bims-amsmem 2022-12-25 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–12–25
sixteen papers selected by
Dipsikha Biswas, Københavns Universitet

Changes in AMPK activity induces cellular senescence in human dental follicle cells.
Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis.
AMPK Promotes Larval Metamorphosis of Mytilus coruscus.
Metformin Attenuates Inflammation and Fibrosis in Thyroid-Associated Ophthalmopathy.
Tumor lysis syndrome promotes cancer chemoresistance and relapse through AMPK inhibition.
CREG1 stimulates AMPK phosphorylation and glucose uptake in skeletal muscle cells.
Effect of AMPK activation and glucose availability on myotube LAT1 expression and BCAA utilization.
Lambda-cyhalothrin induces lipid accumulation in mouse liver is associated with AMPK inactivation.
Small-molecule 7,8-dihydroxyflavone counteracts compensated and decompensated cardiac hypertrophy via AMPK activation.
Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity.
Dexmedetomidine alleviates acute lung injury by promoting Tregs differentiation via activation of AMPK/SIRT1 pathway.
Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review).
Mild hypothermia alleviates early brain injury after subarachnoid hemorrhage via suppressing pyroptosis through AMPK/NLRP3 inflammasome pathway in rats.
Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation.
Dysregulation of Angiopoietin-like-4 Associated with Hyperlipidemia-induced Renal Injury by AMPK/ACC Pathway.
Hepatic Polarized Differentiation Promoted the Maturity and Liver Function of Human Embryonic Stem Cell-Derived Hepatocytes via Activating Hippo and AMPK Signaling Pathways.

Exp Gerontol. 2022 Dec 21. pii: S0531-5565(22)00380-1. [Epub ahead of print]172 112071

Changes in AMPK activity induces cellular senescence in human dental follicle cells.

Christian Morsczeck, Anja Reck, Torsten E Reichert.

  Dental Follicle Cells (DFCs) are somatic stem cells with a limited lifespan, but little is known about a possible mechanism of cellular senescence. Previous studies have shown that cellular senescence is associated with increased demand of glycolsis or the "glycolytic metabotype", which can be induced by activation of 5' adenosine monophosphate-activated protein kinase (AMPK), and decreased autophagy. This study examined the role of AMPK in inducing senescence in DFCs. During the induction of cellular senescence, AMPK activity was impaired, suggesting a negative impact on senescence induction. In line with this assumption, cellular senescence was induced upon inhibition of AMPK with a specific siRNA. In addition, after this inhibition, autophagy was also inhibited. Moreover, specific inhibition of autophagy promoted cellular senescence. However, inducers of AMPK such as metformin or AICAR surprisingly increased senescence in DFCs. Interestingly, autophagy was impaired after long-term induction of AMPK with AICAR and metformin. Moreover, activation of AMPK induces the consumption of glucose but decreases NAD/NADH ratio in DFCs that suggest not only "glycolytic metabotype" of DFCs but also Mitochondrial Dysfunction Associated Senescence (MiDAS). Both changes are highly associated with the induction of cellular senescence. Hence, both AMPK activation and inhibition promote the induction of cellular senecence of DFCs.

Keywords:  AMP-kinase; Autophagy; Cellular senescence; Dental follicle cells; Metformin

DOI:  https://doi.org/10.1016/j.exger.2022.112071
Cell Rep. 2022 Dec 20. pii: S2211-1247(22)01758-2. [Epub ahead of print]41(12): 111862

Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis.

Katyayanee Neopane, Natalie Kozlov, Florentina Negoita, Lisa Murray-Segal, Robert Brink, Ashfaqul Hoque, Ashley J Ovens, Gavin Tjin, Luke M McAloon, Dingyi Yu, Naomi X Y Ling, Matthew J Sanders, Jonathan S Oakhill, John W Scott, Gregory R Steinberg, Kim Loh, Bruce E Kemp, Kei Sakamoto, Sandra Galic.

  AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a "myristoyl switch" mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity.

Keywords:  AMPK; CP: Metabolism; adiposity; myristoylation; phosphatase; signal transduction; steatosis

DOI:  https://doi.org/10.1016/j.celrep.2022.111862
Genes (Basel). 2022 Dec 16. pii: 2384. [Epub ahead of print]13(12):

AMPK Promotes Larval Metamorphosis of Mytilus coruscus.

