bims-amsmem 2023-05-07 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023‒05‒07
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet

AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.
Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1.
Solasodine suppresses the metastasis of gastric cancer through claudin-2 via the AMPK/STAT3/NF-κB pathway.
Nicotinamide mononucleotide induces lipolysis by regulating ATGL expression via the SIRT1-AMPK axis in adipocytes.
Effects of different modes and intensities of exercise on longevity proteins in middle-aged mouse skeletal muscle.
Dendritic cell-intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity.
Vitamin B12 alleviates myocardial ischemia/reperfusion injury via the SIRT3/AMPK signaling pathway.
Mulberry extract ameliorates T2DM-related symptoms via AMPK pathway in STZ-HFD-induced C57BL/6J mice.
Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells.
Exosomal miR-663b from "M1" macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through inhibiting the AMPK/Sirt1 axis.
Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity.
Grain-sized moxibustion at Zusanli (ST36) promotes hepatic autophagy in rats with hyperlipidemia by regulating the ULK1 and TFEB expression through the AMPK/mTOR signaling pathway.
Small heterodimer partner interacting leucine zipper protein (SMILE) ameliorates autoimmune arthritis via AMPK signaling pathway and the regulation of B cell activation.
Hypolipidemic effects of macadamia oil are related to AMPK activation and oxidative stress relief: In vitro and in vivo studies.

Exp Cell Res. 2023 Apr 29. pii: S0014-4827(23)00161-1. [Epub ahead of print] 113614

AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.

Ankita Sharma, Sumit Kr Anand, Neha Singh, Upendra Nath Dwivedi, Poonam Kakkar.

  Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine energy-sensing kinase. It gets activated upon a decrease in the cellular energy status as reflected by an increased AMP/ATP ratio, ADP, and also during the conditions of glucose starvation without change in the adenine nucelotide ratio. AMPK functions as a centralized regulator of metabolism, acting at cellular and physiological levels to circumvent the metabolic stress by restoring energy balance. This review intricately highlights the integrated signaling pathways by which AMPK gets activated allosterically or by multiple non-canonical upstream kinases. AMPK activates the ATP generating processes (e.g., fatty acid oxidation) and inhibits the ATP consuming processes that are non-critical for survival (e.g., cell proliferation, protein and triglyceride synthesis). An integrated signaling network with AMPK as the central effector regulates all the aspects of enhanced stress resistance, qualified cellular housekeeping, and energy metabolic homeostasis. Importantly, the AMPK mediated amelioration of cellular stress and inflammatory responses are mediated by stimulation of transcription factors such as Nrf2, SIRT1, FoxO and inhibition of NF-κB serving as main downstream effectors. Moreover, many lines of evidence have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling to fine-tune the metabolic pathways in response to different cellular signals. This review also highlights the critical involvement of AMPK in promoting mitochondrial health, and homeostasis, including mitophagy. Loss of AMPK or ULK1 activity leads to aberrant accumulation of autophagy-related proteins and defective mitophagy thus, connecting cellular energy sensing to autophagy and mitophagy.

Keywords:  AMPK; Autophagy; Cellular stress; Metabolic stress; Mitophagy

DOI:  https://doi.org/10.1016/j.yexcr.2023.113614
Front Pharmacol. 2023 ;14 1148611

Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1.

Gang Ren, Yu-Wei Ding, Lu-Lu Wang, Jian-Dong Jiang.

  Aim: AMPK is the key regulatory kinase mediating the effect of berberine (BBR) and metformin on metabolic improvement. The present study investigated the mechanism of BBR on AMPK activation at low doses, which was different from that of metformin. Methods: Lysosomes were isolated, and AMPK activity assay was performed. PEN2, AXIN1 and UHRF1 were investigated through gain/loss of function approaches, including overexpression, RNA interfering and CRISPR/Cas9-mediated gene knockout. Immunoprecipitation was utilized for detecting the interaction of UHRF1 and AMPKα1 after BBR treatment. Results: BBR activated lysosomal AMPK, but weaker than metformin. AXIN1 mediated BBR's effect on lysosomal AMPK activation, while PEN2 did not. BBR, but not metformin, decreased UHRF1 expression by promoting its degradation. BBR reduced the interaction between UHRF1 and AMPKα1. And overexpression of UHRF1 abolished the effect of BBR on AMPK activation. Conclusion: BBR activated lysosomal AMPK as dependent on AXIN1, but not PEN2. BBR maintained cellular AMPK activity by reducing UHRF1 expression and its interaction with AMPKα1. The mode of action of BBR was different from that of metformin on AMPK activation.

