bims-amsmem 2023-02-19 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–02–19
eleven papers selected by
Dipsikha Biswas, Københavns Universitet

Sex-dimorphic hindbrain lactate regulation of ventromedial hypothalamic nucleus glucoregulatory neuron 5'-AMP-activated protein kinase activity and transmitter marker protein expression.
Role of inorganic polyphosphates in the activation of AMPK in models of Alzheimer's disease.
The protective effect of the mitochondrial-derived peptide MOTS-c on LPS-induced septic cardiomyopathy.
Dehydroepiandrosterone protects against oleic acid-triggered mitochondrial dysfunction to relieve oxidative stress and inflammation via activation of the AMPK-Nrf2 axis by targeting GPR30 in hepatocytes.
Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling.
Depletion of mitochondrial polyP levels increase the phosphorylation of AMPK protein and compromises oxygen consumption in SH-SY5Y cells.
Rho A/ROCK1 signaling-mediated metabolic reprogramming of valvular interstitial cells toward Warburg effect accelerates aortic valve calcification via AMPK/RUNX2 axis.
Klotho promotes AMPK activity and maintains renal vascular integrity by regulating the YAP signaling pathway.
Activating autophagy and ferroptosis of 3‑Chloropropane‑1,2‑diol induces injury of human umbilical vein endothelial cells via AMPK/mTOR/ULK1.
Carnosol inhibits cerebral ischemia-reperfusion injury by promoting AMPK activation.
Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis.

Neuropeptides. 2023 Feb 02. pii: S0143-4179(23)00005-7. [Epub ahead of print]99 102324

Sex-dimorphic hindbrain lactate regulation of ventromedial hypothalamic nucleus glucoregulatory neuron 5'-AMP-activated protein kinase activity and transmitter marker protein expression.

Prabhat R Napit, Md Haider Ali, A S M Hasan Mahmood, Mostafa M H Ibrahim, Karen P Briski.

   BACKGROUND: The oxidizable glycolytic end-product L-lactate is a gauge of nerve cell metabolic fuel stability that metabolic-sensory hindbrain A2 noradrenergic neurons impart to the brain glucose-regulatory network. Current research investigated the premise that hindbrain lactate deficiency exerts sex-specific control of energy sensor and transmitter marker protein responses to hypoglycemia in ventromedial hypothalamic nucleus (VMN) glucose-regulatory nitrergic and γ-aminobutyric acid (GABA) neurons.
METHODS: Nitric oxide synthase (nNOS)- or glutamate decarboxylase65/67 (GAD)-immunoreactive neurons were laser-catapult-microdissected from male and female rat VMN after subcutaneous insulin injection and caudal fourth ventricular L-lactate or vehicle infusion for Western blot protein analysis.
RESULTS: Hindbrain lactate repletion reversed hypoglycemia-associated augmentation (males) or inhibition (females) of nitrergic neuron nNOS expression, and prevented up-regulation of phosphorylated AMPK 5'-AMP-activated protein kinase (pAMPK) expression in those neurons. Hypoglycemic suppression of GABAergic neuron GAD protein was averted by exogenous lactate over the rostro-caudal length of the male VMN and in the middle region of the female VMN. Lactate normalized GABA neuron pAMPK profiles in hypoglycemic male (caudal VMN) and female (all VMN segments) rats. Hypoglycemic patterns of norepinephrine (NE) signaling were lactate-dependent throughout the male VMN, but confined to the rostral and middle female VMN.
CONCLUSIONS: Results document, in each sex, regional VMN glucose-regulatory transmitter responses to hypoglycemia that are controlled by hindbrain lactate status. Hindbrain metabolic-sensory regulation of hypoglycemia-correlated nitric oxide or GABA release may entail AMPK-dependent mechanisms in specific VMN rostro-caudal segments in each sex. Additional effort is required to examine the role of hindbrain lactoprivic-sensitive VMN neurotransmitters in lactate-mediated attenuation of hypoglycemic hyperglucagonemia and hypercorticosteronemia in male and female rats.

Keywords:  AMPK; Corticosterone; L-lactate; Nitric oxide; Norepinephrine; Sex differences

DOI:  https://doi.org/10.1016/j.npep.2023.102324
Biophys J. 2023 Feb 10. pii: S0006-3495(22)01627-7. [Epub ahead of print]122(3S1): 95a-96a

Role of inorganic polyphosphates in the activation of AMPK in models of Alzheimer's disease.