Wen Zhang, Yuyi Wang, Xiaomeng Hu, Zhongsheng Zhou, Youting Zhu, Xiao Liang, Jin-Long Yang.

  Metamorphosis is a critical process in the transition from planktonic life to benthic life for marine invertebrates, which is accompanied by a large amount of energy consumption. Previous studies have proved that AMP-activated protein kinase (AMPK), as a vital energy regulator, plays a prominent role in mediating the growth and development of terrestrial animals. However, its function in the growth and development of marine invertebrates, especially in metamorphosis, remains elusive. This study explored the function of AMPK in the larval metamorphosis of Mytilus coruscus. The full-length cDNA of AMPK genes in M. coruscus was cloned and characterized, which is composed of three subunits, McAMPKα, McAMPKβ, and McAMPKγ. Pharmacological tests demonstrated that through the application of an AMPK activator, AMP substantially enhanced the larval metamorphosis rate (p < 0.05). By contrast, the larval metamorphosis rate decreased significantly after being treated with the AMPK inhibitor Compound C (p < 0.05). McAMPK gene knock-down resulted in a reduction in McAMPK gene expression (p < 0.05), and the larval metamorphosis of M. coruscus was significantly restrained (p < 0.05). These results indicated that AMPK signaling is vital in the larval metamorphosis of M. coruscus, which advances further understanding in exploring the molecular mechanisms in the metamorphosis of marine invertebrate larvae.

Keywords:  AMPK genes; Mytilus coruscus; RNA interference; activator; inhibitor; metamorphosis

DOI:  https://doi.org/10.3390/genes13122384
Int J Mol Sci. 2022 Dec 07. pii: 15508. [Epub ahead of print]23(24):

Metformin Attenuates Inflammation and Fibrosis in Thyroid-Associated Ophthalmopathy.

Zhihui Xu, Huijing Ye, Wei Xiao, Anqi Sun, Shenglan Yang, Te Zhang, Xiaotong Sha, Huasheng Yang.

  The pathogenesis of thyroid-associated ophthalmopathy (TAO) is still unclear, and therapeutic drugs have great limitations. As metformin has multiple therapeutic effects in many autoimmune diseases, we explored the effects of metformin on TAO in an in vitro fibroblast model. We used orbital connective tissues and fibroblasts that were obtained from TAO patients and normal controls. The activity of adenosine monophosphate-activated protein kinase (AMPK) and the levels of inflammatory or fibrotic factors were examined by immunofluorescence (IF) and immunohistochemistry (IHC). Quantitative real-time polymerase chain reaction (qPCR), cytokine quantification by enzyme-linked immunosorbent sssay (ELISA), IF, and western blotting (WB) were used to measure the expression of factors related to inflammation, fibrosis, and autophagy. To determine the anti-inflammatory and antifibrotic mechanisms of metformin, we pretreated cells with metformin, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, an AMPK activator) or compound C (CC, an AMPK inhibitor) for 24 h and used WB to verify the changes in protein levels in the AMPK/mammalian target of rapamycin (mTOR) pathway. We determined that the low activity of AMPK in the periorbital tissue of TAO patients may be closely related to the occurrence and development of inflammation and fibrosis, and metformin exerts multiple effects by activating AMPK in TAO. Furthermore, we suggest that AMPK may be a potential target of TAO therapy.

Keywords:  AMPK; metformin; orbital fibroblast; thyroid-associated ophthalmopathy

DOI:  https://doi.org/10.3390/ijms232415508
Int Immunopharmacol. 2022 Dec 15. pii: S1567-5769(22)01053-0. [Epub ahead of print]114 109568

Tumor lysis syndrome promotes cancer chemoresistance and relapse through AMPK inhibition.

Eslam E Abd El-Fattah.

