bims-amsmem 2023-02-26 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–02–26
24 papers selected by
Dipsikha Biswas, Københavns Universitet

Activated AMPK-mediated glucose uptake and mitochondrial dysfunction is critically involved in the glutamate-induced oxidative injury in HT22 cell.
DT-010 Exerts Cardioprotective Effects by Regulating the Crosstalk between the AMPK/PGC-1α Pathway and ERp57.
AMPK hyperactivity maintains the survival of vasculogenic T cells in patients with Takayasu's arteritis.
FOXA2 plays a critical role in hepatocellular carcinoma progression and lenvatinib-associated drug resistance.
A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease.
Platycodin D stimulates AMPK activity to inhibit the neurodegeneration caused by reactive oxygen species-induced inflammation and apoptosis.
Interplays of AMPK and TOR in Autophagy Regulation in Yeast.
Genetic polymorphisms of PRKAA1 (AMPKα1) and postherpetic pain susceptibility: Multicenter, randomized control, and haplotype analysis study.
Downregulation of miR-137 Facilitates CD4+ T Cell Pyroptosis in Systemic Lupus Erythematosus via Stimulating AMPK Pathway.
The role of CaMKK2 in Golgi-associated vesicle trafficking.
Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.
Artesunate alleviates intracerebral hemorrhage secondary injury by inducing ferroptosis in M1-polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway.
AMPK phosphorylates and stabilises copper transporter 1 to synergise metformin and copper chelator for breast cancer therapy.
Luteolin improves vasoconstriction function and survival of septic mice via AMPK/NF-κB pathway.
Modulation of AMPK/ TET2/ 5-hmC axis in response to metabolic alterations as a novel pathway for obesity-related colorectal cancer development.
Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy.
Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models.
Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.
Intracellular Calcium Overload and Activation of CaMKK/AMPK Signaling Are Related to the Acceleration of Muscle Glycolysis of Broiler Chickens Subjected to Acute Stress.
Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis.
The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway.
Hedgehog signal activates Ampk via Smoothened to promote autophagy and lipid degradation in hepatocytes.
Concentration-Dependent Cellular Uptake of Graphene Oxide Quantum Dots Promotes the Odontoblastic Differentiation of Dental Pulp Cells via the AMPK/mTOR Pathway.
Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis.

Tissue Cell. 2023 Feb 14. pii: S0040-8166(23)00027-7. [Epub ahead of print]81 102039

Activated AMPK-mediated glucose uptake and mitochondrial dysfunction is critically involved in the glutamate-induced oxidative injury in HT22 cell.

Shao-Peng Lin, Jingyi Bu, Shan Ye, Qiangda Xie, Jue-Xian Wei, Xiaofang Yin, Fen Mei, Pei-Yi Lin, Xiao-Hui Chen.

   BACKGROUND: Accumulation of glutamate damages neurons via the reactive oxygen species (ROS) injury, which was involved in the development of neurodegenerative diseases. However, the mechanism of neuronal oxidative stress damage caused by glutamate and the intervention targets still needs to be further studied. This study explored whether 5' adenosine monophosphate-activated protein kinase (AMPK)-induced glucose metabolic and mitochondrial dysfunction were related to glutamate-dependent ROS injury of the neuron.
METHODS: Neuronal oxidative stress injury was induced by glutamate treatment in HT-22 cells. Western blotting was used to evaluate the phosphorylation of the AMPK. The XF24 Flux Analyzer was used to measure the effect of glutamate and Compound C (a well-known pharmacological inhibitor of AMPK phosphorylation) on the cellular oxygen consumption rate (OCR) of HT-22 cells. Glucose uptake, intracellular ROS, mitochondrial potential, apoptosis and cell viability were quantified using biochemical assays.
RESULTS: Glutamate caused the phosphorylation of AMPK and subsequently promoted the glucose uptake. Furthermore, AMPK-mediated glucose uptake enhanced OCR and increased the intracellular ROS levels in neurons. The pharmacological inhibition of AMPK phosphorylation by Compound C attenuated glutamate-induced toxicity in HT22 cells by regulating the glucose uptake/mitochondrial respiration/ROS pathway.
CONCLUSIONS: The AMPK phosphorylation/glucose uptake/mitochondrial respiration/ROS pathway was involved in glutamate-induced excitotoxic injury in HT22 cells. The inhibition of AMPK phosphorylation may be a potential target for the development of therapeutic agents for treating the glutamate-induced neurotoxicity.

Keywords:  AMPK; Apoptosis; Glutamate; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.tice.2023.102039
Cardiovasc Ther. 2023 ;2023 8047752

DT-010 Exerts Cardioprotective Effects by Regulating the Crosstalk between the AMPK/PGC-1α Pathway and ERp57.

Xiaojing Zhang, Ximin Wu, Huihui Hu, Xiaoping Liu, Zhanfang Kang, Xin Deng.

The AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway performs a crucial role in energy metabolism and mitochondrial network. Our previous study found that DT-010, a novel danshensu (DSS) and tetramethylpyrazine (TMP) conjugate, had significant cardioprotective properties in vitro and in vivo. We also reported that ERp57 served as a major target of DSS using the chemical proteomics approach. In this article, we focus on exploring the interrelationship between the regulation of the AMPK/PGC-1α pathway and promoting ERp57 expression induced by DT-010 in tert-butylhydroperoxide- (t-BHP-) induced H9c2 cell injury. The results showed that DT-010 activated the AMPK/PGC-1α pathway and increased ERp57 protein expression. Importantly, the above phenomenon as well as the mitochondrial function can be partially reversed by siRNA-mediated ERp57 suppression. Meanwhile, silencing AMPK significantly inhibited the ERp57 expression induced by DT-010. In addition, molecular docking and kinase assay in vitro revealed that DT-010 had no direct regulation effects on AMPK activity. Taken together, DT-010 exerted cardioprotective effects by regulating the crosstalk of AMPK/PGC-1α pathway and ERp57, representing a potential therapeutic agent for ischemic heart disease.

