ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells

Glioblastoma(GBM)is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment(TME).In this environment,myeloid cells,such as myeloid-derived suppressor cells(MDSCs),play a pivotal role in suppressing antitumor immunity.Lipometabolism is closely related to the function of myeloid cells.Here,our study reports that acetyl-CoA acetyltransferase 1(ACAT1),the key enzyme of fatty acid oxidation(FAO)and ketogenesis,is significantly downregulated in the MDSCs infiltrated in GBM patients.To investigate the effects of ACAT1 on myeloid cells,we generated mice with myeloid-specific(LyzM-cre)depletion of ACAT1.The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically.The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1(CXCLI)of macrophages(Mo).Overall,our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

Reconciling host-microbiota metabolic incompatibility safeguards male fertility

The symbiotic relationship between the host and microbiota is widely acknowledged as mutually beneficial.However,due to significant differences in metabolic substrates and products between prokaryotic bacteria and mammalian cells,mechanisms must exist to reconcile the metabolic incompatibility between the host and microbiota.We report that host enzymes are required to detoxify gut microbiota-derived acetate to maintain male fertility in mice.The combined deletion of acetyl-CoA synthetase short-chain family member 1 and 2(ACSS1 and ACSS2),two enzymes consuming acetate in mammals,leads to excessive accumulation of acetate in circulation.This accumulation causes metabolic acidosis,blocking spermatogenesis and rendering male mice infertile.ACSS1/2-deficient germ cells exhibit comprehensive metabolic alterations with nicotinamide adenine dinucleotide(NAD+)deficiency that impairs betaine production.Supplementation with betaine restores spermatogenesis and fertility in ACSS1/2-deficient mice.Thus,the inevitable production of acetate by gut bacteria and its reproductive toxicity to the host represents an unappreciated metabolic incompatibility between the host and microbiota,which is reconciled by ACSS1/2.

Modulation of Guard Cell Turgor and Drought Folerance by a Peroxisomal Acetate-Malate Shunt

In plants, stomatal movements are tightly controlled by changes in cellular turgor pressure. Carbohydrates produced by glycolysis and the tricarboxylic acid cycle play an important role in regulating turgor pressure. Here, we describe anArabidopsis mutant, bzul, isolated in a screen for elevated leaf temperature in response to drought stress, which displays smaller stomatal pores and higher drought resistance than wild-type plants. BZU1 encodes a known acetyl-coenzyme A synthetase, ACN1, which acts in the first step of a metabolic pathway converting acetate to malate in peroxisomes. We showed that BZUl/ACNl-mediated acetate-to-malate conversion provides a shunt that plays an important role in osmoregulation of stomatal turgor. We found that the smaller stomatal pores in the bzul mutant are a consequence of reduced accumu- lation of malate, which acts as an osmoticum and/or a signaling molecule in the control of turgor pressure within guard cells, and these results provided new genetic evidence for malate-regulated stomatal movement. Collectively, our results indicate that a peroxisomal BZUl/ACNl-mediated acetate--malate shunt regulates drought resistance by controlling the turgor pressure of guard cells in Arabidopsis.