Bromodomain and extra-terminal domain (BET) proteins, which function partly through MYC proto-oncogene (MYC), are critical epigenetic readers and emerging therapeutic targets in cancer. Whether and how BET inhibition simultaneously induces metabolic remodeling in cancer cells remains unclear. Here we find that even transient BET inhibition by JQ-1 and other pan-BET inhibitors (pan-BETis) blunts liver cancer cell proliferation and tumor growth. BET inhibition decreases glycolytic gene expression but enhances mitochondrial glucose and glutamine oxidative metabolism revealed by metabolomics and isotope labeling analysis. Specifically, BET inhibition downregulates miR-30a to upregulate glutamate dehydrogenase 1 (GDH1) independent of MYC, which produces α- ketoglutarate for mitochondrial oxidative phosphorylation (OXPHOS). Targeting GDH1 or OXPHOS is synthetic lethal to BET inhibition, and combined BET and OXPHOS inhibition therapeutically prevents liver tumor growth in vitro and in vivo. Together, we uncover an important epigenetic-metabolic crosstalk whereby BET inhibition induces MYC-independent and GDH1-dependent glutamine metabolic remodeling that can be exploited for innovative combination therapy of liver cancer.
It is crucial to understand the glucose control within our bodies. Bariatric/metabolic surgeries, including laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB), provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes (T2D). For the first time, a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics. Apolipoprotein A-IV (apoA-IV) was revealed to be increased dramatically in diabetic obese patients following LSG, and a similar effect was observed in patients after RYGB surgery. Moreover, recombinant apoA-IV protein treatment was proven to enhance insulin secretion in isolated human islets. These results showed that apoA-IV may play a crucial role in glycemic control in humans, potentially through enhancing insulin secretion in human islets. ApoA-IV was further shown to enhance energy expenditure and improve glucose tolerance in diabetic rodents, through stimulating glucose-dependent insulin secretion in pancreatic β cells, partially via Gαs-coupled GPCR/cAMP (G protein-coupled receptor/cyclic adenosine monophosphate) signaling. Furthermore, T55–121, truncated peptide 55–121 of apoA-IV, was discovered to mediate the function of apoA-IV. These collective findings contribute to our understanding of the relationship between apoA-IV and glycemic control, highlighting its potential as a biomarker or therapeutic target in managing and improving glucose regulation.
Distinct phospholipid species display specific distribution patterns across cellular membranes, which are important for their structural and signaling roles and for preserving the integrity and functionality of the plasma membrane and organelles. Recent advancements in lipid biosensor technology and imaging modalities now allow for direct observation of phospholipid distribution, trafficking, and dynamics in living cells. These innovations have markedly advanced our understanding of phospholipid function and regulation at both cellular and subcellular levels. Herein, we summarize the latest developments in phospholipid biosensor design and application, emphasizing the contribution of cutting-edge imaging techniques to elucidating phospholipid dynamics and distribution with unparalleled spatiotemporal precision.
Histone methylation plays a crucial role in tumorigenesis. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that regulates chromatin structure and gene expression. EZH2 inhibitors (EZH2is) have been shown to be effective in treating hematologic malignancies, while their effectiveness in solid tumors remains limited. One of the major challenges in the treatment of solid tumors is their hypoxic tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) is a key hypoxia responder that interacts with EZH2 to promote tumor progression. Here we discuss the implications of the relationship between EZH2 and hypoxia for expanding the application of EZH2is in solid tumors.
Atherosclerosis is the major contributor to cardiovascular mortality worldwide. Alternate day fasting (ADF) has gained growing attention due to its metabolic benefits. However, the effects of ADF on atherosclerotic plaque formation remain inconsistent and controversial in atherosclerotic animal models. The present study was designed to investigate the effects of ADF on atherosclerosis in apolipoprotein E-deficient (Apoe−/−) mice. Eleven-week-old male Apoe−/− mice fed with Western diet (WD) were randomly grouped into ad libitum (AL) group and ADF group, and ADF aggravated both the early and advanced atherosclerotic lesion formation, which might be due to the disturbed cholesterol profiles caused by ADF intervention. ADF significantly altered cholesterol metabolism pathways and down-regulated integrated stress response (ISR) in the liver. The hepatic expression of activating transcription factor 3 (ATF3) was suppressed in mice treated with ADF and hepatocyte-specific overexpression of Aft3 attenuated the effects of ADF on atherosclerotic plaque formation in Apoe−/− mice. Moreover, the expression of ATF3 could be regulated by Krüppel-like factor 6 (KLF6) and both the expressions of ATF3 and KLF6 were regulated by hepatic cellular ISR pathway. In conclusion, ADF aggravates atherosclerosis progression in Apoe−/− mice fed on WD. ADF inhibits the hepatic ISR signaling pathway and decreases the expression of KLF6, subsequently inhibiting ATF3 expression. The suppressed ATF3 expression in the liver mediates the deteriorated effects of ADF on atherosclerosis in Apoe−/− mice. The findings suggest the potentially harmful effects when ADF intervention is applied to the population at high risk of atherosclerosis.
Skeletal muscle plays a vital role in the regulation of systemic metabolism, partly through its secretion of endocrine factors which are collectively known as myokines. Altered myokine levels are associated with metabolic diseases, such as type 2 diabetes (T2D). The significance of interorgan crosstalk, particularly through myokines, has emerged as a fundamental aspect of nutrient and energy homeostasis. However, a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major challenge. In this review, we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades, namely interleukin 6 (IL-6), irisin, myostatin (MSTN), growth differentiation factor 11 (GDF11), fibroblast growth factor 21 (FGF21), apelin, brain-derived neurotrophic factor (BDNF), meteorin-like (Metrnl), secreted protein acidic and rich in cysteine (SPARC), β-aminoisobutyric acid (BAIBA), Musclin, and Dickkopf 3 (Dkk3). Related to these, we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and disease. Despite significant advancements in myokine research, many myokines remain challenging to measure accurately and investigate thoroughly. Hence, new research techniques and detection methods should be developed and rigorously tested. Therefore, developing a comprehensive perspective on myokine biology is crucial, as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.
Major life transitions are always difficult because change costs energy. Recent findings have demonstrated how mitochondrial oxidative phosphorylation (OxPhos) defects increase the energetic cost of living and that excessive integrated stress response (ISR) signaling may prevent cellular identity transitions during development. In this perspective, we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity. The energetic cost of cellular differentiation has not been directly quantified, representing a gap in knowledge. We propose that the ISR is an energetic checkpoint evolved to (i) prevent OxPhosdeficient cells from engaging in excessively costly transitions and (ii) allow ISRpositive cells to recruit systemic energetic resources by signaling via GDF15 and the brain.
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 tests 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.