bims-amsmem 2022-09-04 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022‒09‒04
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.
Activation of AMP-activated protein kinase ablated the formation of aortic dissection by suppressing vascular inflammation and phenotypic switching of vascular smooth muscle cells.
GnRH receptor mediates lipid storage in female adipocytes via AMPK pathway.
Salvianolic acid A promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes through regulation of the AMPK-PGC1α signalling pathway.
Benzoylaconine improves mitochondrial function in oxygen-glucose deprivation and reperfusion-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis.
PACAP attenuates hepatic lipid accumulation through the FAIM/AMPK/IRβ axis during overnutrition.
CIDEA Regulates De Novo Fatty Acid Synthesis in Bovine Mammary Epithelial Cells by Targeting the AMPK/PPARγ Axis and Regulating SREBP1.
SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice.
Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK-dependent mechanisms.
Isoginkgetin, a Potential CDK6 Inhibitor, Suppresses SLC2A1/GLUT1 Enhancer Activity to Induce AMPK-ULK1-Mediated Cytotoxic Autophagy in Hepatocellular Carcinoma.
miRNA-323a-3p promoted intracranial, aneurysm-induced inflammation via AMPK/NF-κB signaling pathway by AdipoR1.
Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis.
The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway.

Biochim Biophys Acta Rev Cancer. 2022 Aug 27. pii: S0304-419X(22)00110-X. [Epub ahead of print]1877(5): 188785

AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene.

Vasudevarao Penugurti, Yasaswi Gayatri Mishra, Bramanandam Manavathi.

Metabolic reprogramming is a unique but complex biochemical adaptation that allows solid tumors to tolerate various stresses that challenge cancer cells for survival. Under conditions of metabolic stress, mammalian cells employ adenosine monophosphate (AMP)-activated protein kinase (AMPK) to regulate energy homeostasis by controlling cellular metabolism. AMPK has been described as a cellular energy sensor that communicates with various metabolic pathways and networks to maintain energy balance. Earlier studies characterized AMPK as a tumor suppressor in the context of cancer. Later, a paradigm shift occurred in support of the oncogenic nature of AMPK, considering it a contextual oncogene. In support of this, various cellular and mouse models of tumorigenesis and clinicopathological studies demonstrated increased AMPK activity in various cancers. This review will describe AMPK's pro-tumorigenic activity in various malignancies and explain the rationale and context for using AMPK inhibitors in combination with anti-metabolite drugs to treat AMPK-driven cancers.

DOI: https://doi.org/10.1016/j.bbcan.2022.188785
Int Immunopharmacol. 2022 Aug 29. pii: S1567-5769(22)00661-0. [Epub ahead of print]112 109177

Activation of AMP-activated protein kinase ablated the formation of aortic dissection by suppressing vascular inflammation and phenotypic switching of vascular smooth muscle cells.

Lei Lei, Yanrong Zhou, Tiemao Wang, Zhi Zheng, Liang Chen, Youmin Pan.

  BACKGROUND: Aortic dissection (AD) is a fatal vascular disease in absence of effective pharmaceutical therapy. Adenosine monophosphate-activated protein kinase α (AMPKα) plays a critical role in various cardiovascular diseases. Whether AMPKα is involved in the pathogenesis of aortic dissection remains unknown. We aimed to determine whether activation of AMPKα prevents the formation of AD.METHODS AND RESULTS: Reduced expression of phosphorylated AMPKα (Thr172) and exacerbated phenotypic switching were observed in human aortic tissues from aortic dissection patients compared with those in tissues from controls. In vivo, the formation of aortic dissection in ApoE-/- mice was successfully induced by continuous infusion of angiotensin II (AngII) for two weeks, characterized by the activation of vascular inflammation, infiltration of macrophages and phenotypic switching of vascular smooth muscle cells (VSMCs). rAAV2-mediated overexpression of constitutively active AMPKα (CA-AMPKα) enhanced the expression of phosphorylated AMPKα (Thr172) and attenuated AngII-induced occurrence of aortic dissection by suppressing the infiltration of macrophages, activation of vascular inflammation and phenotypic switching of VSMCs. The pathogenesis above was conversely exacerbated by rAAV2-mediated overexpression of dominant negative AMPKα2 (DN-AMPKα). In vitro, we demonstrated that the administration of an AMPK agonist (AICAR) or transfection of CA-AMPKα induced the activation of AMPKα and then ameliorated AngII-induced phenotypic switching in the VSMCs and inflammation in the bone marrow-derived macrophages (BMDMs). This could be reversed by the addition of AMPK inhibitor compound C or transfection of DN-AMPKα.
CONCLUSION: Impaired activation of AMPKα may increase the susceptibility to aortic dissection. Our findings verified the protective effects of AMPKα on the formation of aortic dissection and may provide evidence for clinical prevention or treatment.