  Cancer is a disease caused when cells divide uncontrollably and spread into surrounding tissues. There are different therapeutic modalities that control cancer growth, of which surgery, chemotherapy, and radiotherapy. Chemotherapy is a cancer treatment approach in which medications are used to inhibit cell proliferation and tumor multiplication, thus avoiding invasion and metastasis and thus eradicate cancer. One of the common complications associated with cancer chemotherapy is rapid lysis of expanding tumor cells, known as tumor lysis syndrome (TLS). TLS is associated with number of metabolic changes such as hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. Among the consequences of hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia is the inhibition of 5' AMP-activated protein kinase (AMPK). Inhibition of AMPK induced different cancer chemo-resistance mechanisms such as cancer stem cells (CSCs), p-glycoproteins, Octamer-binding transcription factor 4 (OCT-4), homeobox protein NANOG, Krüppel-like factor 4 (KLF4) and immune microenvironment and thus leads to poor response to chemotherapy and even relapses after treatment. Our review aims to uncover new mechanisms underlying the metabolic consequences of tumor lysis on AMPK in tumor microenvironment. In this review, we also investigated the effect of AMPK on different cancer chemo-resistance mechanisms such as cancer stem cells, p-glycoproteins, OCT-4, NANOG, KLF4 and immune microenvironment.

Keywords:  AMPK; CSCs; Cancer; Chemoresistance; Tumor lysis syndrome

DOI:  https://doi.org/10.1016/j.intimp.2022.109568
Biochem Biophys Res Commun. 2022 Dec 10. pii: S0006-291X(22)01693-X. [Epub ahead of print]641 162-167

CREG1 stimulates AMPK phosphorylation and glucose uptake in skeletal muscle cells.

Ayumi Goto, Yuki Endo, Hitoshi Yamashita.

  The cellular repressor of adenovirus early region 1A-stimulated gene 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and energy metabolism. It also binds to insulin-like growth factor 2 receptor (IGF2R), a protein implicated in muscle regeneration. However, whether CREG1 regulates the regeneration and metabolism of skeletal muscles via IGF2R remains unclear. This study investigates the role of CREG1 in skeletal muscle regeneration and glucose uptake in C2C12 myotubes and a cardiotoxin (CTX)-induced mouse skeletal muscle regeneration model. CTX-treated skeletal muscle showed significantly higher levels of IGF2R, CREG1, phospho-AMPKα Thr172, and GLUT4 proteins. Similarly, treatment of myotubes with CREG1 also stimulated AMPKα phosphorylation and GLUT4 expression. CREG1-induced AMPKα phosphorylation and 2DG uptake in myotubes were suppressed by IGF2R knockdown and Compound C, an AMPK inhibitor. These results suggest that CREG1 stimulates glucose uptake in skeletal muscles partially through AMPK activation. Hence, CREG1 plays an essential role in muscle regeneration by affecting glucose metabolism in skeletal muscles.

Keywords:  AMPK; CREG1; Glucose uptake; IGF2R; Muscle regeneration; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bbrc.2022.12.028
Amino Acids. 2022 Dec 22.

Effect of AMPK activation and glucose availability on myotube LAT1 expression and BCAA utilization.

Caroline N Rivera, Rachel M Watne, Zoe A Brown, Samantha A Mitchell, Andrew J Wommack, Roger A Vaughan.

  Those with insulin resistance often display increased circulating branched-chain amino acids (BCAA), which has been largely attributable to reduced BCAA catabolic capacity. Metabolic stimuli such as exercise activates AMP-activated kinase (AMPK), which promotes the metabolism of BCAA and induction/activation of BCAA catabolic enzymes. Though much attention has been paid to BCAA catabolic machinery, few studies have assessed the effect of AMPK activation on the predominant BCAA transporter, L-type amino acid transporter 1 (LAT1). This study assessed the effect of AMPK activation on LAT1 expression via common chemical AMPK activators in a cell model of skeletal muscle. C2C12 myotubes were treated with either 1 mM AICAR, 1 mM Metformin, or filter-sterilized water (control) for 24 h with either low- (5 mM) or high-glucose (25 mM) media. LAT1 and pAMPK protein content were measured via western blot. BCAA media content was measured using liquid chromatography-mass spectrometry. AICAR treatment significantly increased pAMPK and reduced LAT1 expression. Collectively, pAMPK and LAT1 displayed a significant inverse relationship independent of glucose levels. During low-glucose experiments, AICAR-treated cells had higher BCAA media content compared to other groups, and an inverse relationship between LAT1 and BCAA media content was observed, however, these effects were not consistently observed during high-glucose conditions. Further investigation with AICAR with and without concurrent LAT1 inhibition (via JPH203) also revealed reduced BCAA utilization in AICAR-treated cells regardless of LAT1 inhibition (which also independently reduced BCAA utilization). pAMPK activation via AICAR (but not Metformin) may reduce LAT1 expression and BCAA uptake in a glucose-dependent manner.

