Biology subjects

Li, W.-h.

Publications and source records attributed to Li, W.-h..

4 recordsLinked to original sources

bioRxiv2022

GPR84-Mediated Signal Transduction Promotes Brown Adipocyte Function

G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, may be involved in various metabolic conditions but the mechanism remains unclear. We found that GPR84 is highly expressed and functions in brown adipose tissue (BAT). GPR84 knockout mice exhibited increased adiposity and vulnerability to cold exposure after aging, along with an increased BAT lipid content and decreased BAT activation compared to wild-type control mice. In vitro, primary brown adipocytes from GPR84 knockout mice showed reduced expression of thermogenic genes and lower O2 consumption. The GPR84 agonist 6-OAU reversed these effects and restored brown adipocyte activation. In vivo and in vitro results showed that BAT defects in GPR84 knockout mice were attributed to mitochondrial dysfunction. GPR84 activation greatly affected intracellular calcium efflux, further influencing mitochondrial respiration. GPR84 activates BAT by controlling the mitochondrial calcium content and respiration, suggesting a therapeutic target for activating BAT and treating metabolic diseases. HIGHLIGHTSO_LIHigh expression of GPR84 in brown adipocytes is induced by cold stimulation. C_LIO_LIAged GPR84 knockout mice exhibit brown adipose tissue defects under cold exposure. C_LIO_LIGPR84 knockout mice show reduced mitochondrial function of brown adipocytes. C_LIO_LIGPR84 activation improves brown adipocyte functions. C_LI

physiology↗

bioRxiv2022

Redox sensing by SENP1 augments insulin secretion early after high-fat feeding in mice

Pancreatic {beta}-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. In {beta}-cells from overweight humans without diabetes, and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. {beta}-cell RNA-seq suggests altered metabolic pathways early following HFD, where we find increased basal oxygen consumption, proton leak, but a more reduced cytosolic redox state. Increased {beta}-cell exocytosis after 2-day HFD is dependent on this reduced intracellular redox and requires the sentrin-specific SUMO-protease-1 (SENP1). Mice with either pancreas- or {beta}-cell-specific SENP1 deletion fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day HFD. Mechanistically, redox-sensing by SENP1 requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained {beta}-cell exocytosis and increases SENP1 sensitivity to regulation by redox signals.

cell biology↗

bioRxiv2021

Zn2+ acts as a brake signal for axonal transport by directly inhibiting motor protein progression

Accurate delivery of cargo over long distances through axonal transport requires precise spatiotemporal regulation and relies on microtubule function. Here we discover that Zn2+ influx via depolarization inhibits axonal transport. Zn2+-mediated inhibition is nonselective for cargo. Elevated Zn2+ (IC50 >> 5-10 nM) reduces both lysosomal and mitochondrial motility in primary rat hippocampal neurons and HeLa cells. We further reveal that Zn2+ directly binds to microtubules, inhibiting movement of motor proteins (kinesin and dynein) and promoting detachment of neuronal-specific MAPs (Tau, DCX, and MAP2C). We finally provide a detailed model of microtubule interactions with Tau, DCX, dynein, kinesin, and predict microtubule Zn2+ binding sites. Our results reveal that Zn2+ acts to inhibit the microtubule binding of tau, DCX, and MAP2C and can directly block the progression of motor proteins on microtubules. Intraneuronal Zn2+, therefore, is a critical signal for regulating axonal transport and microtubulebased processes.

cell biology↗

bioRxiv2021

Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis

Amino acid metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an amino acid (AA) transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5-/- and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is directly regulated by Wnt/{beta}-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2 (VEGFR2). Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs. Significance StatementAmino acid metabolism in vascular endothelium is important for angiogenesis. SLC38A5 (solute carrier family 38 member 5) is an amino acid (AA) transporter for shuttling neutral AAs such as glutamine across cell membrane. Our work demonstrate that Slc38a5 is highly enriched in retinal vascular endothelium. SLC38A5 regulates endothelial cell glutamine uptake and vascular growth factor receptors to impact blood vessels growth in retinal development and in retinopathies. This work uncovered a novel role of SLC38A5 as a metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in blood vessel endothelium. Findings from this study also suggest that targeting SLC38A5 or relevant AAs can be a new way to protect against retinopathy.

developmental biology↗