Lindsey M Riggs, Maria E Solesio Torregrosa.

DOI: https://doi.org/10.1016/j.bpj.2022.11.711
Acta Biochim Biophys Sin (Shanghai). 2023 Feb 13.

The protective effect of the mitochondrial-derived peptide MOTS-c on LPS-induced septic cardiomyopathy.

Jiaqi Wu, Danrui Xiao, Kaiwen Yu, Kudureti Shalamu, Ben He, Min Zhang.

  <p indent="0mm">Septic cardiomyopathy is associated with mechanisms such as excessive inflammation, oxidative stress, regulation of calcium homeostasis, endothelial dysfunction, mitochondrial dysfunction, and cardiomyocyte death, and there is no effective treatment at present. MOTS-c is a mitochondria-derived peptide (MDP) encoded by mitochondrial DNA (mtDNA) that protects cells from stresses in an AMPK-dependent manner. In the present study, we aim to explore the protective effect of MOTS-c on lipopolysaccharide (LPS)-induced septic cardiomyopathy. LPS is used to establish a model of septic cardiomyopathy. Our results demonstrate that MOTS-c treatment reduces the mRNA levels of inflammatory cytokines ( <italic>IL-1β</italic>, <italic>IL-4</italic>, <italic>IL-6</italic>, and <italic>TNFα</italic>) in cardiomyocytes and the levels of circulating myocardial injury markers, such as CK-MB and TnT, alleviates cardiomyocyte mitochondrial dysfunction and oxidative stress, reduces cardiomyocyte apoptosis, activates cardioprotection-related signaling pathways, including AMPK, AKT, and ERK, and inhibits the inflammation-related signaling pathways JNK and STAT3. However, treatment with the AMPK pathway inhibitor compound C (CC) abolishes the positive effect of MOTS-c on LPS stress. Collectively, our research suggests that MOTS-c may attenuate myocardial injury in septic cardiomyopathy by activating AMPK and provides a new idea for therapeutic strategies in septic cardiomyopathy. </p>.

Keywords:  AMPK pathway; MOTS-c; inflammation; myocardial apoptosis; septic cardiomyopathy

DOI:  https://doi.org/10.3724/abbs.2023006
Mol Immunol. 2023 Feb 09. pii: S0161-5890(23)00018-4. [Epub ahead of print]155 110-123

Dehydroepiandrosterone protects against oleic acid-triggered mitochondrial dysfunction to relieve oxidative stress and inflammation via activation of the AMPK-Nrf2 axis by targeting GPR30 in hepatocytes.

Yao Yao, Huihui Wang, Ying Yang, Zhihao Jiang, Haitian Ma.

  Fatty liver hemorrhage syndrome (FLHS) seriously threatens the health and performance of laying hens, and the occurrence and development of FLHS are closely related to oxidative damage and inflammation; thus, diets supplemental with activated substances to relive the oxidative stress and inflammation maybe effectively control the occurrences of FLHS. Dehydroepiandrosterone (DHEA) has beneficial effects in fat-reduction, anti-oxidation and anti-inflammation, and it was widely applied to alleviate multiple metabolic-related diseases; however, there are few reports on whether DHEA can prevent against metabolic-related diseases by modulating oxidative stress and inflammation, especially FLHS in laying hens. Herein, present study aimed to investigate the regulatory actions and potential molecular mechanism of DHEA on inflammation and oxidative stress triggered by oleic acid (OA)-stimulation in primary chicken hepatocytes and chicken hepatocellular carcinoma cell line (LMH). The results showed that DHEA significantly alleviated oxidative stress challenged by OA-stimulation via activation of AMP-activated protein kinase (AMPK)-nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in hepatocytes, which led to relieving effect of DHEA on inflammatory by inhibiting mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) signaling pathways. Mechanistically, we found that the activation of AMPK-Nrf2 signaling pathway by DHEA treatment was mediated by G-protein coupled estrogen receptor (GPR30/GPER) in OA-stimulated hepatocytes. Further investigation found that DHEA activated the GPR30-mediated AMPK-Nrf2 signaling pathways to increase antioxidant capacity and inhibit mitochondrial reactive oxygen species (ROS) overproduction, which thereby inhibiting the activation of ROS-induced MAPK and NF-κB signaling pathways in OA-stimulated hepatocytes. Overall, these data demonstrated that DHEA attenuates the oxidative stress and inflammation triggered by OA-stimulation, and these beneficial effects of DHEA are achieved by activating the GPR30-mediated AMPK-Nrf2 signaling to prevent the impairment of mitochondrial function, and thereby inhibiting the activation of ROS-induced MAPK and NF-κB signaling pathways in hepatocytes. These results revealed the effects and mechanisms of DHEA on oxidative stress and inflammation, and also provide substantial information to support it as a potential nutritional supplement in preventing the occurrences of FLHS in laying hens and other metabolic-related diseases in animals and humans.