Keywords:  Insulin resistance; Isoleucine; Leucine; Skeletal muscle; Valine; pAMPK:AMPK

DOI:  https://doi.org/10.1007/s00726-022-03224-7
Food Chem Toxicol. 2022 Dec 15. pii: S0278-6915(22)00761-X. [Epub ahead of print] 113563

Lambda-cyhalothrin induces lipid accumulation in mouse liver is associated with AMPK inactivation.

Daqian Yang, Xiaotong Sun, Xiangjuan Wei, Boya Zhang, Xingpei Fan, Haining Du, Ruijiao Zhu, Yuri Oh, Ning Gu.

  Lambda-cyhalothrin (LCT) is a critical synthetic Type II pyrethroid insecticide widely applied. Several studies suggest pyrethroids could induce fat accumulation, promote adipogenesis, and impair liver function. Now, the influences of LCT on the hepatic lipid metabolism and the cellular mechanism is still unknown. AMPK has important function in regulating cellular energy balance. To indicate the potential pathogenesis of liver injury caused by LCT exposure, ICR mice were orally administrated with LCT at a dose of 0.4 mg/kg and 2 mg/kg. The results suggest that LCT induced obesity, dyslipidemia and hepatic steatosis. In addition, LCT also induced oxidative stress, liver function injury, and disorganized structure of the liver. Furthermore, upregulation of PPARγ, FASN, and SREBP1c expression, as well as reduction of PPARα and FGF21 expression, bringing with decreases of phosphorylated ratios of AMPK and ACC were found in LCT-L group. These results indicate that LCT at 0.4 mg/kg could result in dyslipidemia and NAFLD in mice. In addition, activation of AMPK in hepatocytes effectively attenuated the effects of LCT. The detailed mechanism of LCT-induced hepatic steatosis is associated with AMPK and its downsteam genes. Activation of AMPK might be a novel protection against the progression of hepatic steatosis induced by LCT.

Keywords:  AMPK; Dyslipidemia; Hepatic steatosis; Lambda-cyhalothrin; Lipid accumulation

DOI:  https://doi.org/10.1016/j.fct.2022.113563
J Geriatr Cardiol. 2022 Nov 28. 19(11): 853-866

Small-molecule 7,8-dihydroxyflavone counteracts compensated and decompensated cardiac hypertrophy via AMPK activation.

Peng-Zhou Hang, Pei-Feng Li, Jie Liu, Feng-Feng Li, Ting-Ting Chen, Yang Pan, Man-Ru Zhang, Hua-Qing Yu, Hong-Yu Ji, Zhi-Min DU, Jing Zhao.

BACKGROUND: Pathological cardiac hypertrophy is a compensated response to various stimuli and is considered a key risk factor for heart failure. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid derivative that acts as a small-molecule brain-derived neurotrophic factor mimetic. The present study aimed to explore the potential role of 7,8-DHF in cardiac hypertrophy.
METHODS: Kunming mice and H9c2 cells were exposed to transverse aortic constriction or isoproterenol (ISO) with or without 7,8-DHF, respectively. F-actin staining was performed to calculate the cell area. Transcriptional levels of hypertrophic markers, including ANP, BNP, and β-MHC, were detected. Echocardiography, hematoxylin-eosin staining, and transmission electron microscopy were used to examine the cardiac function, histology, and ultrastructure of ventricles. Protein levels of mitochondria-related factors, such as adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), were detected.
RESULTS: 7,8-DHF inhibited compensated and decompensated cardiac hypertrophy, diminished the cross-sectional area, and alleviated the mitochondrial disorders of cardiomyocytes. Meanwhile, 7,8-DHF reduced the cell size and repressed the mRNA levels of the hypertrophic markers of ISO-treated cardiomyocytes. In addition, 7,8-DHF activated AMPK and PGC-1α signals without affecting the protein levels of mitochondrial dynamics-related molecules. The effects of 7,8-DHF were eliminanted by Compound C, an AMPK inhibitor.
CONCLUSIONS: These findings suggest that 7,8-DHF inhibited cardiac hypertrophy and mitochondrial dysfunction by activating AMPK signaling, providing a potential agent for the treatment of pathological cardiac hypertrophy.

