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High fructose promotes MYCN-amplified neuroblastoma progression through NgBR-ACSS2-mediated biosynthesis of acetyl-CoA
Hu, Wenquan; Wang, Xiang; Fang, Zhi; Zhang, Jing; Tirumalasetty, Munichandra Babu; Miao, Qing Robert
MYCN amplification, a characteristic of aggressive neuroblastoma, presents therapeutic challenges. This study uncovered the potential effects of a fructose metabolite, acetate, on the transcriptional regulation of MYCN expression, which is still largely unexplored. We elucidated the pivotal role of acyl-coenzyme A (acyl-CoA) synthetase short-chain family member 2 (ACSS2), found to be heightened in MYCN-amplified neuroblastoma. We demonstrated that ACSS2 enhanced MYCN gene transcription and growth of MYCN-amplified neuroblastoma. Our results revealed a new mechanism wherein ACSS2 orchestrates MYCN transcription by escalating acetyl-CoA levels and histone acetylation, hinting at a metabolic participation in forcibly dictating MYCN regulation. We further demonstrated that fructose or acetate exacerbated neuroblastoma growth, which can be halted by the ACSS2 inhibitor. We further identified the Nogo-B receptor (NgBR) as the trigger for ACSS2 induction through the Akt-SREBP-1 pathway. Our findings propose NgBR as a novel therapeutic target, emphasizing the promising potential of metabolic therapies for managing aggressive MYCN-amplified neuroblastoma.
PMID: 40616844
ISSN: 2211-1247
CID: 5888662
ACSS2 protects against alcohol-induced hepatocyte ferroptosis through regulation of hepcidin expression
Wang, Mengyao; Wen, Xiao; Feng, Zian; Choubey, Mayank; Chen, Shasha; Pan, Ruru; Gong, Ke; Tirumalasetty, Munichandra Babu; Gao, Fei; Liao, Chenzhong; Yin, Zequn; Zhang, Shuang; He, Yong; Chen, Houzao; Cao, Yang; Miao, Qing Robert; Hu, Wenquan; Duan, Yajun
Acetate is the end product of alcohol metabolism. Acyl-CoA synthetase short-chain family member 2 (ACSS2) converts acetate to acetyl-CoA, involving metabolic pathways and epigenetic regulation. However, the function of ACSS2-mediated epigenetic control in alcoholic liver disease (ALD) remains incompletely understood. We demonstrate that alcohol downregulates hepatic ACSS2, causing acetate accumulation in the liver and serum. This disrupts iron metabolism and hepatic ferroptosis, triggering liver injury and inflammation. Mechanistically, ACSS2 binds CREB binding protein (CBP) to mediate histone acetylation and regulate hepcidin antimicrobial peptide 1/2 (HAMP1/2) transcription. ACSS2 deficiency downregulates HAMP1/2, causing systemic iron dyshomeostasis and ferroptosis, which is restored by overexpression of HAMP1/2. Iron chelators or ferroptosis inhibitors attenuates alcohol-induced liver injury in ACSS2-deficient mice. Our study uncovers the epigenetic mechanisms of ACSS2-mediated ferroptosis and its role in ALD progression.
PMCID:12215787
PMID: 40593779
ISSN: 2041-1723
CID: 5887852
Correction: A Longer Biliopancreatic Limb and Shorter Common Channel Enhance Weight Loss But May Have Harmful Effects in Mouse Models of Roux-en-Y Gastric Bypass
Lau, Raymond; Stevenson, Matthew; Tirumalasetty, Munichandra Babu; Lee, Jenny; Hall, Christopher; Miao, Qing; Brathwaite, Collin; Ragolia, Louis
PMID: 39612057
ISSN: 1708-0428
CID: 5780012
A Longer Biliopancreatic Limb and Shorter Common Channel Enhance Weight Loss But May Have Harmful Effects in Mouse Models of Roux-en-Y Gastric Bypass
Lau, Raymond; Stevenson, Matthew; Tirumalasetty, Munichandra Babu; Lee, Jenny; Hall, Christopher; Miao, Qing; Brathwaite, Collin; Ragolia, Louis
BACKGROUND:RYGB consists of the Roux limb (RL), the biliopancreatic limb (BPL), and the common channel (CC). There is no consensus on the optimal limb lengths. METHODS:Using a mouse model of RYGB, 30 diet-induced obese mice were divided into two groups with varying BPL and CC lengths: a standard BPL with a long CC (RYGB S) and a long BPL with a short CC (RYGB L). Additionally, 9 age-matched, lean control mice (LC) were also included in this study. RESULTS:RYGB S had limb lengths of RL = 17%, BPL = 24%, and CC = 59%. RYGB L had limb lengths of RL = 17%, BPL = 32%, and CC = 51%. RYGB S and RYGB L had 67% and 40% survival, respectively. Mortality in RYGB L included more instances where the cause of death was not apparent. RYGB L demonstrated greater weight loss, lower energy expenditure, and lower heart mass as compared to RYGB S. Both RYGB groups had lower epidydimal fat mass, spleen mass, and bone mineral density compared to LC. RYGB L had a lower heart mass than RYGB S and LC. While the relative abundance of Eubacterium was lower in RYGB L than in RYGB S, no other gut microbiota differences were observed. CONCLUSIONS:A longer BPL with a shorter CC induces greater weight loss but may lead to adverse effects, including lower heart mass, reduced bone density, and deaths with unclear causes.