Keywords:  AMPK; AXIN1; UHRF1; berberine; metformin

DOI:  https://doi.org/10.3389/fphar.2023.1148611
Chem Biol Interact. 2023 Apr 28. pii: S0009-2797(23)00187-4. [Epub ahead of print] 110520

Solasodine suppresses the metastasis of gastric cancer through claudin-2 via the AMPK/STAT3/NF-κB pathway.

Kexin Su, Xuan Yao, Chenxu Guo, Chunmei Qian, Yiying Wang, Xiaoqi Ma, Xiaoyu Wang, Yifu Yang.

  Gastric cancer (GC) is one of the most common malignancies, and it has become the third most common malignant tumour in the world. Targeting metastasis has also become a key and difficult point in the treatment of GC. Solasodine is an active ingredient isolated from Solanum nigrumL. for the treatment of various cancers, such as breast cancer, pancreatic cancer and lung cancer. In the present study, we investigated the role and mechanism of solasodine in inhibiting GC. In vitro, we found that solasodine not only promoted cell death but also inhibited the migration and invasion of HGC27 and AGS cells. Solasodine regulated epithelial-mesenchymal transition (EMT) and reduced the expression of claudin-2 (CLDN2). Moreover, overexpression of CLDN2 inhibited the prometastatic phenotype and EMT of GC, and solasodine recovered this phenotype. Furthermore, the knockdown of CLDN2 had the opposite effect. We also found that the AMPK activators metformin and AICAR activated phosphorylation of AMPK and downregulated the expression of RhoA and CLDN2, indicating that AMPK was the upstream regulator of CLDN2. Solasodine could also activate AMP-activated protein kinase (AMPK) and inhibit the phosphorylation of STAT3 and the nuclear translocation of NF-κB. Therefore, solasodine may have prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway. In vivo, we established a xenograft model to investigate the phosphorylation of AMPK and the expression of CLDN2 from tumour tissues, and we found that solasodine inhibited tumour growth through AMPK-CLDN2 pathway. To sum up, solasodine prevented EMT by modulating the AMPK/STAT3/NF-κB/CLDN2 signalling pathway, becoming a new solution for inhibiting GC metastasis.

Keywords:  AMPK; Claudin-2; EMT; Gastric cancer; Solasodine

DOI:  https://doi.org/10.1016/j.cbi.2023.110520
Biochem Biophys Rep. 2023 Jul;34 101476

Nicotinamide mononucleotide induces lipolysis by regulating ATGL expression via the SIRT1-AMPK axis in adipocytes.

Yukiko Imi, Reina Amano, Nanaho Kasahara, Yuichiro Obana, Tetsuya Hosooka.

  Nicotinamide adenine dinucleotide (NAD+) -dependent protein deacetylase SIRT1 plays an important role in the regulation of metabolism. Although the administration of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to ameliorate metabolic disorders, such as insulin resistance and glucose intolerance, the direct effect of NMN on the regulation of lipid metabolism in adipocytes remains unclear. We here investigated the effect of NMN on lipid storage in 3T3-L1 differentiated adipocytes. Oil-red O staining showed that NMN treatment reduced lipid accumulation in these cells. NMN was found to enhance lipolysis in adipocytes since the concentration of glycerol in the media was increased by NMN treatment. Western blotting and real-time RT-PCR analysis revealed that adipose triglyceride lipase (ATGL) expression at both protein and mRNA level was increased with NMN treatment in 3T3-L1 adipocytes. Whereas NMN increased SIRT1 expression and AMPK activation, an AMPK inhibitor compound C restored the NMN-dependent upregulation of ATGL expression in these cells, suggesting that NMN upregulates ATGL expression through the SIRT1-AMPK axis. NMN administration significantly decreased subcutaneous fat mass in mice on a high-fat diet. We also found that adipocyte size in subcutaneous fat was decreased with NMN treatment. Consistent with the alteration of fat mass and adipocyte size, the ATGL expression in subcutaneous fat was slightly, albeit significantly, increased with NMN treatment. These results indicate that NMN suppresses subcutaneous fat mass in diet-induced obese mice, potentially in part via the upregulation of ATGL. Unexpectedly, the reduction in fat mass as well as ATGL upregulation with NMN treatment were not observed in epididymal fat, implying that the effects of NMN are site-specific in adipose tissue. Thus, these findings provide important insights into the mechanism of NMN/NAD+ in the regulation of metabolism.

Keywords:  3T3-L1 adipocytes; Adipose triglyceride lipase; Mice; Nicotinamide mononucleotide; White adipose tissue

DOI:  https://doi.org/10.1016/j.bbrep.2023.101476
Physiol Int. 2023 May 02.

Effects of different modes and intensities of exercise on longevity proteins in middle-aged mouse skeletal muscle.

Shota Inoue, Kyohei Matsuura, Daisuke Eguchi, Masahiro Wakayama, Kosuke Ono, Hanlin Jiang, Hideki Moriyama.