DOI: https://doi.org/10.11909/j.issn.1671-5411.2022.11.002
Chem Biol Drug Des. 2022 Dec 22.

Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity.

Denis A Babkov, Olga N Zhukovskaya, Anastasia A Brigadirova, Diana R Prilepskaya, Alexandra A Kolodina, Abbas Haider S Abbas, Anatolii S Morkovnik, M Elizabeth Sobhia, Ketan Ghosh, Alexander A Spasov.

  This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl-N'-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action. Using prove of concept in vivo study we show that dual targeting compound 7a has a disease-modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism.

Keywords:  AMPK; PTP1B; diabetes mellitus; obesity

DOI:  https://doi.org/10.1111/cbdd.14198
Inflammopharmacology. 2022 Dec 19.

Dexmedetomidine alleviates acute lung injury by promoting Tregs differentiation via activation of AMPK/SIRT1 pathway.

Zheng-Tao Zhang, Ke Xie, Ren-Jie Luo, Dan-Ying Zhang, Zhi-Wei He, Ke-Feng Li, Shi-Hui Lin, Fang Xu.

   OBJECTIVES: To explore the anti-inflammatory effect and the potential mechanism of dexmedetomidine in ARDS/ALI.
MATERIALS AND METHODS: C57BL/6 mice and EL-4 cells were used in this research. The ALI model was established by CLP. The level of inflammatory cytokines in the lung and blood, the severity of lung injury, the expression of Foxp3, and the proportion of Tregs were detected before and after dexmedetomidine treatment. The expression of the AMPK/SIRT1 after dexmedetomidine treatment was detected in vivo and in vitro. After blocking the AMPK/SIRT1 pathway or depleting Tregs in vivo, the level of the inflammatory response, tissue injury, and Tregs differentiation were detected again to clarify the effect of dexmedetomidine.
RESULTS: Dexmedetomidine significantly reduced systemic inflammation and lung injury in CLP mice. Dexmedetomidine enhanced the Foxp3 expression in the lungs and the frequency of Tregs in the spleen. Dexmedetomidine up-regulated the protein expression of p-AMPK and SIRT1 in lungs and EL-4 cells and facilitated the differentiation of naïve CD4+ T cells into Tregs in vitro. Meanwhile, DEX also increased the expression of Helios in Treg cells.
CONCLUSIONS: DEX could improve ARDS/ALI by facilitating the differentiation of Tregs from naïve CD4+ T cells via activating the AMPK/SIRT1 pathway.

Keywords:  AMP-activated protein kinase; Acute lung injury; Acute respiratory distress syndrome; Dexmedetomidine; Regulatory T cells; Sirtuin1

DOI:  https://doi.org/10.1007/s10787-022-01117-5
Mol Med Rep. 2023 Feb;pii: 35. [Epub ahead of print]27(2):

Role of the AMPK/SIRT1 pathway in non‑alcoholic fatty liver disease (Review).

Putri Anggreini, Hadi Kuncoro, Sri Adi Sumiwi, Jutti Levita.

  Non‑alcoholic fatty liver disease (NAFLD) is an increasingly prevalent ailment worldwide. Moreover, de novo lipogenesis (DNL) is considered a critical factor in the development of NAFLD; hence, its inhibition is a promising target for the prevention of fatty liver disease. There is evidence to indicate that AMP‑activated protein kinase (AMPK) and sirtuin 1 (SIRT1) may play a crucial role in DNL and are the regulatory proteins in type 2 diabetes mellitus, obesity and cardiovascular disease. Therefore, AMPK and SIRT1 may be promising targets for the treatment of NAFLD. The present review article thus aimed to summarize the findings of clinical studies published during the past decade that suggested the beneficial effects of AMPK and SIRT1, using their specific activators and their combined effects on fatty liver disease.