Keywords:  AMPKα; Aortic dissection; Inflammation; Phenotypic switching

DOI:  https://doi.org/10.1016/j.intimp.2022.109177
Int J Med Sci. 2022 ;19(9): 1442-1450

GnRH receptor mediates lipid storage in female adipocytes via AMPK pathway.

Xiaoyong Li, Xueyan Zhang, Zhaojun Shen, Zhengyun Chen, Hanzhi Wang, Xinmei Zhang.

  Objective: Due to high levels of serum gonadotropin-releasing hormone (GnRH), perimenopausal or menopausal women, girls with central precocious puberty, women of polycystic ovary syndrome, and females receiving long-term GnRH agonist (GnRHa) treatment are at substantially higher risk of developing obesity. However, it remains poorly understood how GnRH affects body weight. Here, we explored whether the gonadotropin-releasing hormone receptor (GnRHR) was expressed in adipocytes and how GnRHR mediated lipid accumulation and the development of obesity. Methods: The samples were from 18 patients with benign tumors operated between 01/2018 and 06/2018 at the Women's Hospital School of Medicine Zhejiang University. Immunofluorescence, Western Blotting, and RT-PCR were used to detect whether the GnRH receptor was expressed in the specimens and human preadipocytes-subcutaneous (HPA-s). The GnRH receptor agonist diphereline with different concentrations was used to stimulate the HPA-s cells for 24, 48, and CCK-8 was used to detect cell proliferation. Oil red-O staining was used to detect lipid droplets in mature adipocytes. The phosphorylation of AMPK-Ser485/Thr172 was detected by Western Blotting. Results: GnRH receptor was expressed in all 18 human subcutaneous adipose tissue specimens. Cultured HPA-s expressed the GnRH receptor, and the expression increased during the process of cell maturation. The GnRH receptor agonist diphereline can stimulate the proliferation of HPA-s cells, which can advance the earliest occurrence of lipid droplets in HPA-s cells and the occurrence of lipid droplets in 50% cells by 1-2 days. Diphereline can stimulate the increase in the number of lipid droplets in mature adipocytes. The phosphorylation level of AMPK-Ser485/Thr172 in mature adipocytes was decreased by diphereline. Conclusion: The GnRH receptor was expressed in adipocytes. As adipocytes mature, GnRH receptor expression gradually increased. GnRHa stimulates the proliferation of HPA-s, promotes adipocyte maturation, increases the formation of lipid droplets in mature adipocytes, and inhibits the activation of the AMPK pathway in adipocytes. Our findings may elucidate the mechanism of obesity in these female populations and provide some evidence on how GnRH contributes to obesity. Additionally, these results provide theoretical support for further research on the mechanisms of obesity, thus enhancing our understanding of the functional diversity of GnRH and establishing a new theoretical basis for the impact of GnRH on metabolism.

Keywords:  AMP-activated protein kinases; Gonadotropin-releasing hormone; adipocytes; gonadotropin-releasing hormone receptor; obesity; women

DOI:  https://doi.org/10.7150/ijms.74335
Adipocyte. 2022 Dec;11(1): 562-571

Salvianolic acid A promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes through regulation of the AMPK-PGC1α signalling pathway.

