Biology subjects

Zheng, Z.-Z.

Publications and source records attributed to Zheng, Z.-Z..

4 recordsLinked to original sources

bioRxiv2026

Glucose is a ligand-like trigger for secretion of postprandial GLP-1

Glucagon-like peptide 1 (GLP-1) is secreted from the intestinal L cells in a glucose-dependent manner. However, the mechanism underlying how glucose stimulates the secretion remains unclear. Here, we found that glucose at postprandial concentrations near the Km of GK for glucose ([~]10 mM), as well as nonmetabolizable glucose analogs, triggers GLP-1 secretion by intestinal L cells through directly binding to glucokinase (GK), without increasing intracellular ATP levels. We also show that in postprandially high glucose, glucose-bound GK interacts and inhibits KATP, as assessed by immunoprecipitation and FRET-FLIM analyses, as well as patch clamping. In addition, we have utilized GK mutants identified in diabetics, demonstrating that those mutants defective in binding to glucose impair GLP-1 secretion in however high glucose, whereas mutants constitutively bound to glucose with defects in catalysis, promote GLP-1 secretion even in low glucose. Furthermore, the KATP mutant unable to bind to GK blocks GLP-1 secretion in high glucose. We have also provided evidence showing that sodium-glucose cotransporter 1 (SGLT1) plays an important role in the basal secretion of GLP-1, but not in high glucose. We have thus revealed that glucose the molecule itself and GK act as a ligand and the receptor, respectively, to induce GLP-1 secretion in response to high glucose, providing new therapeutic avenues targeting metabolic diseases.

biochemistry↗

bioRxiv2024

AMPK acts to remove immune barriers to CD8+ T cell-mediated immunity against hepatocellular carcinoma

Dysregulated metabolism in tumor tissues, and para-tumor tissues alike, can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib that specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates the lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of HCC in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity towards HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We have further found that the HCC tissues in aldometanib-treated mice are massively infiltrated with CD8+ T cells, which is not seen in mice with liver-specific knockout of AMPK. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow the cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a life-long manageable disease, may potentially usher in a new era of cancer therapy.

immunology↗

bioRxiv2023

Lithocholic acid phenocopies rejuvenating and life-extending effects of calorie restriction

Calorie restriction (CR) is a dietary intervention to promote health and longevity. CR causes various metabolic changes in both the production and circulation of metabolites; however, it remains unclear which of the changed metabolite(s) can account for the physiological benefits of CR. Through metabolomic analysis of metabolites undergoing abundance changes during CR and subsequent functional validation, we found that lithocholic acid (LCA) is the only metabolite that alone can recapitulate the effects of CR, including activation of AMPK and the rejuvenating effects of muscle regeneration, grip strength and running capacity in mice. Interestingly, LCA also activates AMPK and exerts life- and health-extending effects in Caenorhabditis elegans and Drosophila melanogaster, indicating that these animal models are able to transmit the signalling of LCA once administered. Knockout of AMPK abrogates LCA-induced phenotypes, in nematodes and flies, as well as in mice. Together, we have identified that administration of the CR-upregulated metabolite LCA alone can confer anti-ageing benefits to metazoans, in an AMPK-dependent manner.

physiology↗

bioRxiv2022

New efficient intercellular spread mode of respiratory syncytial virus contributes to neutralization escape and persistence

There is no licensed vaccine or therapeutic antibody for respiratory syncytial virus (RSV). The induction of high-titer, potent neutralizing antibodies cannot completely inhibit breakthrough infection and enhanced respiratory disease (ERD), encouraging a focus on the relationship between virus intercellular spread and neutralizing antibodies. By blocking the known intercellular spread modes and with the aid of ultrahigh-resolution imaging, we observed a new efficient mode of intercellular spread in which RSV-infected cells directly transfer viral materials (including viral replication factories) to neighboring cells through protruding open-ended microfilament-rich intercellular nanotubes. The new mode is virion-independent and antibody-insensitive, beginning as early as 3 h post infection. Furthermore, replication-defective viral genomes (DVGs) might also utilize the new mode, facilitating the establishment of latent viral infections. Therefore, our data provide a new perspective on RSV cell-to-cell spread and might help to explain the immune escape and latent persistence of paramyxoviruses.

microbiology↗