Biology subjects

Lee-Okada, H.-C.

Publications and source records attributed to Lee-Okada, H.-C..

4 recordsLinked to original sources

bioRxiv2026

PLCXD2 preferentially hydrolyzes phosphatidylinositol and supports retinal lipid homeostasis and photoreceptor integrity

PLCXD proteins have been linked to phosphoinositide metabolism for more than a decade, and PLCXD2 activity has been associated with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] depletion, yet its preferred direct substrate has remained unresolved. Here, cellular lipidomics showed that catalytically active PLCXD2 reduced the major phosphatidylinositol (PI) 38:4 species, with more modest phosphoinositide changes and increased diacylglycerol (DAG) and phosphatidic acid (PA). Using recombinant PLCXD2 and acyl-chain-matched substrates, we found that PLCXD2 hydrolyzed PI substantially more efficiently than PI(4,5)P2 and most other phosphoinositides tested. In Plcxd2-deficient retina, PI abundance was preserved, whereas DAG and PA were reduced without broad changes in major membrane phospholipid classes. PLCXD2 loss was associated with early structural abnormalities at the photoreceptor-bipolar synaptic interface, followed by outer nuclear layer thinning and reduced electroretinographic a-wave responses. These findings identify PLCXD2 as a PI-preferring mammalian PLC and reveal an endogenous role in retinal lipid homeostasis and outer retinal integrity.

biochemistry↗

bioRxiv2024

The lysosomal membrane protein LAMP2B mediates microlipophagy to target obesity-related disorders

Lifestyle diseases, such as obesity, diabetes, and metabolic syndrome, are leading health problems, most of which are related to abnormal lipid metabolism. Lysosomes can degrade lipid droplets (LDs) via microautophagy. Here, we report the molecular mechanism and pathophysiological roles of microlipophagy, regulated by the lysosomal membrane protein LAMP2B. Our study revealed that LAMP2B interacts with phosphatidic acid, facilitating lysosomal-LD interactions and enhancing lipid hydrolysis via microlipophagy depending on endosomal sorting complexes required for transport. Correlative light and electron microscopy demonstrated direct LDs uptake into lysosomes at contact sites. Moreover, LAMP2B overexpression in mice prevents high-fat diet-induced obesity, insulin resistance, and adipose tissue inflammation; liver lipidomics analysis suggested enhanced triacylglycerol hydrolysis. Overall, the findings of this study elucidated the mechanism of microlipophagy, which could be promising for the treatment of obesity and related disorders.

cell biology↗

bioRxiv2024

Dysregulated expanded endocannabinoid system as therapeutic targets of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of upper and lower motor neurons. ALS patients often manifest systemic metabolic abnormalities such as glucose intolerance. Herein, to elucidate the systemic metabolic changes related to ALS progression, we performed metabolomics analysis on the serum of ALS patients and identified several metabolites associated with the disease progression, including metabolites involved in the expanded endocannabinoid system (ECS). In particular, the levels of N-acyl taurines (NAT) were correlated with the longitudinal change in the revised ALS functional rating scale (ALSFRS-R) rating. In vitro experiments with ALS cell models and in vivo studies with SOD1G93A transgenic mice revealed that PF-04457845, a fatty amide acid hydrolase (FAAH) inhibitor, up-regulated the expanded ECS, particularly the levels of NATs and N-acyl ethanolamine and ameliorates motor neuron degeneration through the regulation of microglial polarization, synapse plasticity, and neuronal development. Our study indicates that dysregulation of the expanded ECS is associated with ALS progression and a target for novel disease-modifying therapies.

neuroscience↗

bioRxiv2022

FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P1. Vitamin B12 (B12) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B12 receptor, by S1P1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B12 worsened EAE and eliminated FTY720s efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.

neuroscience↗