bims-amsmem 2022-10-09 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022‒10‒09
nine papers selected by
Dipsikha Biswas, Københavns Universitet

Metformin mitigates cholesterol accumulation via the AMPK/SIRT1 pathway to protect osteoarthritis chondrocytes.
AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation.
The AMPK pathway in fatty liver disease.
The beta subunit of AMP-activated protein kinase is critical for cell cycle progression and parasite development in Toxoplasma gondii.
Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism.
DMSO-soluble smoking particles up-regulates the vascular endothelin receptors through AMPK-SIRT1 and MAPK pathways.
AMPK phosphorylates NAMPT to regulate NAD+ homeostasis under ionizing radiation.
A long-term high-fat diet influences brain damage and is linked to the activation of HIF-1α/AMPK/mTOR/p70S6K signalling.
Maternal exercise improves epithelial development of fetal intestine by enhancing apelin signaling and oxidative metabolism.

Biochem Biophys Res Commun. 2022 Sep 29. pii: S0006-291X(22)01330-4. [Epub ahead of print]632 113-121

Metformin mitigates cholesterol accumulation via the AMPK/SIRT1 pathway to protect osteoarthritis chondrocytes.

Hengte Xing, Chuancai Liang, Chenyu Wang, Xiongfeng Xu, Yong Hu, Bo Qiu.

  In this study, we aim to investigate the effect of metformin on cholesterol synthesis and efflux-related genes in chondrocytes during osteoarthritis (OA) and explore the underlying mechanisms. Primary chondrocytes were harvested from Wistar rat cartilage and divided into control and treatment groups. Chondrocytes in the treatment group were treated with interleukin-1β (IL-1β) mimicking the inflammatory environment of osteoarthritis. Subsequently, RT-qPCR, Western blotting, immunofluorescence staining, and Cell Counting Kit-8 (CCK-8) were conducted. Significant reductions in phosphorylated AMP-activated protein kinase (p-AMPK) and silent information regulator 1 (SIRT1) protein expression were observed in both human OA chondrocytes and cultured primary murine chondrocytes treated with IL-1β, while AMP-activated protein kinase (AMPK) was not inhibited. Moreover, in the presence of IL-1β, metformin significantly increased the expression of p-AMPK and SIRT1 at the protein and mRNA level. Meanwhile, metformin could reverse IL-1β-induced cartilage extracellular matrix degradation in chondrocytes from the rat model of OA (treated by IL-β) by activating the AMPK/SIRT1 pathway. Moreover, metformin activated AMPK and SIRT1, mediated by the activation of SREBP-2 and HMGCR in OA chondrocytes. Inhibiting AMPK/SIRT1 activity by its specific inhibitor could suppress IL-1β-induced expression of LXRα, ABCA1 and ApoA1 and cholesterol efflux. Thus, metformin inhibits cholesterol synthesis and promotes cholesterol efflux by activating the AMPK/SIRT1 pathway in OA chondrocytes. This study improves our understanding of the effect of metformin on cholesterol accumulation in OA chondrocytes.

Keywords:  AMPK; Cholesterol; Chondrocytes; Metformin; Osteoarthritis; SIRT1

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.074
BMB Rep. 2022 Oct 05. pii: 5694. [Epub ahead of print]

AMPK-induced mitochondrial biogenesis decelerates retinal pigment epithelial cell degeneration under nutrient starvation.

Yujin Park, Yeeun Jeong, Sumin Son, Dong-Eun Kim.

The implications of nutrient starvation due to aging on the degeneration of the retinal pigment epithelium (RPE) is yet to be fully explored. We examined the involvement of AMPK activation in mitochondrial homeostasis and its relationship with the maintenance of a healthy mitochondrial population and epithelial characteristics of RPE cells under nutrient starvation. Nutrient starvation induced mitochondrial senescence, which led to the accumulation of reactive oxygen species (ROS) in RPE cells. As nutrient starvation persisted, RPE cells underwent pathological epithelial-mesenchymal transition (EMT) via the upregulation of TWIST1, a transcription regulator which is activated by ROS-induced NF-κB signaling. Enhanced activation of AMPK with metformin decelerated mitochondrial senescence and EMT progression through mitochondrial biogenesis, primed by activation of PGC1-α. Thus, by facilitating mitochondrial biogenesis, AMPK protects RPE cells from the loss of epithelial integrity due to the accumulation of ROS in senescent mitochondria under nutrient starvation.
Front Physiol. 2022 ;13 970292

The AMPK pathway in fatty liver disease.

