Nucleotide metabolism is linked to cysteine availability.

The small molecule erastin inhibits the cystine-glutamate antiporter, system xc-, which leads to intracellular cysteine and glutathione depletion. This can cause ferroptosis, which is an oxidative cell death process characterized by uncontrolled lipid peroxidation. Erastin and other ferroptosis inducers have been shown to affect metabolism but the metabolic effects of these drugs have not been systematically studied. To this end, we investigated how erastin impacts global metabolism in cultured cells and compared this metabolic profile to that caused by the ferroptosis inducer RAS-selective lethal 3 or in vivo cysteine deprivation. Common among the metabolic profiles were alterations in nucleotide and central carbon metabolism. Supplementing nucleosides to cysteine-deprived cells rescued cell proliferation in certain contexts, showing that these alterations to nucleotide metabolism can affect cellular fitness. While inhibition of the glutathione peroxidase GPX4 caused a similar metabolic profile as cysteine deprivation, nucleoside treatment did not rescue cell viability or proliferation under RAS-selective lethal 3 treatment, suggesting that these metabolic changes have varying importance in different scenarios of ferroptosis. Together, our study shows how global metabolism is affected during ferroptosis and points to nucleotide metabolism as an important target of cysteine deprivation.

The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1.

Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2) functions as a mediator of mTOR signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.

Methionine restriction and antitumor immunity.

Fang et al. recently reported in Cancer Cell that methionine restriction increases antitumor immunity by enhancing cyclic GMP-AMP synthase (cGAS) activity and promoting its dissociation from chromatin. This finding identifies a potential strategy to target cGAS demethylation in cancer therapy by altering methionine metabolism.

Methionine availability influences essential H3K36me3 dynamics during cell differentiation.

Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2. Methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.

Polystyrene microplastics trigger adiposity in mice by remodeling gut microbiota and boosting fatty acid synthesis.

Microplastic (MP) pollution has become a global environmental problem, with particular concerns for its harmful effects on human health. Several studies have demonstrated that MP can penetrate animals and humans resulting in tissue dysfunction, but their influences on metabolism remain poorly understood. In this study, we investigated the impact of MP exposure on metabolism and the results showed that different treatment doses produce a bidirectional modulatory effects on mice. When exposed to high concentrations of MP, mice lost significant weight, while those in the lowest concentration treatment group showed little change, but those treated at relatively low concentrations became overweight. There was excessive lipid accumulation in these heavier mice, with a better appetite and lower activity level. Transcriptome sequencing revealed that MPs increased fatty acid synthesis in the liver. In addition, the gut microbiota composition of the MPs-induced obese mice was remodeled, which would enhance the nutrient absorption capacity of the intestine. Our results uncovered an MP dose-dependent lipid metabolism in mice and a non-unidirectional model of the physiological responses to different MP concentrations was proposed. These results provided new insights into the seemingly contradictory effects of MP on metabolism in the previous study.

Polyethylene microplastics impede the innate immune response by disrupting the extracellular matrix and signaling transduction.

Microplastics (MPs) can accumulate in animal organs. Numerous studies have linked MPs with immune system. However, the impact of MPs on immune response remains unclear. This study examined the innate immune response of mice exposed to 5 µm MPs. In the lipopolysaccharide challenge, mice treated with MPs exhibited lower levels of serum immune factors and activated immune cells. MPs disrupted immune-related receptors and cause dysfunction in cell signal transduction within the liver and spleen. Proteomic analysis revealed that MPs impede the activation of serum immune-related signals. In addition, the tissue section imaging exhibited a significant enrichment of MPs in the extracellular matrix (ECM), consistent with the ECM dysfunction and immune receptor suppression. Therefore, our data suggest excessive MPs accumulation in ECM inhibits cell signaling pathways, thereby suppressing the activation of immune responses. We propose the biotoxicity of MPs is partly through the MP disruption of ECM (MPDEM).

OLFR734 Mediates Glucose Metabolism as a Receptor of Asprosin.

Asprosin is a fasting-induced hormone that promotes glucose production in the liver and stimulates appetite in the hypothalamus by activating the cAMP signaling pathway via an unknown G protein-coupled receptor (GPCR). However, the bona fide receptor of Asprosin is unclear. Here, we have identified that the olfactory receptor OLFR734 acts as a receptor of Asprosin to modulate hepatic glucose production. Olfr734 knockout mice show a blunted response to Asprosin, including attenuated cAMP levels and hepatic glucose production, and improved insulin sensitivity. As Olfr734 deficiency dramatically attenuates both fasting and high-fat-diet-induced glucose production, our results demonstrate a critical role of OLFR734 as a receptor of Asprosin to maintain glucose homeostasis during fasting and in obesity.