DOI: https://doi.org/10.1155/2023/8047752
Clin Exp Rheumatol. 2023 Feb 23.

AMPK hyperactivity maintains the survival of vasculogenic T cells in patients with Takayasu's arteritis.

Mengyao Sun, Xin Zhang, Yuanyuan Hao, Pengcheng Yin, Jinghai Hu, Ming Zheng, Zhenke Wen, Xiyu Liu, Chunxi Wang.

OBJECTIVES: Takayasu's arteritis (TAK) is a progressive autoimmune vasculitis that mainly affects the aorta and its major branches. While recent studies have identified proinflammatory T cells, including Th1 and Th17 cells, as the dominant infiltrates in the arterial adventitia, mechanisms underpinning the maintenance of such vasculogenic T cells remain obscure.
METHODS: 75 patients with TAK and 30 age-matched healthy controls were enrolled in this study. CD4 T cells from TAK patients were activated with anti-CD3/CD28 beads to mimic vasculogenic T cells. The survival of T cells was detected by quantifying Annexin-V+7-AAD+ fractions. Expression and activity of AMP-activated protein kinase (AMPK) were determined using phosflow cytometry and immunoblots. Specific inhibitors and shRNA were applied to block the function of AMPK and Notch1, while erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were used to reflect the disease activity of TAK patients.
RESULTS: T cells from TAK patients undergo spontaneous differentiation into vasculogenic proinflammatory T cells with prolonged survival capacity. Mechanistic explorations uncover AMPK hyperactivity in such T cells from TAK patients, promoting mitochondrial metabolism and their survival. Such AMPK hyperactivity results from the robust Notch1 activity in TAK T cells. Accordingly, T cell-intrinsic phosphor-AMPK reflects the disease activity in clinical TAK patients.
CONCLUSIONS: AMPK hyperactivity is essential for maintaining the vasculogenic proinflammatory T cells in TAK patients, serving as a promising therapeutic target for TAK management.

DOI: https://doi.org/10.55563/clinexprheumatol/th1an2
Biosci Trends. 2023 Feb 24.

FOXA2 plays a critical role in hepatocellular carcinoma progression and lenvatinib-associated drug resistance.

Zhengxia Wang, Junyi Shen, Chuwen Chen, Tianfu Wen, Chuan Li.

  Hepatic forkhead box protein A2 (FOXA2) is a crucial transcription factor for liver development and metabolic homeostasis. However, its role in hepatocellular carcinoma (HCC) progression and lenvatinib-related drug resistance remains unknown. In this study, the level of FOXA2 expression was found to be lower in HCC tissues than in paired adjacent tumor tissues. A low level of FOXA2 expression was associated with aggressive tumor characteristics (vascular invasion and poor differentiation). A low level of FOXA2 expression was found to be an independent risk factor for tumor recurrence (hazard ratio (HR): 1.899, P < 0.001) and long-term survival (HR: 2.011, P = 0.003) in HCC patients after hepatectomy. In xenograft animal models, FOXA2 overexpression significantly inhibited tumor growth. Moreover, FOXA2 overexpression was found to enhance the inhibitory effect of lenvatinib on HCC cells by upregulating the adenosine monophosphate-activated protein kinase-mechanistic target of rapamycin (AMPK-mTOR) pathway. Conversely, inhibition of adenosine monophosphate-activated protein kinase (AMPK) or stimulation of mechanistic target of rapamycin (mTOR) attenuated the sensitization of cells overexpressing FOXA2 to lenvatinib. Similarly, FOXA2 overexpression augmented the antitumor effect of lenvatinib in animal models with xenograft tumors. FOXA2 overexpression increased autophagy in HCC cells treated with lenvatinib. Lenvatinib treatment activated the platelet-derived growth factor receptor-extracellular regulated protein kinase (PDGFR-ERK) pathway in HCC. FOXA2 overexpression further downregulated the PDGFR-ERK pathway through the activation of the AMPK-mTOR axis. In conclusion, FOXA2 was identified as an independent risk factor for HCC after hepatectomy. FOXA2 was found to be closely associated with the biological progression of HCC. By modulating the AMPK-mTOR-autophagy signaling pathway, FOX2 significantly augmented antitumor effect of lenvatinib in HCC.

Keywords:  AMPK-mTOR pathway; FOXA2; drug resistance; hepatocellular carcinoma; lenvatinib

DOI:  https://doi.org/10.5582/bst.2022.01535
Kidney Int. 2023 Feb 18. pii: S0085-2538(23)00122-9. [Epub ahead of print]

A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease.

Pascale Gluais Dagorn, Bjoern Buchholz, Andre Kraus, Battsetseg Batchuluun, Hester Bange, Laura Blockken, Gregory R Steinberg, David E Moller, Sophie Hallakou-Bozec.

  Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator, adenosine monophosphate stimulated protein kinase (AMPK), has been implicated as a promising new therapeutic target. To address this hypothesis, we determined the effects of a potent and selective clinical stage direct allosteric AMPK activator, PXL770, in canine and patient-derived 3D cyst models and an orthologous mouse model of ADPKD. PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. In an inducible, kidney epithelium-specific Pkd1 knockout mouse model, PXL770 produced kidney AMPK pathway engagement, prevented the onset of kidney failure (reducing blood urea by 47%), decreased cystic index by 26% and lowered the kidney weight to body weight ratio by 35% compared to untreated control Pkd1 knockout mice. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication.

Keywords:  ADPKD; Chronic kidney disease; animal model; fibrosis; inflammation; mitochondria; renal pathology; uremia

DOI:  https://doi.org/10.1016/j.kint.2023.01.026
J Ethnopharmacol. 2023 Feb 18. pii: S0378-8741(23)00162-9. [Epub ahead of print] 116294

Platycodin D stimulates AMPK activity to inhibit the neurodegeneration caused by reactive oxygen species-induced inflammation and apoptosis.

Jing-Tian Zhang, Li-Ya Xie, Qiong Shen, Wei Liu, Ming-Han Li, Rui-Yi Hu, Jun-Nan Hu, Zi Wang, Chen Chen, Wei Li.

   ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) was considered to be a neurodegenerative disease that caused cognitive impairment. Reactive Oxidative stress (ROS) was considered to be one of a major cause of the onset and progression of AD. Platycodin D (PD), a representative saponin from Platycodon grandiflorum, has conspicuous antioxidant activity. However, whether PD could protect nerve cell against oxidative injury remains unknown.
AIM OF STUDY: This study investigated the regulatory effects of PD on neurodegeneration caused by ROS. To determine whether PD could play its own antioxidant role in neuronal protection.
MATERIALS AND METHODS: First, PD(2.5, 5 mg/kg) ameliorated the memory impairment induced by AlCl3 (100 mg/kg) combined with D-galactose (D-Gal) (200 mg/kg) in mice, using the radial arm maze (RAM) test, and neuronal apoptosis in the hippocampus was evaluated by hematoxylin and eosin staining (HE). Next, the effects of PD (0.5, 1, and 2 μM) on okadaic-acid (OA) (40 nM) -induced apoptosis and inflammation of HT22 cells were investigated. Mitochondrial ROS production was measured by fluorescence staining. The potential signaling pathways were identified through Gene Ontology enrichment analysis. The role of PD in regulating AMP-activated protein kinase (AMPK) was assessed using siRNA silencing of genes and an ROS inhibitor.
RESULTS: In vivo, PD improved memory in mice, and recovered the morphological changes of brain tissue and nissl bodies. In vitro experiment, PD increased cell viability (p < 0.01; p < 0.05;p < 0.001), decreased apoptosis (p < 0.01), reduced excessive ROS and MDA, rised SOD and CAT content(p < 0.01; p < 0.05). Morover, it can block the inflammatory response caused by ROS. Be important, PD strengthen antioxidant ability by elevating AMPK activation both in vivo and in vitro. Furthermore, molecular docking suggested a good likelihood of PD-AMPK binding.
CONCLUSION: AMPK activity is vital for the neuroprotective effect of PD, suggesting that PD may be a potential pharmaceutical agent to treat ROS-induced neurodegeneration.

Keywords:  AMPK; Alzheimer's disease; Neurodegeneration; Platycodin D; ROS

DOI:  https://doi.org/10.1016/j.jep.2023.116294
Cells. 2023 Feb 04. pii: 519. [Epub ahead of print]12(4):

Interplays of AMPK and TOR in Autophagy Regulation in Yeast.

John-Patrick Alao, Luc Legon, Aleksandra Dabrowska, Anne-Marie Tricolici, Juhi Kumar, Charalampos Rallis.

  Cells survey their environment and need to balance growth and anabolism with stress programmes and catabolism towards maximum cellular bioenergetics economy and survival. Nutrient-responsive pathways, such as the mechanistic target of rapamycin (mTOR) interact and cross-talk, continuously, with stress-responsive hubs such as the AMP-activated protein kinase (AMPK) to regulate fundamental cellular processes such as transcription, protein translation, lipid and carbohydrate homeostasis. Especially in nutrient stresses or deprivations, cells tune their metabolism accordingly and, crucially, recycle materials through autophagy mechanisms. It has now become apparent that autophagy is pivotal in lifespan, health and cell survival as it is a gatekeeper of clearing damaged macromolecules and organelles and serving as quality assurance mechanism within cells. Autophagy is hard-wired with energy and nutrient levels as well as with damage-response, and yeasts have been instrumental in elucidating such connectivities. In this review, we briefly outline cross-talks and feedback loops that link growth and stress, mainly, in the fission yeast Schizosaccharomyces pombe, a favourite model in cell and molecular biology.

Keywords:  S. pombe; ageing; caloric restriction; fission yeast; lifespan; mTOR; rapamycin

DOI:  https://doi.org/10.3390/cells12040519
Front Mol Neurosci. 2023 ;16 1128429

Genetic polymorphisms of PRKAA1 (AMPKα1) and postherpetic pain susceptibility: Multicenter, randomized control, and haplotype analysis study.

Yang Mei, Qi Chen, Yu-Ping Li, Yao-Hua Chen, Juan Xia, Jie Zeng, Le-Hua Yu, Wei Li, Jian Cui.

  Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) is a pivotal regulatory protein in energy metabolism. In a pilot study, we found that AMPK-associated energy metabolism imbalance in neurons contributes to the occurrence and maintenance of neuropathic pain (NeP). This study aimed to explore the relationship between genetic polymorphisms of AMPK gene (Rs13361707, rs3792822, and rs10074991) in PRKAA1 and postherpetic neuralgia (PHN) in Chinese individuals. Hundred and thirty two patients with PHN and 118 control individuals were enrolled in this study. All blood samples were shuffled and blinded to the person performing the haplotype analysis. Rs13361707, rs3792822, and rs10074991 PRKAA1 genotypes were identified in all participants. Dominant and recessive models were used for evaluating the association between these nucleotide polymorphisms and PHN susceptibility. A haplotype analysis of PHN patients and healthy controls was performed. Clinical characteristics between the two groups were not significantly different (p > 0.05) except that the ages in control subjects were younger than the PHN patients (p < 0.05). Genotypes and allele frequencies are significantly different between the PHN patients and control subjects for the rs13361707 and rs10074991 polymorphisms (p < 0.05), but not for rs3792822 (p > 0.05). In addition, the CCG haplotype of rs13361707-rs3792822-rs10074991 correlated negatively with PHN occurrence, but TCA was positively correlated with PHN (p < 0.05). Our results indicate that PRKAA1 gene polymorphisms rs13361707 and rs10074991 were associated with a risk of PHN, and that the CCG haplotype of rs13361707-rs3792822-rs10074991 correlated negatively with PHN occurrence in haplotype analysis. TCA was positively associated with PHN in Chinese individuals.

Keywords:  AMPK; Chinese population; PRKAA1; polymorphism; postherpetic neuralgia

DOI:  https://doi.org/10.3389/fnmol.2023.1128429
J Immunol Res. 2023 ;2023 1241774

Downregulation of miR-137 Facilitates CD4+ T Cell Pyroptosis in Systemic Lupus Erythematosus via Stimulating AMPK Pathway.

Aimin Gong, Long Mi, Fangzhi Wei, Yanping Zhuang, Yitian Song, Chengdan Pan, Xuan Zhang, Guiling Lin, Zhiquan Wu, Ying Liu.

Objective: From the pathogenic mechanism point of view, systemic lupus erythematosus (SLE) features prominently in T lymphocyte apoptosis. Yet the regulatory mechanism underlying SLE cell apoptosis remains to be explored. This research intends to clarify the role played by miR-137 in SLE and the underlying mechanisms.
Methods: Twenty SLE patients (SLE group) and twenty healthy controls (control group) were selected, from whom peripheral blood CD4+ T cells were isolated via magnetic-activated cell sorting. Reverse transcription-polymerase chain reaction (RT-PCR) quantified miR-137 and AMP-activated protein kinase (AMPK) in CD4+ T cells. Further, transfection of miR-137 mimics and inhibitors into CD4+ T cells was carried out to alter miR levels. Levels of pyroptosis, apoptosis, and inflammatory- and pyroptosis-related proteins were determined through PI staining, flow cytometry, and Western blotting, respectively. A luciferase reporter gene assay identified the targeting relation between miR-137 and AMPK.
Results: SLE patients showed downregulated miR-137 and upregulated AMPK in CD4+ T cells than controls. miR-137 upregulation by miR-137 mimic transfection inhibited Jurkat cell pyroptosis and apoptosis at both mRNA and protein levels and suppressed NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome activity and pyroptosis-related protein gasdermin D (GSDMD), while miR-137 inhibitor transfection contributed to completely opposite effects. miR-137 directly targeted AMPK, as indicated by the luciferase reporter gene assay. Furthermore, miR-137 inhibitor intervention induced healthy CD4+ T cell pyroptosis and apoptosis via mediating AMPK, whereas miR-137 mimic transfection into CD4+ T cells of SLE patients leads to opposite results.
Conclusion: Upregulating miR-137 inhibits CD4+ T cell pyroptosis in SLE patients by modulating the AMPK pathway, suggesting the potential diagnostic and therapeutic role of miR-137 in SLE.

DOI: https://doi.org/10.1155/2023/1241774
Biochem Soc Trans. 2023 Feb 23. pii: BST20220833. [Epub ahead of print]

The role of CaMKK2 in Golgi-associated vesicle trafficking.

Grace Kennedy, Olivia Gibson, Dáire T O'Hare, Ian G Mills, Emma Evergren.

  Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine-protein kinase, that is involved in maintaining various physiological and cellular processes within the cell that regulate energy homeostasis and cell growth. CaMKK2 regulates glucose metabolism by the activation of downstream kinases, AMP-activated protein kinase (AMPK) and other calcium/calmodulin-dependent protein kinases. Consequently, its deregulation has a role in multiple human metabolic diseases including obesity and cancer. Despite the importance of CaMKK2, its signalling pathways and pathological mechanisms are not completely understood. Recent work has been aimed at broadening our understanding of the biological functions of CaMKK2. These studies have uncovered new interaction partners that have led to the description of new functions that include lipogenesis and Golgi vesicle trafficking. Here, we review recent insights into the role of CaMKK2 in membrane trafficking mechanisms and discuss the functional implications in a cellular context and for disease.

Keywords:  Golgi apparatus; calmodulin; protein–serine–threonine kinases; trafficking

DOI:  https://doi.org/10.1042/BST20220833
ASN Neuro. 2023 Jan-Dec;15:15 17590914231159226

Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.

Jinjing Jia, Jiayi Yin, Yu Zhang, Guangtao Xu, Min Wang, Haiying Jiang, Li Li, Xiansi Zeng, Dongsheng Zhu.

  Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Keywords:  AMPK/Sirt1/PGC1α; Alzheimer's disease; mitochondrial biogenesis; neuroprotection; thioredoxin-1

DOI:  https://doi.org/10.1177/17590914231159226
Basic Clin Pharmacol Toxicol. 2023 Feb 23.