Jialin Sun, Ping Leng, Xiao Li, Qie Guo, Jun Zhao, Yu Liang, Xiaolei Zhang, Xue Yang, Jing Li.

  Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes (T2DM). Decreased mitochondrial abundance and function were found in white adipose tissue (WAT) of T2DM patients. Therefore, promoting WAT mitochondrial biogenesis and improving adipocyte metabolism may be strategies to prevent and reverse T2DM. Salvianolic acid A (SAA) has been found to exert anti-diabetic and lipid disorder-improving effects. However whether SAA benefits mitochondrial biogenesis and function in adipose tissue is unclear. Here, we evaluated SAA's effect on mitochondrial biogenesis and function in 3T3-L1 adipocytes and investigated its potential regulatory mechanism. Results showed that SAA treatment significantly promoted the transcription and expression of peroxisome proliferator-activated receptor γ coactivator- 1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Meanwhile, SAA treatment significantly promoted mitochondrial biogenesis by increasing mitochondrial DNA (mtDNA) quantity, mitochondrial mass, and expression of mitochondrial respiratory chain enzyme complexes III and complex IV. These enhancements were accompanied by enhanced phosphorylation of AMPK and ACC and were suppressed by Compound C, a specific AMPK inhibitor. Furthermore, SAA treatment improved adipocytes mitochondrial respiration and stimulated ATP generation. These findings indicate that SAA exerts a potential therapeutic capacity against adipocytes mitochondrial dysfunction in diabetes by activating the AMPK-PGC-1α pathway.

Keywords:  3T3-L1 adipocytes; AMPK; PGC-1α; Salvianolic acid A; mitochondrial biogenesis; mitochondrial function

DOI:  https://doi.org/10.1080/21623945.2022.2116790
Korean J Physiol Pharmacol. 2022 Sep 01. 26(5): 325-333

Benzoylaconine improves mitochondrial function in oxygen-glucose deprivation and reperfusion-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis.

Leijie Chen, Laixing Yan, Weiwei Zhang.

  Heart failure (HF) has become one of the severe public health problems. The detailed role of mitochondrial function in HF was still unclear. Benzoylaconine (BAC) is a traditional Chinese medicine, but its role in HF still needs to be explored. In this study, oxygen-glucose deprivation and reperfusion (OGD/R) was executed to mimic the injury of H9C2 cells in HF. The viability of H9C2 cells was assessed via MTT assay. OGD/R treatment markedly decreased the viability of H9C2 cells, but BAC treatment evidently increased the viability of OGD/R-treated H9C2 cells. The apoptosis of H9C2 was enhanced by OGD/R treatment but suppressed by BAC treatment. The mitochondrial membrane potential was evaluated via JC-1 assay. BAC improved the mitochondrial function and suppressed oxidative stress in OGD/R-treated H9C2 cells. Moreover, Western blot analysis revealed that the protein expression of p-AMPK and PGC-1α were reduced in OGD/R-treated H9C2 cells, which was reversed by BAC. Rescue assays indicated that AMPK attenuation reversed the BAC-mediated protective effect on OGD/R-treated cardiomyocytes. Moreover, BAC alleviated myocardial injury in vivo. In a word, BAC modulated the mitochondrial function in OGD/R-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis. The findings might provide support for the application of BAC in the treatment of HF.

Keywords:  AMP-activated protein kinases; Benzoylaconine; Cardiomyocytes; Mitochondrial function

DOI:  https://doi.org/10.4196/kjpp.2022.26.5.325
Mol Metab. 2022 Aug 30. pii: S2212-8778(22)00153-3. [Epub ahead of print] 101584

PACAP attenuates hepatic lipid accumulation through the FAIM/AMPK/IRβ axis during overnutrition.

Wei Luo, Jiaxin Dai, Jianmin Liu, Yongmei Huang, Ziqiong Zheng, Pei Xu, Yi Ma.