Chunqiu Fang, Jianheng Pan, Ning Qu, Yuting Lei, Jiajun Han, Jingzhou Zhang, Dong Han.

  Lipid metabolism disorders are the primary causes for the occurrence and progression of various liver diseases, including non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) caused by a high-fat diet and ethanol. AMPK signaling pathway plays an important role in ameliorating lipid metabolism disorders. Progressive research has clarified that AMPK signal axes are involved in the prevention and reduction of liver injury. Upregulation of AMK can alleviate FLD in mice induced by alcohol or insulin resistance, type 2 diabetes, and obesity, and most natural AMPK agonists can regulate lipid metabolism, inflammation, and oxidative stress in hepatocytes, consequently regulating FLD in mice. In NAFLD and AFLD, increasing the activity of AMPK can inhibit the synthesis of fatty acids and cholesterol by down-regulating the expression of adipogenesis gene (FAS, SREBP-1c, ACC and HMGCR); Simultaneously, by increasing the expression of fatty acid oxidation and lipid decomposition genes (CPT1, PGC1, and HSL, ATGL) involved in fatty acid oxidation and lipid decomposition, the body's natural lipid balance can be maintained. At present, some AMPK activators are thought to be beneficial during therapeutic treatment. Therefore, activation of AMPK signaling pathway is a potential therapeutic target for disorders of the liver. We summarized the most recent research on the role of the AMPK pathway in FLD in this review. Simultaneously, we performed a detailed description of each signaling axis of the AMPK pathway, as well as a discussion of its mechanism of action and therapeutic significance.

Keywords:  AMPK signaling pathway; alcoholic fatty liver; lipid accumulation; lipid metabolism; non-alcoholic fatty liver

DOI:  https://doi.org/10.3389/fphys.2022.970292
Cell Mol Life Sci. 2022 Sep 28. 79(10): 532

The beta subunit of AMP-activated protein kinase is critical for cell cycle progression and parasite development in Toxoplasma gondii.

Jichao Yang, Xuke Yang, Anqi Liu, Yaqiong Li, Zhipeng Niu, Congcong Lyu, Xiaohan Liang, Ningbo Xia, Jianmin Cui, Mingjun Li, Ping Wu, Chao Peng, Bang Shen.

  Toxoplasma gondii is a widespread eukaryotic pathogen that causes life-threatening diseases in humans and diverse animals. It has a complex life cycle with multiple developmental stages, which are timely adjusted according to growth conditions. But the regulatory mechanisms are largely unknown. Here we show that the AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis in eukaryotes, plays crucial roles in controlling the cell cycle progression and bradyzoite development in Toxoplasma. Deleting the β regulatory subunit of AMPK in the type II strain ME49 caused massive DNA damage and increased spontaneous conversion to bradyzoites (parasites at chronic infection stage), leading to severe growth arrest and reduced virulence of the parasites. Under alkaline stress, all Δampkβ mutants converted to a bradyzoite-like state but the cell division pattern was significantly impaired, resulting in compromised parasite viability. Moreover, we found that phosphorylation of the catalytic subunit AMPKα was greatly increased in alkaline stressed parasites, whereas AMPKβ deletion mutants failed to do so. Phosphoproteomics found that many proteins with predicted roles in cell cycle and cell division regulation were differentially phosphorylated after AMPKβ deletion, under both normal and alkaline stress conditions. Together, these results suggest that the parasite AMPK has critical roles in safeguarding cell cycle progression, and guiding the proper exist of the cell cycle to form mature bradyzoites when the parasites are stressed. Consistent with this model, growth of parasites was not significantly altered when AMPKβ was deleted in a strain that was naturally reluctant to bradyzoite development.

Keywords:  AMPK; Bradyzoite development; Cell cycle; Phosphorylation; Toxoplasma gondii

DOI:  https://doi.org/10.1007/s00018-022-04556-z
Front Genet. 2022 ;13 884037

Profile analysis and functional modeling identify circular RNAs in nonalcoholic fatty liver disease as regulators of hepatic lipid metabolism.

Yang Xie, Yi Cao, Can-Jie Guo, Xing-Ya Guo, Ya-Fang He, Qing-Yang Xu, Feng Shen, Qin Pan.

  Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, associated with an outcome of hepatic fibrosis/cirrhosis and hepatocellular carcinoma. However, limited exploration of the underlying mechanisms hinders its prevention and treatment. To investigate the mechanisms of epigenetic regulation in NAFLD, the expression profile of circular RNA (circRNA) of rodents in which NAFLD was induced by a high-fat, high-cholesterol (HFHC) diet was studied. Modeling of the circRNA-microRNA (miRNA) -mRNA regulatory network revealed the functional characteristics of NAFLD-specific circRNAs. The targets and effects in the liver of such NAFLD-specific circRNAs were further assessed. Our results uncovered that the downregulation of 28 annotated circRNAs characterizes HFHC diet-induced NAFLD. Among the downregulated circRNAs, long intergenic non-protein coding RNA, P53 induced transcript (LNCPINT) -derived circRNAs (circ_0001452, circ_0001453, and circ_0001454) targeted both miR-466i-3p and miR-669c-3p. Their deficiency in NAFLD abrogated the circRNA-based inhibitory effect on both miRNAs, which further inactivated the AMPK signaling pathway via AMPK-α1 suppression. Inhibition of the AMPK signaling pathway promotes hepatic steatosis, depending on the transcriptional and translational upregulation of lipogenic genes, such as those encoding sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) in hepatocytes. The levels of LNCPINT-derived circRNAs displayed a negative association with hepatic triglyceride (TG) concentration. These findings suggest that loss of LNCPINT-derived circRNAs may underlie NAFLD via miR-466i-3p- and miR-669c-3p-dependent inactivation of the AMPK signaling pathway.

Keywords:  AMPK; circular RNA; microRNA; nonalcoholic fatty liver disease; signaling pathway

DOI:  https://doi.org/10.3389/fgene.2022.884037
Chem Biol Interact. 2022 Sep 29. pii: S0009-2797(22)00408-2. [Epub ahead of print] 110203

DMSO-soluble smoking particles up-regulates the vascular endothelin receptors through AMPK-SIRT1 and MAPK pathways.

Yuying Wang, Pan Zhang, Ting Wang, Dongfeng Yao, Yongheng Shi, Jiping Liu, Bin Wang, Hao Wei, Weihai Liu, Cang-Bao Xu, Chuan Wang.

  Smoking is a well-known risk factor for cardiovascular diseases. However, the mechanisms behind how smoking leads to vasospasm are not fully elucidated. Endothelin receptors are involved in the pathogenesis of cardiovascular diseases. This study examined whether cigarette smoke could induce up-regulation of vascular endothelin receptors through AMPK-SIRT1 and MAPK pathways. The results show that DMSO-soluble smoking particles (DSP) up-regulated the protein expressions of endothelin receptors and the contractile responses. Furthermore, the inhibition of MAPK or activation of AMPK-SIRT1 markedly attenuated DSP-enhanced vasoconstriction and the protein expression of endothelin receptors. The in vivo study showed that DSP increased the blood pressure of the rats and down-regulated p-AMPKα, SIRT1, and up-regulated endothelin receptors, p-ERK1/2, and P38 protein expressions. However, treatment with resveratrol attenuated vasoconstriction, endothelin receptor proteins expression, and blood pressure in vivo. In conclusion, this suggests that cigarette smoke up-regulates the vascular endothelin receptors through AMPK-SIRT1 and MAPK pathways.

Keywords:  AMPK; Cigarette smoke; Endothelin receptors; MAPK; Myograph; SIRT1

DOI:  https://doi.org/10.1016/j.cbi.2022.110203
Open Biol. 2022 Oct;12(10): 220213

AMPK phosphorylates NAMPT to regulate NAD+ homeostasis under ionizing radiation.

Xiaoyu Liao, Xiaoke Huang, Xin Li, Xuemei Qiu, Mi Li, Rui Liu, Tao He, Qingfeng Tang.