Keywords:  AMP‑activated protein kinase; mechanism; non‑alcoholic fatty liver disease; randomized control trial; sirtuin 1

DOI:  https://doi.org/10.3892/mmr.2022.12922
Brain Res Bull. 2022 Dec 16. pii: S0361-9230(22)00345-8. [Epub ahead of print]193 72-83

Mild hypothermia alleviates early brain injury after subarachnoid hemorrhage via suppressing pyroptosis through AMPK/NLRP3 inflammasome pathway in rats.

Zhaopeng Zhou, Zhuanghua Liu, Chenxu Zhang, Wang Zhang, Chunlei Zhang, Tao Chen, Yuhai Wang.

  As a subtype of stroke, subarachnoid hemorrhage (SAH) has a notoriously high rate of disability and mortality owing to the lack of effective intervention. Early brain injury (EBI) is the main factor responsible for the dismal prognosis of SAH patients. The current study intends to explore the molecular mechanism underlying the effect of MH on EBI after SAH from a novel perspective of pyroptosis, a highly specific inflammatory programmed cell death, in the SAH rat model. Sprague-Dawley (SD) rats were divided into different groups in accordance with various treatments. In the treatment group, the rats underwent mild hypothermia for 4 h after modeling; in the inhibitor group, Compound C (an inhibitor of AMPK) was administered intravenous injections (i.v.) 30 min before modeling. Neurological score, neuronal death, brain water content, inflammatory reaction, and expression levels of pyroptosis-related proteins were evaluated in the rats. Our results indicate that the MH therapy significantly increased the neurological score and assuaged brain edema, neuronal injury, and inflammatory reaction induced by SAH. Meanwhile, MH therapy upregulated the level of AMPK phosphorylation whereas downregulated the protein expressions of NLRP3, ASC, cleaved caspase-1, GSDMD, IL-1β, and IL-18. The reversed effect of MH therapy by Compound C concretely indicated that MH therapy inhibited pyroptosis through an AMPK-dependent pathway. Our study also found that MH therapy potently curbed the increasing trend of brain temperature (BT), rectal temperature (RT), and ICP after SAH. Taken together, our data indicate that the neuroprotective effects of MH therapy were manifested by inhibiting pyroptosis via the AMPK/NLRP3 inflammasome pathway, which may serve as a promising therapy for the intervention of SAH.

Keywords:  Early brain injury; Mild hypothermia; NLRP3; Pyroptosis; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1016/j.brainresbull.2022.12.004
Cells. 2022 Dec 09. pii: 3988. [Epub ahead of print]11(24):

Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation.

Ying Zhou, Jia-Jie Yang, Yuan Cheng, Ge-Xuan Feng, Rong-Hui Yang, Yuan Yuan, Li-Yong Wang, Miao Wang, Lu Kong.

  The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did not survive after LMNA knockout (KO) or even KD. Evidently, the functions of lamin A/C differ between the liver and adipose tissue. To date, the mechanism of hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our in-depth study aimed to identify the molecular connection between lamin A/C and pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function experiments were performed to investigate functional changes and the related molecular pathways in 7701 cells. Adenosine 5' monophosphate-activated protein kinase α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) and subsequently inhibited lipid synthesis but induced glycolysis in both HCC cells and normal cells. According to the mass spectrometry analysis, lamin A/C potentially regulated AMPKα activation through its chaperone proteins, ATPase or ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of the two HCC cell lines more efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of prelamin A.

Keywords:  AMPK; LMNA; hepatocellular carcinoma; lipid metabolism

DOI:  https://doi.org/10.3390/cells11243988
Curr Pharm Des. 2022 Dec 19.

Dysregulation of Angiopoietin-like-4 Associated with Hyperlipidemia-induced Renal Injury by AMPK/ACC Pathway.

Wenhui Qiu, Luyang Huang, Yueqiang Li, Qingquan Liu, Yongman Lv.