Artesunate alleviates intracerebral hemorrhage secondary injury by inducing ferroptosis in M1-polarized microglia and suppressing inflammation through AMPK/mTORC1/GPX4 pathway.

Guanfeng Xie, Yubing Liang, Wen Gao, Liya Wu, Yan Zhang, Ziming Ye, Chao Qin.

  Intracerebral hemorrhage (ICH) is a catastrophic subtype of stroke with severe morbidity and mortality. However, little progress has been made in the subsequent secondary injury. Artesunate, a water-soluble semi-synthetic derivative of artemisinin, exhibits remarkable pharmacological effects on anti-neuroinflammation. However, the effects of artesunate on ICH remain unknown. In the present study, hemoglobin (Hb) treatment in BV2 cell and collagenase type IV intracerebroventricular injection in Sprague-Dawley rats were used to establish in vitro and in vivo ICH models, respectively. For in vivo, the neurological scores, hematoma volume, brain edema, inflammatory factors and iron deposition were evaluated. Besides, lipopolysaccharide (LPS) was used in in vitro to polarize BV2 cell to M1 phenotype. Cell viability, cellular reactive oxygen species (ROS), Fe2+ concentration, and lipid peroxidation levels, ferroptosis associated proteins and mRNA, morphological of mitochondria were measured in vitro. Additionally, the AMP-activated protein kinase (AMPK)/Mammalian/mechanistic target of rapamycin (mTOR) pathway were measured by western blot and immunofluorescence staining. The present in vivo results indicated that artesunate significantly ameliorated neurological deficits, hematoma volume and brain edema in ICH rats. Besides, artesunate suppressed the M1-microglia relative inflammatory factors and upregulated iron deposition. For in vitro, artesunate significantly selectively decreased the viability of LPS-stimulated BV2 cell. Furthermore, ROS and lipid peroxidation levels were upregulated. And the glutathione peroxidase 4 (GPX4) were silenced via the AMPK/mTORC1 axis. Our finding supports that artesunate ameliorates the ICH secondary injury both in vitro and in vivo by inducing ferroptosis in microglia and further inhibiting inflammation mainly through the AMPK/mTORC1/GPX4 pathway. This finding may provide a novel target for ICH treatment.

Keywords:  AMPK/mTORC1 pathway; Artesunate; ferroptosis; intracerebral hemorrhage; microglia

DOI:  https://doi.org/10.1111/bcpt.13848
Br J Cancer. 2023 Feb 17.

AMPK phosphorylates and stabilises copper transporter 1 to synergise metformin and copper chelator for breast cancer therapy.

Xiaomei Zhang, Qiwei Jiang, Yaqing Su, Lang Bu, Zicheng Sun, Xueji Wu, Bing Gao, Lei Wang, Ying Lin, Wei Xie, Jianping Guo.

BACKGROUND: Predominant roles of copper and its transporter, copper transporter 1 (CTR1), in tumorigenesis have been explored recently; however, the upstream regulation of CTR1 and combinational intervention of copper chelators in malignancies remain largely unclear.
METHODS: CRISPR/Cas9-based kinome screening was used to identify the CTR1 upstream kinases. Immunofluorescence assays were utilised to detect CTR1 localisation. In vitro kinase assays and mass spectrometry were performed to detect CTR1 phosphorylation. Ubiquitination assays were performed to validate CTR1 stability. Colony formation, EdU labelling, Annexin V-FITC/PI-based apoptosis assays were carried out to detect the drug effect on cell growth and apoptosis. Xenografted mouse models were employed to investigate drug effects in vivo.
RESULTS: We identify that CTR1 undergoes AMPK-mediated phosphorylation, which enhances CTR1 stabilisation and membrane translocation by affecting Nedd4l interaction, resulting in increased oncogenic roles in breast cancer. Importantly, activation of AMPK with its agonist metformin markedly enhances CTR1 levels, and leads to the combinational usage of AMPK agonists and copper chelators for breast cancer treatment.
CONCLUSIONS: Our findings not only reveal the crosstalk between energy response and copper uptake via AMPK-mediated CTR1 phosphorylation and stability but also highlight the strategy to combat breast cancer by a combination of AMPK agonists and copper chelators.
SIGNIFICANCE: The connection between energy response and copper homoeostasis is linked by AMPK phosphorylating and stabilising CTR1, which provides a promising strategy to combat breast cancer by combining AMPK agonists and copper chelators.

DOI: https://doi.org/10.1038/s41416-022-02127-4
Heliyon. 2023 Feb;9(2): e13330

Luteolin improves vasoconstriction function and survival of septic mice via AMPK/NF-κB pathway.

Bin Liu, Hailong Su.

  Septic shock, the leading cause of death in sepsis, is related to vasoconstriction dysfunction. To investigate the effects of Luteolin (LTL), a flavonoid polyphenol compound, on vasoconstriction dysfunction in septic mice and the underlying mechanism, cecal ligation and puncture (CLP) surgery was performed on wild-type C57BL/6 mice to induce septic shock. Mice were intraperitoneally injected with 0.2 mg/kg LTL within 10 min after CLP surgery with or without 20 mg/kg Compound C (AMPK inhibitor) (CC) 1 h before CLP surgery, and re-administrated every 12 h. The survival rate, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) were explored. After the mice were sacrificed, the vasoconstriction function, inflammatory indicators, and possible regulatory signaling pathways were examined. Our data showed that CLP decreased the survival rate, SAP, DAP, MAP, vasoconstriction function, and expression of ADRA1A and p-AMPK/AMPK, as well as increased the mRNA expression of inflammatory cytokines and iNOS, the serum levels of inflammatory cytokines, and the levels of iNOS, p-p65/p65, and p-IκBα/IκBα in aortas (P < 0.05), which could be reversed by LTL treatment (P < 0.05). However, inhibition of AMPK could abolish the protective effects of LTL (P < 0.05). In conclusion, our study manifested that LTL could prevent vasoconstriction dysfunction and increase survival of septic mice via activating AMPK, which suggested that LTL could be a novel therapeutic option for patients with sepsis.