  Physical exercise represents one of the most effective approaches to anti-aging. The goal of this study was to verify the effects of different modes and intensities of exercise on longevity proteins in the skeletal muscle in midlife. Middle-aged mice were trained in aerobic or resistance exercise for 8 weeks, and the changes in sirtuin 1 (SIRT1), adenosine monophosphate-activated kinase (AMPK), and mammalian target of rapamycin (mTOR) pathways in the skeletal muscle were evaluated by western blotting. Long-term exercise had no effects on skeletal muscle SIRT1 abundance, whereas high-intensity aerobic exercise increased AMPK phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Low-intensity resistance exercise facilitated Akt/mTOR/p70 ribosomal protein kinase S6 (p70S6K) signaling but did not induce muscle hypertrophy. Conversely, high-intensity resistance exercise stimulated muscle hypertrophy without phosphorylation of mTOR signaling-related proteins. These results suggest the importance of setting exercise modes and intensities for anti-aging in midlife.

Keywords:  AMPK; SIRT1; exercise; mTOR; skeletal muscle

DOI:  https://doi.org/10.1556/2060.2023.00152
JCI Insight. 2023 May 04. pii: e157948. [Epub ahead of print]

Dendritic cell-intrinsic LKB1-AMPK/SIK signaling controls metabolic homeostasis by limiting the hepatic Th17 response during obesity.

Hendrik Jp van der Zande, Eline C Brombacher, Joost M Lambooij, Leonard R Pelgrom, Anna Zawistowska-Deniziak, Thiago A Patente, Graham A Heieis, Frank Otto, Arifa Ozir-Fazalalikhan, Maria Yazdanbakhsh, Bart Everts, Bruno Guigas.

  Obesity-associated metabolic inflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of dendritic cells (DCs). Here, we report that hepatic DCs from high-fat diet (HFD)-fed obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11cΔLKB1) worsened HFD-driven hepatic steatosis and impaired glucose homeostasis. Loss of LKB1 in DCs was associated with increased expression of T helper 17-polarizing cytokines and accumulation of hepatic IL-17A+ T helper cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11cΔLKB1 mice. Mechanistically, deficiency of the canonical LKB1 target AMPK in HFD-fed CD11cΔAMPKα1 mice recapitulated neither the hepatic Th17 phenotype nor the disrupted metabolic homeostasis, suggesting the involvement of other and/or additional LKB1 downstream effectors. We indeed provide evidence that the control of Th17 responses by DCs via LKB1 is actually dependent on both AMPKalpha1 and AMPK-related salt-inducible kinase(s) signaling. Altogether, our data reveal a key role for LKB1 signaling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 responses.

Keywords:  Dendritic cells; Immunology; Metabolism; Obesity; T cells

DOI:  https://doi.org/10.1172/jci.insight.157948
Biomed Pharmacother. 2023 Apr 29. pii: S0753-3322(23)00550-4. [Epub ahead of print]163 114761

Vitamin B12 alleviates myocardial ischemia/reperfusion injury via the SIRT3/AMPK signaling pathway.

Yuhong Qin, Yani Shi, Qi Yu, Shenglan Yang, Ying Wang, Xiaojia Dai, Guoxing Li, Zhe Cheng.

  AIM: To examine the protective effect of vitamin B12 against myocardial ischemia/reperfusion (I/R) injury and elucidate its underlying mechanism of action.METHODS: Mice were subjected to myocardial I/R injury by left anterior descending coronary artery (LAD) occlusion followed by 24 h reperfusion. Cardiac function and injury were evaluated by echocardiography, triphenyl tetrazolium chloride (TTC) and cardiac troponin T (cTnT) staining, and measuring lactate dehydrogenase (LDH) levels. In addition, various molecular and biochemical methods, as well as RNA sequencing were used to determine the effects and mechanism of action of vitamin B12 on I/R injury.
RESULTS: We found that high doses of vitamin B12 inhibited myocardial I/R injury. Furthermore, our data indicated that vitamin B12 supplementation alleviated cardiac dysfunction and injury by mitigating oxidative stress and apoptosis through downregulation of Nox2, the Ac-SOD2/SOD2 and Bax/Bcl-2 ratios and cleaved caspase-3 expression, and upregulation of SIRT3 expression and AMPK activity. However, these effects were largely reversed following treatment with the SIRT3 inhibitor, 3-TYP. Our RNA-sequencing data further demonstrated that vitamin B12 supplementation reduced inflammation during I/R injury.
CONCLUSION: High doses of vitamin B12 supplements improved myocardial I/R injury by suppressing the accumulation of reactive oxygen species and apoptosis of myocardial tissue through modulation of the SIRT3/AMPK signaling pathway, while reducing inflammation. Our findings suggested that vitamin B12 administered at high doses could be a potential therapy for myocardial I/R damage.