  Radiation-induced oral mucositis is the most common complication for patients who receive head/neck radiotherapy. Nicotinamide adenine dinucleotide (NAD+) is vital for DNA damage repair under ionizing radiation, through functioning as either the substrate for protein poly(ADP-ribosyl)ation at DNA break sites or the cofactor for multiple DNA repair-related enzymes, which therefore can result in a significant consumption of cellular NAD+ during DNA repair. Mammalian cells produce NAD+ mainly by recycling nicotinamide via the salvage pathway, in which the rate-limiting step is governed by nicotinamide phosphoribosyltransferase (NAMPT). However, whether NAMPT is co-opted under ionizing radiation to timely fine-tune NAD+ homeostasis remains elusive. Here we show that ionizing radiation evokes NAMPT activation within 30 min without apparent changes in its protein expression. AMPK rapidly phosphorylates NAMPT at S314 under ionizing radiation, which reinforces the enzymatic activity of NAMPT by increasing NAMPT binding with its substrate phosphoribosyl pyrophosphate (PRPP). AMPK-mediated NAMPT S314 phosphorylation substantially restores NAD+ level in the irradiated cells and facilitates DNA repair and cell viability. Our findings demonstrate a new post-translational modification-based signalling route, by which cells can rapidly orchestrate NAD+ metabolism to support DNA repair, thereby highlighting NAMPT as a potential target for the prevention of ionizing radiation-induced injuries.

Keywords:  AMPK; NAD+; NAMPT; ionizing radiation; phosphorylation

DOI:  https://doi.org/10.1098/rsob.220213
Front Neurosci. 2022 ;16 978431

A long-term high-fat diet influences brain damage and is linked to the activation of HIF-1α/AMPK/mTOR/p70S6K signalling.

Fei Chen, Wen-Min Yi, Sheng-Yuan Wang, Ming-Hao Yuan, Jie Wen, Hong-Yan Li, Qian Zou, Shu Liu, Zhi-You Cai.

  High-fat diets (HFDs) are related to the incidence of obesity and diabetes, but the effect of high-fat diet-induced brain damage remains to be clarified. In our study, we found that 24 weeks of a HFD effectively induced obesity and a change in fur color in mice. In addition, the mice also exhibited deficits in learning and memory. We further found that autophagic flux was impaired in mice after HFD feeding. Hypoxia-inducible factor 1α (HIF-1α) expression was significantly increased in HFD-fed mice, and HFD feeding inhibited adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and induced mechanistic target of rapamycin (mTOR) phosphorylation and p70S6K expression. Treatment of HFD-induced BV2 cell model with palmitic acid (PA) was used to further verify a similar result. We concluded that improving tissue hypoxia or enhancing autophagy through the AMPK/mTOR/p70S6K pathway may be a relevant strategy for improving obesity- and ageing-related disorders.

Keywords:  AMPK/m TOR pathway; HIF-1α; ageing; autophagy; high-fat (HF) diet; obesity

DOI:  https://doi.org/10.3389/fnins.2022.978431
Am J Physiol Regul Integr Comp Physiol. 2022 Oct 03.

Maternal exercise improves epithelial development of fetal intestine by enhancing apelin signaling and oxidative metabolism.

Song Ah Chae, Jun Seok Son, Jeanene M de Avila, Min Du, Mei-Jun Zhu.

  Obesity in pregnancy is currently the leading cause of gestational complications for the mother and fetus worldwide. Maternal obesity (MO), common in western societies, impedes development of intestinal epithelium in the fetuses, which causes disorders in the nutrient absorption and intestine-related immune responses in offspring. Here, using a mouse model of maternal exercise (ME), we found that exercise during pregnancy protects the impairment of fetal intestinal morphometrical formation and epithelial development due to MO. MO decreased villus length and epithelial proliferation markers in E18.5 fetal small intestine, which was increased due to ME. The expression of the epithelial differentiation markers, Lyz1, Muc2, and Tff3, in fetal small intestine was decreased due to MO, but protected by ME. Consistently, the biomarkers related to mitochondrial biogenesis and oxidative metabolism were down-regulated in MO fetal small intestine but recovered by ME. Apelin injection to dams partially mirrored the beneficial effects of ME. ME and apelin injection activated AMPK, the down-stream target of apelin receptor signaling, which might mediate the improvement of fetal epithelial development and oxidative metabolism. These findings suggest that ME, a highly accessible intervention, is effective in improving fetal intestinal epithelium of obese dams. Apelin-AMPK-mitochondrial biogenesis axis provides amenable therapeutic targets to facilitate fetal intestinal development of obese mothers.

Keywords:  AMPK; apelin; exercise; fetal epithelium; maternal obesity

DOI:  https://doi.org/10.1152/ajpregu.00128.2022