematopoietic stem and progenitor cells (HSPCs). Following transplantation into irradiated mice, the animals produced red blood cells (RBCs) with the EGFA domain (EGFA-GPA RBCs) displayed on their surface. These animals showed significantly reduced plasma PCSK9 (66.5% decrease) and reduced LDL levels (40% decrease) for as long as 12 months post-transplantation. Furthermore, the EGFA-GPA mice remained lean for life and maintained normal body weight under high-fat diet. Hematopoietic stem cell gene therapy can generate red blood cells expressing an EGFA - glycophorin A chimeric protein as a practical and long-term strategy for treating chronic hyperlipidemia and obesity.

bioengineering↗