Keywords:  AMPK-Nrf2 signaling pathway; Dehydroepiandrosterone; G-protein coupled estrogen receptor; Hepatocytes; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.molimm.2023.01.008
Biophys J. 2023 Feb 10. pii: S0006-3495(22)03005-3. [Epub ahead of print]122(3S1): 380a-381a

Role of AMPK pathway inactivation in high fat diet related cardiac electrophysiological remodeling.

Michael W Rudokas, Marine Cacheux, Xiaohong Wu, Madelyn E Hummel, Lawrence H Young, Fadi G Akar.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2089
Biophys J. 2023 Feb 10. pii: S0006-3495(22)01625-3. [Epub ahead of print]122(3S1): 95a

Depletion of mitochondrial polyP levels increase the phosphorylation of AMPK protein and compromises oxygen consumption in SH-SY5Y cells.

Renata Torres da Costa, Matheus Moreira Perez, Ernest Scoma, Vedangi D Hambardikar, Lindsey M Riggs, Maria E Solesio Torregrosa.

DOI: https://doi.org/10.1016/j.bpj.2022.11.709
Cell Death Dis. 2023 Feb 11. 14(2): 108

Rho A/ROCK1 signaling-mediated metabolic reprogramming of valvular interstitial cells toward Warburg effect accelerates aortic valve calcification via AMPK/RUNX2 axis.

Huiruo Liu, Hang Yin, Zhen Wang, Qiuhuan Yuan, Feng Xu, Yuguo Chen, Chuanbao Li.

The aberrant differentiation of valvular interstitial cells (VICs) to osteogenic lineages promotes calcified aortic valves disease (CAVD), partly activated by potentially destructive hemodynamic forces. These involve Rho A/ROCK1 signaling, a mechano-sensing pathway. However, how Rho A/ROCK1 signaling transduces mechanical signals into cellular responses and disrupts normal VIC homeostasis remain unclear. We examined Rho A/ROCK1 signaling in human aortic valves, and further detected how Rho A/ROCK1 signaling regulates mineralization in human VICs. Aortic valves (CAVD n = 22, normal control (NC) n = 12) from patients undergoing valve replacement were investigated. Immunostaining and western blotting analysis indicated that Rho A/ROCK1 signaling, as well as key transporters and enzymes involved in the Warburg effect, were markedly upregulated in human calcified aortic valves compared with those in the controls. In vitro, Rho A/ROCK1-induced calcification was confirmed as AMPK-dependent, via a mechanism involving metabolic reprogramming of human VICs to Warburg effect. Y-27632, a selective ROCK1 inhibitor, suppressed the Warburg effect, rescued AMPK activity and subsequently increased RUNX2 ubiquitin-proteasome degradation, leading to decreased RUNX2 protein accumulation in human VICs under pathological osteogenic stimulus. Rho A/ROCK1 signaling, which is elevated in human calcified aortic valves, plays a positive role in valvular calcification, partially through its ability to drive metabolic switching of VICs to the Warburg effect, leading to altered AMPK activity and RUNX2 protein accumulation. Thus, Rho A/ROCK1 signaling could be an important and unrecognized hub of destructive hemodynamics and cellular aerobic glycolysis that is essential to promote the CAVD process.

DOI: https://doi.org/10.1038/s41419-023-05642-1
Int J Med Sci. 2023 ;20(2): 194-205

Klotho promotes AMPK activity and maintains renal vascular integrity by regulating the YAP signaling pathway.

Lei Luo, Jianming Guo, Yi Li, Te Liu, Lingyun Lai.