  OBJECTIVE: Pituitary adenylate cyclase-activating polypeptide (PACAP) was reported to attenuate hepatic lipid accumulation in overnutrition-related metabolic disorder, mediated by up-regulation of fas apoptosis inhibitory molecule (FAIM). However, how PACAP regulates FAIM in metabolic tissues remains to be addressed. Here we investigated the underlying mechanism on the role of PACAP in ameliorating metabolic disorder and examined the potential therapeutic effects of PACAP in preventing the progression of metabolic associated fatty liver disease (MAFLD).METHODS: Mouse models with MAFLD induced by high-fat diet were employed. Different doses of PACAP were intraperitoneally administrated. Western blot, luciferase assay, lentiviral-mediated gene manipulations and animal metabolic phenotyping analysis were performed to explore the signaling pathway involved in PACAP function.
RESULTS: PACAP ameliorated the excessive hepatic lipid accumulation and inhibited lipogenesis in HFD-fed C57BL/6J mice. Mechanistically, PACAP activated the FAIM-AMPK-IRβ axis to inhibit the expression of lipid synthesis genes, and FAIM mediated the effects of PACAP. FAIM suppression via lentiviral-mediated shRNA inhibited the activation of AMPK, whereas FAIM overexpression promoted AMPK activation. PACAP increased the promoter activity of FAIM gene through activating PKA-CREB signaling pathway.
CONCLUSION: Our work demonstrated that the administration of PACAP represented a feasible approach for treating hepatic lipid accumulation in MAFLD. The findings reveal the molecular mechanism that PACAP increase FAIM expression and activates the FAIM/AMPK/IRβ signaling axis, thus inhibits lipogenesis to mediate its beneficial effects.

Keywords:  AMPK; FAIM; Hepatic lipid accumulation; IRβ; PACAP; lipogenesis

DOI:  https://doi.org/10.1016/j.molmet.2022.101584
J Agric Food Chem. 2022 Aug 30.

CIDEA Regulates De Novo Fatty Acid Synthesis in Bovine Mammary Epithelial Cells by Targeting the AMPK/PPARγ Axis and Regulating SREBP1.

Ji Cheng, Dianwen Xu, Lisha Chen, Wenjin Guo, Guiqiu Hu, Juxiong Liu, Shoupeng Fu.

  Cell-death-inducing DNA fragmentation factor-α-like effector A (CIDEA) is a lipid-droplet-associated protein that helps to promote lipid metabolism in adipocytes of mice and humans. However, studies on the regulatory mechanism of CIDEA on lipid metabolism in the mammary glands of dairy cows are rare. Therefore, the role of CIDEA in bovine mammary epithelial cells (bMECs) was investigated in this study. The CIDEA expression levels in the mammary glands of high-fat-milk-producing cows were significantly higher compared to those in low-fat-milk-producing cows. Results of in vitro studies in bMECs showed that the inhibition of CIDEA inhibited the expression of fatty acid synthesis-related genes and triglyceride (TAG) synthesis-related genes. Conversely, the overexpression of CIDEA leads to an increase in the content of TAG and fatty acid. The results of mechanistic studies indicated that the overexpression of CIDEA inhibits AMP-activated protein kinase (AMPK) activity, which enhances the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and consequently increases the TAG content. Furthermore, the overexpression of CIDEA promoted the nuclear translocation of sterol regulatory element-binding protein 1 (SREBP1). Therefore, a theoretical framework is provided by this study for the regulation of lipid metabolism in dairy cows by means of nutrition and the hormone targeting of CIDEA.

Keywords:  AMPK; CIDEA; SREBP1; bMECs; milk fat

DOI:  https://doi.org/10.1021/acs.jafc.2c05226
Acta Pharmacol Sin. 2022 Aug 30.

SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice.

Ze-Yu Li, Guo-Qing Lu, Jing Lu, Pan-Xia Wang, Xiao-Lei Zhang, Yong Zou, Pei-Qing Liu.