PMID: 39516446
ISSN: 1708-0428
CID: 5752272
Editorial: Community series in epigenetic regulation in cardiovascular diseases, volume III [Editorial]
Wang, Zhihua; Miao, Qing Robert; Xu, Suowen; Pillai, Indulekha C L; Rau, Christoph D
PMCID:11059069
PMID: 38689860
ISSN: 2297-055x
CID: 5734192
Transcription factor 21 accelerates vascular calcification in mice by activating the IL-6/STAT3 signaling pathway and the interplay between VSMCs and ECs
Zhao, Xiao-Kang; Zhu, Meng-Meng; Wang, Sheng-Nan; Zhang, Ting-Ting; Wei, Xiao-Ning; Wang, Cheng-Yi; Zheng, Juan; Zhu, Wen-Ya; Jiang, Mei-Xiu; Xu, Suo-Wen; Yang, Xiao-Xiao; Duan, Ya-Jun; Zhang, Bu-Chun; Han, Ji-Hong; Miao, Qing R; Hu, Hao; Chen, Yuan-Li
Vascular calcification is caused by the deposition of calcium salts in the intimal or tunica media layer of the aorta, which increases the risk of cardiovascular events and all-cause mortality. However, the mechanisms underlying vascular calcification are not fully clarified. Recently it has been shown that transcription factor 21 (TCF21) is highly expressed in human and mouse atherosclerotic plaques. In this study we investigated the role of TCF21 in vascular calcification and the underlying mechanisms. In carotid artery atherosclerotic plaques collected from 6 patients, we found that TCF21 expression was upregulated in calcific areas. We further demonstrated TCF21 expression was increased in an in vitro vascular smooth muscle cell (VSMC) osteogenesis model. TCF21 overexpression promoted osteogenic differentiation of VSMC, whereas TCF21 knockdown in VSMC attenuated the calcification. Similar results were observed in ex vivo mouse thoracic aorta rings. Previous reports showed that TCF21 bound to myocardin (MYOCD) to inhibit the transcriptional activity of serum response factor (SRF)-MYOCD complex. We found that SRF overexpression significantly attenuated TCF21-induced VSMC and aortic ring calcification. Overexpression of SRF, but not MYOCD, reversed TCF21-inhibited expression of contractile genes SMA and SM22. More importantly, under high inorganic phosphate (3 mM) condition, SRF overexpression reduced TCF21-induced expression of calcification-related genes (BMP2 and RUNX2) as well as vascular calcification. Moreover, TCF21 overexpression enhanced IL-6 expression and downstream STAT3 activation to facilitate vascular calcification. Both LPS and STAT3 could induce TCF21 expression, suggesting that the inflammation and TCF21 might form a positive feedback loop to amplify the activation of IL-6/STAT3 signaling pathway. On the other hand, TCF21 induced production of inflammatory cytokines IL-1β and IL-6 in endothelial cells (ECs) to promote VSMC osteogenesis. In EC-specific TCF21 knockout (TCF21ECKO) mice, VD3 and nicotine-induced vascular calcification was significantly reduced. Our results suggest that TCF21 aggravates vascular calcification by activating IL-6/STAT3 signaling and interplay between VSMC and EC, which provides new insights into the pathogenesis of vascular calcification. TCF21 enhances vascular calcification by activating the IL-6-STAT3 signaling pathway. TCF21 inhibition may be a new potential therapeutic strategy for the prevention and treatment of vascular calcification.