  The development and formation of mammalian blood vessels are closely related to the regulation of signal transduction pathways. Klotho/AMPK and YAP/TAZ signaling pathways are closely related to angiogenesis, but the internal relationship between them is not clear. In this study, we found that Klotho heterozygous deletion mice (Klotho+/- mice) had obvious thickening of the renal vascular wall, obvious enlargement of vascular volume, and significant proliferation and pricking of vascular endothelial cells. Western blot showed that the expression levels of total YAP protein, p-YAP protein (Ser127 and Ser397), p-MOB1, MST1, LATS1, and SAV1 in renal vascular endothelial cells were significantly lower in Klotho+/- mice than in wild-type mice. Knockdown of endogenous Klotho in HUVECs accelerated their ability to divide and form vascular branches in the extracellular matrix. Meanwhile, the results of CO-IP western blot showed that the expression of LATS1 and p-LATS1 interacting with AMPK protein decreased significantly, and the ubiquitination level of YAP protein also decreased significantly in vascular endothelial cells of kidney tissue of Klotho+/- mice. Subsequently, continuous overexpression of exogenous Klotho protein in Klotho heterozygous deficient mice effectively reversed the abnormal renal vascular structure by weakening the expression of the YAP signal transduction pathway. Therefore, we confirmed that Klotho and AMPKα proteins were highly expressed in vascular endothelial cells of adult mouse tissues and organs; this resulted in a phosphorylation modification of YAP protein, closed the activity of the YAP/TAZ signal transduction pathway, and inhibited the growth and proliferation of vascular endothelial cells. When Klotho was absent, the phosphorylation modification of YAP protein by AMPKα was inhibited, resulting in the activation of the YAP/TAZ signal transduction pathway and finally inducing the excessive proliferation of vascular endothelial cells.

Keywords:  AMPK/YAP pathway; Klotho; Vascular structure integrity

DOI:  https://doi.org/10.7150/ijms.80220
Mol Med Rep. 2023 Mar;pii: 76. [Epub ahead of print]27(3):

Activating autophagy and ferroptosis of 3‑Chloropropane‑1,2‑diol induces injury of human umbilical vein endothelial cells via AMPK/mTOR/ULK1.

Xin Yi, Xiao Long, Canzhang Liu.

  3‑Chloropropane‑1,2‑diol (3‑MCPD) is an internationally recognized food pollutant. 3‑MCPD has reproductive, renal and neurotoxic properties. However, whether 3‑MCPD induces human umbilical vein endothelial cell (HUVEC) injury has not been previously reported. In the present study, HUVECs were treated using 2 µg/ml 3‑MCPD for 24 h at 37˚C. The effects of 3‑MCPD on HUVEC proliferation and cell cycle arrest, death and senescence were then assessed using Cell Counting Kit‑8 (CCK‑8), flow cytometry and β‑galactosidase staining, respectively. Whether 3‑MCPD induced ferroptosis was evaluated using JC‑1 and FerroOrange staining and transmission electron microscopy. A small interfering RNA targeting AMPK was used to assess whether 3‑MCPD promoted ferroptosis via AMPK signaling. The results demonstrated that 3‑MCPD inhibited HUVEC proliferation in a dose‑dependent manner and induced cell cycle arrest. Furthermore, 3‑MCPD promoted senescence in HUVECs with elevated DNA damage and cell death. The CCK‑8 results demonstrated that ferroptosis and autophagy inhibitors significantly reversed cell death caused by 3‑MCPD. Moreover, 3‑MCPD increased mitochondrial membrane potential, which indicated that 3‑MCPD contributed to mitochondrial dysfunction. 3‑MCPD also markedly increased intracellular Fe2+ levels and lipid peroxidation in HUVECs. The present study assessed the underlying mechanism by which 3‑MCPD activated autophagy and ferroptosis in HUVECs. The data demonstrated that 3‑MCPD significantly increased phosphorylation levels of AMPK and unc‑51 like autophagy activating kinase (ULK1) but significantly decreased phosphorylation of mTOR in HUVECs. Furthermore, silencing of AMPK significantly reversed the increase in autophagy, lipid peroxidation and Fe2+ induced by 3‑MCPD. In conclusion, 3‑MCPD demonstrated a significant damaging effect on HUVECs via induction of autophagy and ferroptosis; such effects may be mediated by AMPK/mTOR/ULK1 signaling. To the best of our knowledge, the present study was the first to demonstrate the mechanism of 3‑MCPD‑induced vascular endothelial cell injury and lays a molecular foundation for the prevention of 3‑MCPD‑related vascular diseases.