   BACKGROUND: Angiopoietin-like protein 4 (Angptl4) is a glycoprotein that is involved in regulating lipid metabolism, which has been indicated as a link between hypertriglyceridemia and albuminuria in glomerulonephropathy. Deregulated lipid metabolism is increasingly recognized as an important risk factor of glomerulonephropathy. This study aimed to investigate the Angptl4 expression in renal tissue and podocyte under hyperlipidemia conditions and explore the potential molecular mechanisms.
OBJECTIVE: The role of Angptl4 in hyperlipidemia-induced glomerular disease and the detailed underlying mechanisms are unclear. This study sought new insights into this issue.
METHODS: We measured Angptl4 levels in the plasma and urine from patients with hyperlipidemia and healthy people. Rats were fed a high fat diet (HFD) to induce dyslipidemia model and the human podocytes were stimulated by palmitic acid as in vivo and in vitro experiments. The podocytes injury and the Angptl4 level in renal tissues were evaluated. Furthermore, the mechanism of Angptl4 on podocytes injury was investigated.
RESULTS: The urinary Angptl4 level was gradually upregulated in both patients with hyperlipidaemia and high fat-diet-induced rats. HFD rats showed increased 24h-urinary protein and glomerular tuft area at week 12. The levels of nephrin and WT-1 were down-regulated, but the Angptl4 levels were markedly upregulated on the glomerular of rats on HFD. In the human podocytes, lipid accumulation accompanied by increases of Angptl4, but the expression of nephrin, WT-1, p-AMPKα and p-ACC was decreased after palmitic acid treatment. However, this injury effect was mediated by the aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR), activator of the low energy sensor AMPK/ACC signaling.
CONCLUSION: This study was the first of its kind to show that podocyte damage induced by dyslipidemia could be associated with upregulated Angptl4 and that patients with hyperlipidemia might have relatively high urinary Angptl4 expression. The dysregulation of Angptl4 in the podocytes under hyperlipidemia is possibly carried out through AMPK/ACC signaling pathway.

Keywords:  AMPK; Angptl4; Dyslipidemia; Hyperlipidemia; Palmitic acid; Podocytes

DOI:  https://doi.org/10.2174/1381612829666221219123937
Cells. 2022 Dec 18. pii: 4117. [Epub ahead of print]11(24):

Hepatic Polarized Differentiation Promoted the Maturity and Liver Function of Human Embryonic Stem Cell-Derived Hepatocytes via Activating Hippo and AMPK Signaling Pathways.

Jue Wang, Ping Situ, Sen Chen, Haibin Wu, Xueyan Zhang, Shoupei Liu, Yiyu Wang, Jinghe Xie, Honglin Chen, Yuyou Duan.

  Hepatocytes exhibit a multi-polarized state under the in vivo physiological environment, however, human embryonic stem cell-derived hepatocytes (hEHs) rarely exhibit polarity features in a two-dimensional (2D) condition. Thus, we hypothesized whether the polarized differentiation might enhance the maturity and liver function of hEHs. In this study, we obtained the polarized hEHs (phEHs) by using 2D differentiation in conjunct with employing transwell-based polarized culture. Our results showed that phEHs directionally secreted albumin, urea and bile acids, and afterward, the apical membrane and blood-bile barrier (BBIB) were identified to form in phEHs. Moreover, phEHs exhibited a higher maturity and capacitity of cellular secretory and drug metabolism than those of non-phEHs. Through transcriptome analysis, it was found that the polarized differentiation induced obvious changes in gene expression profiles of cellular adhesion and membrane transport in hEHs. Our further investigation revealed that the activation of Hippo and AMPK signaling pathways made contributions to the regulation of function and cellular polarity in phEHs, further verifying that the liver function of hEHs was closely related with their polarization state. These results not only demonstrated that the polarized differentiation enhanced the maturity and liver function of hEHs, but also identified the molecular targets that regulated the polarization state of hEHs.

Keywords:  apical membrane; hepatic polarized differentiation; hepatocyte polarity; human embryonic stem cells-derived hepatocytes

DOI:  https://doi.org/10.3390/cells11244117