Keywords:  AMPK; Luteolin; Septic shock; Vascular hyporeactivity; Vasoconstriction dysfunction

DOI:  https://doi.org/10.1016/j.heliyon.2023.e13330
Sci Rep. 2023 Feb 17. 13(1): 2858

Modulation of AMPK/ TET2/ 5-hmC axis in response to metabolic alterations as a novel pathway for obesity-related colorectal cancer development.

Takashi Kon, Yu Sasaki, Yasuhiko Abe, Yusuke Onozato, Makoto Yagi, Naoko Mizumoto, Takayuki Sakai, Matsuki Umehara, Minami Ito, Shuhei Nakamura, Hiroki Goto, Yoshiyuki Ueno.

Obesity is a major risk factor for colorectal cancer (CRC). Sustained hyperglycemia destabilizes tumor suppressor ten-eleven translocation (TET) 2, which is a substrate of AMPK, thereby dysregulating 5-hydroxymethylcytosine (5-hmC). However, the role played by this novel pathway in the development of obesity-related CRC is unclear. In this study, we aimed to evaluate the expression levels of TET2 and 5-hmC in obesity-related CRC and the effects of TET2 expression on the proliferation of CRC cells. To this end, surgically resected CRC samples from seven obese patients (Ob-CRC) and seven non-obese patients (nOb-CRC) were analyzed, and expression levels of the TET family and 5-hmC were compared between the groups. A decrease was observed in TET2 mRNA levels and 5-hmC levels in Ob-CRC compared to that in nOb-CRC. Furthermore, we used CRC cell lines to investigate the relationship between insulin, proliferation, and TET expression and AMPK. In cell lines, glucose and insulin treatments suppressed the expression of TET2 and increased cell proliferation. Downregulation of TET2 using siRNA also induced cell proliferation. An AMPK activator inhibited insulin- or glucose-stimulated cell proliferation and restored TET2 expression. We propose the AMPK-TET2-5-hmC axis as a novel pathway and potential therapeutic target in obesity-related CRC development.

DOI: https://doi.org/10.1038/s41598-023-29958-2
J Diabetes Res. 2023 ;2023 8776878

Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy.

Moein Ala.

Sestrin2 regulates cell homeostasis and is an upstream signaling molecule for several signaling pathways. Sestrin2 leads to AMP-activated protein kinase- (AMPK-) and GTPase-activating protein activity toward Rags (GATOR) 1-mediated inhibition of mammalian target of rapamycin complex 1 (mTORC1), thereby enhancing autophagy. Sestrin2 also improves mitochondrial biogenesis via AMPK/Sirt1/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) signaling pathway. Blockade of ribosomal protein synthesis and augmentation of autophagy by Sestrin2 can prevent misfolded protein accumulation and attenuate endoplasmic reticulum (ER) stress. In addition, Sestrin2 enhances P62-mediated autophagic degradation of Keap1 to release nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 release by Sestrin2 vigorously potentiates antioxidant defense in diabetic nephropathy. Impaired autophagy and mitochondrial biogenesis, severe oxidative stress, and ER stress are all deeply involved in the development and progression of diabetic nephropathy. It has been shown that Sestrin2 expression is lower in the kidney of animals and patients with diabetic nephropathy. Sestrin2 knockdown aggravated diabetic nephropathy in animal models. In contrast, upregulation of Sestrin2 enhanced autophagy, mitophagy, and mitochondrial biogenesis and suppressed oxidative stress, ER stress, and apoptosis in diabetic nephropathy. Consistently, overexpression of Sestrin2 ameliorated podocyte injury, mesangial proliferation, proteinuria, and renal fibrosis in animal models of diabetic nephropathy. By suppressing transforming growth factor beta (TGF-β)/Smad and Yes-associated protein (YAP)/transcription enhancer factor 1 (TEF1) signaling pathways in experimental models, Sestrin2 hindered epithelial-mesenchymal transition and extracellular matrix accumulation in diabetic kidneys. Moreover, modulation of the downstream molecules of Sestrin2, for instance, augmentation of AMPK or Nrf2 signaling and inhibition of mTORC1, has been protective in diabetic nephropathy. Regarding the beneficial effects of Sestrin2 on diabetic nephropathy and its interaction with several signaling molecules, it is worth targeting Sestrin2 in diabetic nephropathy.

DOI: https://doi.org/10.1155/2023/8776878
Nat Commun. 2023 Feb 21. 14(1): 949

Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models.

Christopher Livelo, Yiming Guo, Farah Abou Daya, Vasanthi Rajasekaran, Shweta Varshney, Hiep D Le, Stephen Barnes, Satchidananda Panda, Girish C Melkani.