  Sirtuin3 (SIRT3), a class III histone deacetylase, is implicated in various cardiovascular diseases as a novel therapeutic target. SIRT3 has been proven to be cardioprotective in a model of Ang II-induced cardiac hypertrophy. However, a few small-molecule compounds targeting deacetylases could activate SIRT3. In this study, we generated a novel SIRT3 activator, 3-(2-bromo-4-hydroxyphenyl)-7-hydroxy-2H-chromen-2-one (SZC-6), through structural optimization of the first SIRT3 agonist C12. We demonstrated that SZC-6 directly bound to SIRT3 with Kd value of 15 μM, and increased SIRT3 deacetylation activity with EC50 value of 23.2 ± 3.3 µM. In neonatal rat cardiomyocytes (NRCMs), pretreatment with SZC-6 (10, 20, 40 µM) dose-dependently attenuated isoproterenol (ISO)-induced hypertrophic responses. Administration of SZC-6 (20, 40 and 60 mg·kg-1·d-1, s.c.) for 2 weeks starting from one week prior ISO treatment dose-dependently reversed ISO-induced impairment of diastolic and systolic cardiac function in wild-type mice, but not in SIRT3 knockdown mice. We showed that SZC-6 (10, 20, 40 µM) dose-dependently inhibited cardiac fibroblast proliferation and differentiation into myofibroblasts, which was abolished in SIRT3-knockdown mice. We further revealed that activation of SIRT3 by SZC-6 increased ATP production and rate of mitochondrial oxygen consumption, and reduced ROS, improving mitochondrial function in ISO-treated NRCMs. We also found that SZC-6 dose-dependently enhanced LKB1 phosphorylation, thereby promoting AMPK activation to inhibit Drp1-dependent mitochondrial fragmentation. Taken together, these results demonstrate that SZC-6 is a novel SIRT3 agonist with potential value in the treatment of cardiac hypertrophy partly through activation of the LKB1-AMPK pathway.

Keywords:  LKB1-AMPK pathway; SIRT3; SZC-6; cardiac hypertrophy; mitochondrial malfunction; oxidative stress

DOI:  https://doi.org/10.1038/s41401-022-00966-8
J Cell Mol Med. 2022 Sep 02.

Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK-dependent mechanisms.

Yizhi Bu, Mei Peng, Xinyi Tang, Xu Xu, Yifeng Wu, Alex F Chen, Xiaoping Yang.

  Metformin, a well-known AMPK agonist, has been widely used as the first-line drug for treating type 2 diabetes. There had been a significant concern regarding the use of metformin in people with cardiovascular diseases (CVDs) due to its potential lactic acidosis side effect. Currently growing clinical and preclinical evidence indicates that metformin can lower the incidence of cardiovascular events in diabetic patients or even non-diabetic patients beyond its hypoglycaemic effects. The underlying mechanisms of cardiovascular benefits of metformin largely involve the cellular energy sensor, AMPK, of which activation corrects endothelial dysfunction, reduces oxidative stress and improves inflammatory response. In this minireview, we summarized the clinical evidence of metformin benefits in several widely studied cardiovascular diseases, such as atherosclerosis, ischaemic/reperfusion injury and arrhythmia, both in patients with or without diabetes. Meanwhile, we highlighted the potential AMPK-dependent mechanisms in in vitro and/or in vivo models.

Keywords:  cardiovascular diseases; metformin; protective effect

DOI:  https://doi.org/10.1111/jcmm.17519
Autophagy. 2022 Sep 01.

Isoginkgetin, a Potential CDK6 Inhibitor, Suppresses SLC2A1/GLUT1 Enhancer Activity to Induce AMPK-ULK1-Mediated Cytotoxic Autophagy in Hepatocellular Carcinoma.

Jie Yao, Shuming Tang, Chenyan Shi, Yunzhi Lin, Lanlan Ge, Qinghua Chen, Baoru Ou, Dongyu Liu, Yuyang Miao, Qiujie Xie, Xudong Tang, Jia Fei, Guangyi Yang, Jun Tian, Xiaobin Zeng.