PMCID:10374894
PMID: 36997664
ISSN: 1745-7254
CID: 5594902
Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway
Liu, Chang; Li, Sijie; Zhang, Xiaoxiao; Jin, Chunxiang; Zhao, Baofeng; Li, Liying; Miao, Qing Robert; Jin, Ying; Fan, Zhimin
Chemotherapy can improve the prognosis and overall survival of breast cancer patients, but chemoresistance continues a major problem in clinical. Most breast cancer is estrogen receptor (ER) positive but responds less to neoadjuvant or adjuvant chemotherapy than ER-negative breast cancer. The Nogo-B receptor (NgBR) increases the chemoresistance of ER-positive breast cancer by facilitating oncogene signaling pathways. Here, we further investigated the potential role of NgBR as a novel target to overcome glycolysis-dependent paclitaxel resistance in ER-positive breast cancer. NgBR knockdown inhibited glycolysis and promoted paclitaxel-induced apoptosis by attenuating HIF-1α expression in ER-positive breast cancer cells via NgBR-mediated estrogen receptor alpha (ERα)/hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor-kappa B subunit (NF-κB)/HIF-1α signaling pathways. A ChIP assay further confirmed that NgBR overexpression not only facilitates ERα binding to HIF-1α and GLUT1 genes but also promotes HIF-1α binding to GLUT1, HK2, and LDHA genes, which further promotes glycolysis and induces paclitaxel resistance. In conclusion, our study suggests that NgBR expression is essential for maintaining the metabolism and paclitaxel resistance of ER-positive breast cancer, and the NgBR can be a new therapeutic target for improving chemoresistance in ER-positive breast cancer.
PMID: 36241702
ISSN: 1476-5500
CID: 5352232
Correction to: Nogo-B receptor increases glycolysis and the paclitaxel resistance of estrogen receptor-positive breast cancer via the HIF-1α-dependent pathway
Liu, Chang; Li, Sijie; Zhang, Xiaoxiao; Jin, Chunxiang; Zhao, Baofeng; Li, Liying; Miao, Qing Robert; Jin, Ying; Fan, Zhimin
PMID: 36376422
ISSN: 1476-5500
CID: 5384762
Overexpression of NgBR inhibits high-fat diet-induced atherosclerosis in ApoE-deficiency mice
Gong, Ke; Wang, Mengyao; Wang, Dandan; Gao, Yongyao; Ma, Likun; Yang, Xiaoxiao; Zhu, Xinran; Chen, Shasha; Zhang, Mengxue; Li, Huaxin; Chen, Yuanli; Hu, Wenquan; Miao, Qing R; Iwakiri, Yasuko; Liao, Chenzhong; Duan, Yajun; Han, Jihong
BACKGROUND:Hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) is a risk factor for atherosclerosis. Nogo-B receptor (NgBR) plays important roles in hepatic steatosis and cholesterol transport. However, the effect of NgBR overexpression on atherosclerosis remains unknown. MATERIALS AND METHODS:Apolipoprotein E deficient (ApoE-/-) mice infected with adeno-associated virus (AAV)-NgBR expression vector were fed a high-fat diet for 12 weeks, followed by determination of atherosclerosis and the involved mechanisms. RESULTS:We determined that high expression of NgBR by AAV injection mainly occurs in the liver and it can substantially inhibit en face and aortic root sinus lesions. NgBR overexpression also reduced levels of inflammatory factors in the aortic root and serum, and levels of cholesterol, triglyceride, and free fatty acids in the liver and serum. Mechanistically, NgBR overexpression increased the expression of scavenger receptor type BI and the genes for bile acid synthesis, and decreased the expression of cholesterol synthesis genes by reducing sterol regulatory element-binding protein 2 maturation in the liver, thereby reducing hypercholesterolemia. In addition, NgBR overexpression activated AMP-activated protein kinase α via the Ca2+ signaling pathway, which inhibited fat synthesis and improved hypertriglyceridemia. CONCLUSIONS:Taken together, our study demonstrates that overexpression of NgBR enhanced cholesterol metabolism and inhibited cholesterol/fatty acid synthesis to reduce hyperlipidemia, and reduced vascular inflammation, thereby inhibiting atherosclerosis in ApoE-/- mice. Our study indicates that NgBR might be a potential target for atherosclerosis treatment.
PMCID:10069848
PMID: 36996002
ISSN: 2471-254x
CID: 5468402
Overexpression of NgBR inhibits high-fat diet-induced atherosclerosis in ApoE-deficiency mice
Gong, Ke; Wang, Mengyao; Wang, Dandan; Gao, Yongyao; Ma, Likun; Yang, Xiaoxiao; Zhu, Xinran; Chen, Shasha; Zhang, Mengxue; Li, Huaxin; Chen, Yuanli; Hu, Wenquan; Miao, Qing R.; Iwakiri, Yasuko; Liao, Chenzhong; Duan, Yajun; Han, Jihong
ISI:001159566400001
CID: 5636612