Obesity caused by genetic and environmental factors can lead to compromised skeletal muscle function. Time-restricted feeding (TRF) has been shown to prevent muscle function decline from obesogenic challenges; however, its mechanism remains unclear. Here we demonstrate that TRF upregulates genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt), while Dgat2, involved in triglyceride synthesis is downregulated in Drosophila models of diet- and genetic-induced obesity. Muscle-specific knockdown of Gnmt, Sardh, and CG5955 lead to muscle dysfunction, ectopic lipid accumulation, and loss of TRF-mediated benefits, while knockdown of Dgat2 retains muscle function during aging and reduces ectopic lipid accumulation. Further analyses demonstrate that TRF upregulates the purine cycle in a diet-induced obesity model and AMPK signaling-associated pathways in a genetic-induced obesity model. Overall, our data suggest that TRF improves muscle function through modulations of common and distinct pathways under different obesogenic challenges and provides potential targets for obesity treatments.

DOI: https://doi.org/10.1038/s41467-023-36474-4
Biomolecules. 2023 Jan 29. pii: 250. [Epub ahead of print]13(2):

Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review.

Yi Zhang, Fang Zhou, Jiaheng Guan, Lukun Zhou, Baoan Chen.

  Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.

Keywords:  AMPK; leukemia; lymphoma; metformin; myeloma

DOI:  https://doi.org/10.3390/biom13020250
J Agric Food Chem. 2023 Feb 23.

Intracellular Calcium Overload and Activation of CaMKK/AMPK Signaling Are Related to the Acceleration of Muscle Glycolysis of Broiler Chickens Subjected to Acute Stress.

Hongju Liao, Lin Zhang, Jiaolong Li, Tong Xing, Feng Gao.

  The current study investigated the effect of preslaughter transport on stress response and meat quality of broilers and explored the underlying mechanisms involved in the regulation of muscle glycolysis through calcium/calmodulin-dependent protein kinase kinase (CaMKK)/AMP-activated protein kinase (AMPK) signaling. Results suggested that transport induced stress responses of broilers and caused PSE-like syndrome of pectoralis major muscle. Preslaughter transport enhanced the mRNA expressions of glycogen phosphorylase and glucose transporters, as well as the activities of glycolytic enzymes, which accelerated the breakdown of glycolytic substrates and the accumulation of lactic acid. In addition, acute stress induced abnormal intracellular calcium homeostasis by disrupting calcium channels on the cell membrane and sarcoplasmic reticulum, which led to the activation of CaMKK and promoted AMPK phosphorylation. This study provides evidence that the intracellular calcium overload and the enhancement of CaMKK/AMPK signaling are related to the accelerated muscle glycolysis of broiler chickens subjected to acute stress.

Keywords:  AMPK; CaMKK; acute stress; broiler chicken; glycolysis; meat quality

DOI:  https://doi.org/10.1021/acs.jafc.2c07391
Front Pharmacol. 2023 ;14 1089812

Metformin attenuates fibroblast activation during pulmonary fibrosis by targeting S100A4 via AMPK-STAT3 axis.

Huimin Ji, Hongliang Dong, Yuejiao Lan, Yuqian Bi, Xuan Gu, Yongyue Han, Chongyang Yang, Minghan Cheng, Jian Gao.

  Fibroblasts activation is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis pathogenesis, and transforming growth factor (TGF)-β1 plays a key regulatory role in fibroblast activation. It has been reported that metformin (MET) alleviated bleomycin (BLM)-induced pulmonary fibrosis (PF) by regulating TGF-β1-induced fibroblasts activation, but the underlying mechanisms still deserve further investigations. In this study, MET blocked α-smooth muscle actin (α-SMA) accumulation in vivo accompanied with S100A4 expression and STAT3 phosphorylation inhibition, resulting in attenuating the progression of lung fibrosis after BLM administration. We determined that S100A4 plays critical roles in fibroblasts activation in vitro, evidenced by siRNA knockdown of S100A4 expression downregulated TGF-β1 induced α-SMA production in Human fetal lung fibroblast (HFL1) cells. Importantly, we found for the first time that the expression of S100A4 in fibroblasts was regulated by STAT3. Stattic, an effective small molecule inhibitor of STAT3 phosphorylation, reduced S100A4 level in TGF-β1- treated HFL1 cells accompanied with less α-SMA production. We further found that MET, which inhibits STAT3 phosphorylation by AMPK activation, also inhibits fibroblasts activation by targeting S100A4 in vitro. Together all these results, we conclude that S100A4 contributes to TGF-β1- induced pro-fibrogenic function in fibroblasts activation, and MET was able to protect against TGF-β1-induced fibroblasts activation and BLM-induced PF by down-regulating S100A4 expression through AMPK-STAT3 axis. These results provide a useful clue for a clinical strategy to prevent PF.

Keywords:  S100A4; STAT3; fibroblast activation; metformin; pulmonary fibrosis

DOI:  https://doi.org/10.3389/fphar.2023.1089812
Antioxidants (Basel). 2023 Feb 05. pii: 385. [Epub ahead of print]12(2):

The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway.

Shuyan Zhou, Jacob Hum, Kaan Taskintuna, Stephanie Olaya, Jeremy Steinman, Junfeng Ma, Nady Golestaneh.