  Isoginkgetin (ISO), a natural biflavonoid, exhibited cytotoxic activity against several types of cancer cells. However, its effects on hepatocellular carcinoma (HCC) cells and mechanism remain unclear. Here, we revealed that ISO effectively inhibited HCC cell proliferation and migration in vitro. LC3-II expression and autophagosomes were increased under ISO treatment. In addition, ISO-induced cell death was attenuated by treatment with chloroquine or knockdown of autophagy-related genes (ATG5 or ULK1). ISO significantly suppressed SLC2A1/GLUT1 (solute carrier family 2 member 1) expression and glucose uptake, leading to activation of the AMPK-ULK1 axis in HepG2 cells. Overexpression of SLC2A1/GLUT1 abrogated ISO-induced autophagy. Combining molecular docking with thermal shift analysis, we confirmed that ISO directly bound to the N terminus of CDK6 (cyclin dependent kinase 6) and promoted its degradation. Overexpression of CDK6 abrogated ISO-induced inhibition of SLC2A1/GLUT1 transcription and induction of autophagy. Furthermore, ISO treatment significantly decreased the H3K27ac, H4K8ac and H3K4me1 levels on the SLC2A1/GLUT1 enhancer in HepG2 cells. Finally, ISO suppressed the hepatocarcinogenesis in the HepG2 xenograft mice and the diethylnitrosamine+carbon tetrachloride (DEN+CCl4)-induced primary HCC mice and we confirmed SLC2A1/GLUT1 and CDK6 as promising oncogenes in HCC by analysis of TCGA data and human HCC tissues. Our results provide a new molecular mechanism by which ISO treatment or CDK6 deletion promotes autophagy; that is, ISO targeting the N terminus of CDK6 for degradation inhibits the expression of SLC2A1/GLUT1 by decreasing the enhancer activity of SLC2A1/GLUT1, resulting in decreased glucose levels and inducing the AMPK-ULK1 pathway.

Keywords:  CDK6; SLC2A1/GLUT1; autophagy; hepatocellular carcinoma; isoginkgetin

DOI:  https://doi.org/10.1080/15548627.2022.2119353
Adv Clin Exp Med. 2022 Sep 01.

miRNA-323a-3p promoted intracranial, aneurysm-induced inflammation via AMPK/NF-κB signaling pathway by AdipoR1.

Bing Sun, Zehao Liu, Zhengquan Yu.

  BACKGROUND: An intracranial arterial wall which locally protrudes outward, typically in the capsule and fusiform, is called an intracranial aneurysm (IA). Among these aneurysms, 1-2% might spontaneously rupture before treatment. Anterior and posterior communicating aneurysms are more likely to rupture than other aneurysms, and an anterior communicating aneurysm is more likely to rupture than a posterior communicating aneurysm.OBJECTIVES: To identify the effects of miRNA-323a-3p expression in intracranial aneurysms and its potential regulatory mechanism.
MATERIAL AND METHODS: Patients with IA and healthy volunteers were enrolled, and their serum samples were extracted for the detection of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), IL-6, IL-18, and miRNA-323a-3p. Then, the regulatory effects of miRNA-323a-3p on the above inflammatory factors and AdipoR1/AMPK/NF-kb signaling were also detected in vitro.
RESULTS: The downregulation of miRNA-323a-3p reduced the expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IL-18) in an in vitro model in comparison with the control group. The overexpression of miRNA-323a-3p suppressed the protein expression of adiponectin receptor R1 (AdipoR1) and p-AMPK, and induced NF-κB-p65 protein expression in an in vitro model.
CONCLUSIONS: We showed that AdipoR1 plasmid, AMPK activator 1 or si-NF-κB reduced the pro-inflammatory effects of miRNA-323a-3p in an in vitro model. The miRNA-323a-3p exacerbated the inflammatory reaction in IA through AMPK/NF-κB signaling by AdipoR1. Our findings suggest that miRNA-323a-3p targeting AdipoR1 is promising in further anti-inflammatory treatment of IAs.

Keywords:  ADIPOR1; AMPK; NF-κB; intracranial aneurysm; miRNA-323a-3p

DOI:  https://doi.org/10.17219/acem/151053
Nat Metab. 2022 Sep 01.

Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis.

Bing Zhou, Yunchen Luo, Nana Ji, Cheng Hu, Yan Lu.

Non-alcoholic fatty liver disease (NAFLD) is caused by imbalance in lipid metabolism. In this study, we show that the hepatokine orosomucoid (ORM) 2 is a key regulator of de novo lipogenesis in the liver. Hepatic and plasma ORM2 levels are markedly decreased in obese murine models and patients with NAFLD. Through multiple loss- and gain-of function studies, we demonstrate that ORM2 is essential to maintain hepatic and systemic lipid homeostasis. At the mechanistic level, ORM2 binds to inositol 1, 4, 5-trisphosphate receptor type 2 to activate AMP-activated protein kinase signaling, thereby inhibiting sterol regulatory element binding protein 1c-mediated lipogenic gene program. Notably, intraperitoneal injections of recombinant ORM2 protein or stabilized ORM2-FC fusion protein markedly improved liver steatosis, steatohepatitis and atherosclerosis in preclinical mouse models, without adverse effects on body weight or food intake. Thus, these findings suggest that ORM2 may serve as a potential target for therapeutic intervention in NAFLD, non-alcoholic steatohepatitis and related lipid disorders.

DOI: https://doi.org/10.1038/s42255-022-00627-4
Mol Cancer. 2022 Sep 02. 21(1): 174

The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway.

Yi Zhang, Xiaomeng Liu, Yan Wang, Shihui Lai, Zhiqian Wang, Yudie Yang, Wenhui Liu, Hongquan Wang, Bo Tang.

  BACKGROUND: Chemoresistance is a major factor contributing to the poor prognosis of patients with pancreatic cancer, and cancer stemness is one of the most crucial factors associated with chemoresistance and a very promising direction for cancer treatment. However, the exact molecular mechanisms of cancer stemness have not been completely elucidated.METHODS: m6A-RNA immunoprecipitation and sequencing were used to screen m6A-related mRNAs and lncRNAs. qRT-PCR and FISH were utilized to analyse DDIT4-AS1 expression. Spheroid formation, colony formation, Western blot and flow cytometry assays were performed to analyse the cancer stemness and chemosensitivity of PDAC cells. Xenograft experiments were conducted to analyse the tumour formation ratio and growth in vivo. RNA sequencing, Western blot and bioinformatics analyses were used to identify the downstream pathway of DDIT4-AS1. IP, RIP and RNA pulldown assays were performed to test the interaction between DDIT4-AS1, DDIT4 and UPF1. Patient-derived xenograft (PDX) mouse models were generated to evaluate chemosensitivities to GEM.
RESULTS: DDIT4-AS1 was identified as one of the downstream targets of ALKBH5, and recruitment of HuR onto m6A-modified sites is essential for DDIT4-AS1 stabilization. DDIT4-AS1 was upregulated in PDAC and positively correlated with a poor prognosis. DDIT4-AS1 silencing inhibited stemness and enhanced chemosensitivity to GEM (Gemcitabine). Mechanistically, DDIT4-AS1 promoted the phosphorylation of UPF1 by preventing the binding of SMG5 and PP2A to UPF1, which decreased the stability of the DDIT4 mRNA and activated the mTOR pathway. Furthermore, suppression of DDIT4-AS1 in a PDX-derived model enhanced the antitumour effects of GEM on PDAC.
CONCLUSIONS: The ALKBH5-mediated m6A modification led to DDIT4-AS1 overexpression in PDAC, and DDIT-AS1 increased cancer stemness and suppressed chemosensitivity to GEM by destabilizing DDIT4 and activating the mTOR pathway. Approaches targeting DDIT4-AS1 and its pathway may be an effective strategy for the treatment of chemoresistance in PDAC.

Keywords:  ALKBH5; Chemosensitivity; DDIT4-AS1; Stemness; UPF1

DOI:  https://doi.org/10.1186/s12943-022-01647-0