The dynamic changes in lipids during early embryonic development in mammals have not yet been comprehensively investigated. In a recent paper published in Nature Cell Biology, Jin Zhang et al. reported the dynamic lipid landscapes during preimplantation embryonic development in mice and humans. They highlight the crucial role of lipid unsaturation in regulating embryogenesis.
Ruoxi Zhang, Guido Kroemer, Daolin Tang·06 Mar 2024
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Ferroptosis, characterized by lipid peroxidation-mediated cell demise, is governed by a nuanced interplay of lipid species influencing its vulnerability. Two recent publications in Nature discovered 7-dehydrocholesterol, a cholesterol precursor, as a radical-trapping antioxidant that can suppress ferroptosis, thereby presenting a novel metabolic target to improve ferroptosis-related cancer therapy.
Yang Liu, Shu-Wen Qian, Yan Tang, Qi-Qun Tang·20 Jan 2024
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In addition to their pivotal roles in energy storage and expenditure, adipose tissues play a crucial part in the secretion of bioactive molecules, including peptides, lipids, metabolites, and extracellular vesicles, in response to physiological stimulation and metabolic stress. These secretory factors, through autocrine and paracrine mechanisms, regulate various processes within adipose tissues. These processes include adipogenesis, glucose and lipid metabolism, inflammation, and adaptive thermogenesis, all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment. A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite, cognitive function, energy expenditure, insulin secretion and sensitivity, gluconeogenesis, cardiovascular remodeling, and exercise capacity. In this review, we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating metabolic homeostasis. Furthermore, we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions, shedding light on potential pharmacological treatment strategies for related diseases.
Isocitrate dehydrogenase (IDH) mutations frequently occurr in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) is a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH results in the accumulation of α-KG and promotes astrocyte maturation. However, IDH1 mutation significantly reduces α-KG levels, and increases glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibit astrocyte maturation, and lead to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-K and increasing glutaminolysis. Finally, we found that L-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.
Jie Li, Yue Dong, Tianxing Zhou, He Tian, Xiahe Huang, Yong Q Zhang, Yingchun Wang, Sin Man Lam, Guanghou Shui·18 Jan 2024
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Interorgan lipid transport is crucial for organism development and the maintenance of physiological function. Here, we demonstrate that Drosophila long-chain acyl-CoA synthetase (dAcsl), which catalyzes the conversion of fatty acids into acyl-coenzyme As (acyl-CoAs), plays a critical role in regulating systemic lipid homeostasis. dAcsl deficiency in the fat body leads to the ectopic accumulation of neutral lipids in the gut, along with significantly reduced lipoprotein contents in both the fat body and hemolymph. The aberrant phenotypes were rescued by fat body-specific overexpression of apolipophorin. A multi-omics investigation comprising lipidomics, metabolomics, and proteomics in conjunction with genetic screening revealed that glycosylation processes were suppressed in dAcsl knockdowns. Overexpression of CG9035, human ortholog of which is implicated in the congenital disorder of glycosylation, ameliorated gut lipid accumulation in Drosophila. Aberrant lipoprotein glycosylation led to accelerated proteasome-related degradation and induced ER stress in dAcsl knockdown flies, impairing lipoprotein release into the circulation which compromised interorgan lipid transport between the fat body and the gut. Inhibition of ubiquitin-proteasome-dependent degradation alleviated the phenotype of gut ectopic fat accumulation in dAcsl knockdowns. Finally, we verified that ACSL4, the human homolog of dAcsl, also regulated lipoprotein levels in HepG2 cells, indicating that the role of dAcsl in modulating lipoprotein secretion and systemic lipid homeostasis is possibly conserved in humans.
Tongxing Song, Ming Qi, Yucheng Zhu, Nan Wang, Zhibo Liu, Na Li, Jiacheng Yang, Yanxu Han, Jing Wang, Shiyu Tao, Zhuqing Ren, Yulong Yin, Jinshui Zheng, Bie Tan·17 Jan 2024
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Postnatal growth retardation (PGR) frequently occurs during early postnatal development of piglets and induces high mortality. To date, the mechanism of PGR remains poorly understood. Adipose tissue-derived microbes have been documented to be associated with several disorders of metabolism and body growth. However, the connection between microbial disturbance of adipose tissue and pig PGR remains unclear. Here, we investigated piglets with PGR, and found that the adipose tissue of PGR piglets was characterized by metabolism impairment, adipose abnormality, and specific enrichment of culturable bacteria from Proteobacteria. Gavage of Sphingomonas paucimobilis, a species of Sphingomonas genus from the alphaproteobacteria, induced PGR in piglets. Moreover, this bacterium could also lead to metabolic disorders and susceptibility to acute stress, resulting in weight loss in mice. Mechanistically, multi-omics analysis indicated the changes in lipid metabolism as a response of adipose tissue to abnormal microbial composition. Further experimental test proved that one of the altered lipids phosphatidylethanolamines could rescue the metabolism disorder and growth retardation, thereby suppressing the amount of Sphingomonas in the adipose tissue. Together, these results highlight that the microbe-host crosstalk may regulate the metabolic function of adipose tissue in response to PGR.