  Initially discovered by Makuto Kuro-o in 1997, Klotho is a putative aging-suppressor gene when overexpressed and accelerates aging when deleted in mice. Previously, we showed that α-Klotho regulates retinal pigment epithelium (RPE) functions and protects against oxidative stress. However, the mechanisms by which Klotho influences RPE and retinal homeostasis remain elusive. Here, by performing a series of in vitro and in vivo experiments, we demonstrate that Klotho regulates cell viability under oxidative stress, mitochondrial gene expression and activity by inducing the phosphorylation of AMPK and p38MAPK, which in turn phosphorylate and activate CREB and ATF2, respectively, triggering PGC-1α transcription. The inhibition of Klotho in human RPE cells using CRISPR-Cas9 gene editing confirmed that a lack of Klotho negatively affects RPE functions, including mitochondrial activity and cell viability. Proteomic analyses showed that myelin sheath and mitochondrial-related proteins are downregulated in the RPE/retina of Kl-/- compared to WT mice, further supporting our biochemical observations. We conclude that Klotho acts upstream of the AMPK/PGC-1α pathway and regulates RPE/retinal resistance to oxidative stress, mitochondrial function, and gene and protein expressions. Thus, KL decline during aging could negatively impact retinal health, inducing age-related retinal degeneration.

Keywords:  AMD; AMPK; Klotho; PGC-1a; aging; retina; retinal pigment epithelium

DOI:  https://doi.org/10.3390/antiox12020385
Biochem Cell Biol. 2023 Feb 23.

Hedgehog signal activates Ampk via Smoothened to promote autophagy and lipid degradation in hepatocytes.

Yixing Yao, Tianyuan Li, Tingting Yu, Xin Yang, Yue Wang, Jing Cai, Steven Y Cheng, Chen Liu, Shen Yue.

Studies in the past decade have shown that lipid droplets stored in liver cells under starvation are encapsulated by autophagosomes and fused to lysosomes via the endocytic system. Autophagy responds to a variety of environmental factors inside and outside the cell, so it has a complex signal regulation network. To this end, we first explored the role of HH in autophagy and lipid metabolism. Treatment of normal mouse liver cells with SAG and GDC-0449 revealed elevated phosphorylation of AMPK and increased lipidation of LC3. SAG and GDC-0449 were agonist and antagonist of Smo in canonical Hedgehog pathway respectively, but they played a consistent role in the regulation of autophagy in hepatocytes. We further knocked down the Smo and found that the effects of SAG and GDC-0449 disappeared, indicating that the non-canonical Hedgehog-Smo pathway was involved in the regulation of autophagy in hepatocytes. In addition, SAG and GDC-0449 promoted lipid degradation and inhibited lipid production signals. Knockdown of Smo slowed down the rate of lipid degradation rather than Sufu or Gli1, indicating that Hh signaling regulated the lipid metabolism via Smo. In summary, Hedgehog activates Ampk via Smo to promote autophagy and lipid degradation.

DOI: https://doi.org/10.1139/bcb-2022-0345
ACS Omega. 2023 Feb 14. 8(6): 5393-5405

Concentration-Dependent Cellular Uptake of Graphene Oxide Quantum Dots Promotes the Odontoblastic Differentiation of Dental Pulp Cells via the AMPK/mTOR Pathway.

Ling Lin, Yexin Zheng, Chao Wang, Pei Li, Duoling Xu, Wei Zhao.

As zero-dimension nanoparticles, graphene oxide quantum dots (GOQDs) have broad potential for regulating cell proliferation and differentiation. However, such regulation of dental pulp cells (DPSCs) with different concentrations of GOQDs is insufficiently investigated, especially on the molecular mechanism. The purpose of this study was to explore the effect and molecular mechanism of GOQDs on the odontoblastic differentiation of DPSCs and to provide a theoretical basis for the repair of pulp vitality by pulp capping. CCK-8, immunofluorescence staining, alkaline phosphatase activity assay and staining, alizarin red staining, qRT-PCR, and western blotting were used to detect the proliferation and odontoblastic differentiation of DPSC coculturing with different concentrations of GOQDs. The results indicate that the cellular uptake of low concentration of GOQDs (0.1, 1, and 10 μg/mL) could promote the proliferation and odontoblastic differentiation of DPCSs. Compared with other concentration groups, 1 μg/mL GOQDs show better ability in such promotion. In addition, with the activation of the AMPK signaling pathway, the mTOR signaling pathway was inhibited in DPSCs after coculturing with GOQDs, which indicates that low concentrations of GOQDs could regulate the odontoblastic differentiation of DPSCs by the AMPK/mTOR signaling pathway.

DOI: https://doi.org/10.1021/acsomega.2c06508
Hepatology. 2023 Feb 21.

Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis.

Lili Cheng, R N V Krishna Deepak, Guoqiang Wang, Ziyi Meng, Lei Tao, Mengqing Xie, Wenna Chi, Yuming Zhang, Mingming Yang, Yilie Liao, Ruiqun Chen, Yu Liang, Junyu Zhang, Yuedong Huang, Weihua Wang, Zhiying Guo, Yunfang Wang, Jiandie D Lin, Hao Fan, Ligong Chen.

BACKGROUND AIMS: SLC25A47 was initially identified as mitochondrial hepatocellular carcinoma (HCC)-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism.
APPROACH RESULTS: Treatment of hepatocytes with metformin found that metformin can transcriptionally activate the expression of Slc25a47, which is required for AMPKα phosphorylation. Slc25a47-deficient mice had increased hepatic lipid content, triglycerides and cholesterol levels, and we found that Slc25a47-deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in inhibition of lipogenesis. Moreover, using a diethylnitrosamine (DEN)-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mTOR cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD+ was an endogenous substrate for SLC25A47 and the activity of NAD+-dependent SIRT3 declined in Slc25a47-deficient mice, followed by inactivation of AMPKα.
CONCLUSIONS: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD+ transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating non-alcoholic fatty liver disease (NAFLD) and HCC.

DOI: https://doi.org/10.1097/HEP.0000000000000314