Keywords:  2‑diol; 3‑Chloropropane‑1; autophagy; ferroptosis; human umbilical vein endothelial cells

DOI:  https://doi.org/10.3892/mmr.2023.12963
Brain Res Bull. 2023 Feb 10. pii: S0361-9230(23)00034-5. [Epub ahead of print]195 37-46

Carnosol inhibits cerebral ischemia-reperfusion injury by promoting AMPK activation.

Wen-Chang Xiao, Gang Zhou, Lu Wan, Jun Tu, Yong-Jie Yu, Zhi-Gang She, Chun-Lin Xu, Lei Wang.

   BACKGROUND: Carnosol is a phytopolyphenol (diterpene) found and extracted from plants of Mediterranean diet, which has anti-tumor, anti-inflammatory and antioxidant effects. However, its role in ischemic stroke has not been elucidated.
METHODS: Primary neurons subjected to oxygen-glucose deprivation (OGD) was used to investigate the effect of carnosol in vitro. A mouse MCAO model was used to evaluate the effect of carnosol on ischemic stroke in vivo. The mRNA level of inflammatory and apoptosis-related genes was determined by RT-PCR. The protein level of total and phosphorylated AMPK was determined by WB. H&E and Immunofluorescent assay was used to investigate the necrosis, inflammation and apoptosis in brain tissue.
RESULTS: Carnosol protected the activity of primary neurons subjected to oxygen-glucose deprivation (OGD) in vitro, as well as inhibited inflammation and apoptosis. Furthermore, carnosol could significantly reduce the infarct and edema volume and protect against neurological deficit in vivo, and had a significant inhibitory effect on brain neuroinflammation and apoptosis. Mechanically, carnosol could activate AMPK, and the effect of carnosol on cerebral ischemia-reperfusion injury cell model could be abolished by AMPK phosphorylation inhibitor.
CONCLUSION: Carnosol has a protective effect on ischemic stroke, and this effect is achieved through AMPK activation. Our study demonstrates the protective effect of carnosol on cerebral ischemia-reperfusion injury and provides a new perspective for the clinical treatment of ischemic stroke.

Keywords:  Carnosol; Ischemic stroke; MCAO; OGD; Primary neuron

DOI:  https://doi.org/10.1016/j.brainresbull.2023.02.003
Metabolism. 2023 Feb 10. pii: S0026-0495(23)00119-1. [Epub ahead of print]141 155516

Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis.

Jeongmin Park, So-Young Rah, Hyeong Seok An, Jong Youl Lee, Gu Seob Roh, Stefan W Ryter, Jeong Woo Park, Chae Ha Yang, Young-Joon Surh, Uh-Hyun Kim, Hun Taeg Chung, Yeonsoo Joe.

   OBJECTIVE: Emerging evidence suggests that crosstalk between Kupffer cells (KCs) and hepatocytes protects against non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to the reduction of steatosis in NAFLD remain obscure.
METHODS: Ttp+/+ and Ttp-/- mice were fed with a high-fat diet. Hepatic steatosis was analyzed by Nile Red staining and measurement of inflammatory cytokines. Lipid accumulation and cell death were evaluated in co-culture systems with primary hepatocytes and KCs derived from either Ttp+/+ or Ttp-/- mice.
RESULTS: Tristetraprolin (TTP), an mRNA binding protein, was essential for the protective effects of metformin in NAFLD. Metformin activated TTP via the AMPK-Sirt1 pathway in hepatocytes and KCs. TTP inhibited TNF-α production in KCs, which in turn decreased hepatocyte necroptosis. Downregulation of Rheb expression by TTP promoted hepatocyte lipophagy via mTORC1 inhibition and increased nuclear translocation of transcription factor-EB (TFEB). Consistently, TTP-deficient NAFLD mice failed to respond to metformin with respect to alleviation of hepatic steatosis, protection of hepatocyte necroptosis, or induction of lipophagy.
CONCLUSIONS: TTP, which is essential for the protective effects of metformin, may represent a novel primary therapeutic target in NAFLD.

Keywords:  Hepatocytes; Kupffer cells; Lipophagy; Metformin; Necroptosis; Non-alcoholic fatty liver disease; Sirt1; Tristetraprolin

DOI:  https://doi.org/10.1016/j.metabol.2023.155516