Keywords:  AMPK; Myocardial ischemia/reperfusion injury; SIRT3; Vitamin B12

DOI:  https://doi.org/10.1016/j.biopha.2023.114761
J Ethnopharmacol. 2023 Apr 27. pii: S0378-8741(23)00343-4. [Epub ahead of print] 116475

Mulberry extract ameliorates T2DM-related symptoms via AMPK pathway in STZ-HFD-induced C57BL/6J mice.

Lulu Zhang, Xiuteng Zhou, Huijian Chen, Liangzhen You, Ting Zhang, Meng Cheng, Yudi Yao, Xin Pan, Xinzhou Yang.

  ETHNOPHARMACOLOGICAL RELEVANCE: Mulberry (Morus alba L.) is not only a tasty food but also a beneficial medicinal substance that has been historically used to treat diabetes, as recorded in Tang Ben Cao. Recent research on animal models has shown that the ethyl acetate extract of Morus alba L. fruits (EMF) has hypoglycemic and hypolipidemic properties. However, there is a lack of documentation on the specific mechanisms through which EMF exerts its hypoglycemic effects.OBJECTIVE OF THE STUDY: This study aimed to investigate the impact of EMF on L6 cells and C57/BL6J mice and to elucidate the potential mechanisms underlying its effects. The findings of this study can contribute to the existing evidence for the application of EMF as a therapeutic drug or dietary supplement in the management of type 2 diabetes mellitus (T2DM).
MATERIALS AND METHODS: The UPLC-Q-TOF-MS technique was utilized to gather MS data. Masslynx 4.1 software in conjunction with the SciFinder database and other relevant references were used to analyze and identify the chemical composition of EMF. A series of in vitro investigations including MTT assay, glucose uptake assay and Western blot analysis was performed using an L6 cell model stably expressing IRAP-mOrange after EMF treatment. In vivo investigations were performed on a STZ-HFD co-induced T2DM mouse model, which included assessments of body composition, biochemical tests, histopathological analysis, and Western blot analysis.
RESULTS: MTT results revealed that EMF had no toxic effects on the cells at various concentrations. When EMF was administered to L6 cells, there was an increase in glucose transporter type 4 (GLUT4) translocation activity and a significant dose-dependent enhancement of glucose uptake by L6 myotubes. EMF treatment led to a marked increase in P-AMPK levels and GLUT4 expression in the cells, but these effects was reversed by an AMPK inhibitor (Compound C). In diabetic mice with STZ-HFD-induced diabetes, EMF treatment improved oral glucose tolerance, hyperglycemia, and hyperinsulinemia. Furthermore, EMF supplementation significantly reduced insulin resistance (IR) in diabetic mice, as evaluated using a steady-state model of the insulin resistance index. Histopathological sections demonstrated that acute EMF treatment reduced hepatic steatosis, pancreatic damage, and adipocyte hypertrophy. Western blot analysis demonstrated that EMF treatment also reduced abnormally high PPARγ expression, elevated the level of p-AMPK and p-ACC, and augmented the abundance of GLUT4 in insulin-sensitive peripheral tissues.
SUMMARY: The results suggest that EMF may exert beneficial effects on T2DM through the AMPK/GLUT4 and AMPK/ACC pathways, as well as by regulating PPARγ expression.

Keywords:  AMPK; Hyperglycemia; Hyperlipidemia; Morus alba L.; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.jep.2023.116475
Nat Commun. 2023 May 05. 14(1): 2593

Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells.

Mahesh Pandit, Yun-Seo Kil, Jae-Hee Ahn, Ram Hari Pokhrel, Ye Gu, Sunil Mishra, Youngjoo Han, Yung-Taek Ouh, Ben Kang, Myeong Seon Jeong, Jong-Oh Kim, Joo-Won Nam, Hyun-Jeong Ko, Jae-Hoon Chang.

Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.

DOI: https://doi.org/10.1038/s41467-023-38316-9
Aging (Albany NY). 2023 May 04. 15

Exosomal miR-663b from "M1" macrophages promotes pulmonary artery vascular smooth muscle cell dysfunction through inhibiting the AMPK/Sirt1 axis.

Honghong Ma, Yang Yu, Lirong Mo, Qian Chen, Hui Dong, Yan Xu, Bing Zhuan.

  BACKGROUND: Inflammatory mediators from macrophages are proven to be involved in pulmonary vascular remodeling in pulmonary hypertension (PH). Here, this study intends to explore the mechanism of "M1" macrophage-derived exosomal miR-663b in pulmonary artery smooth muscle cells (PASMCs) dysfunctions and pulmonary hypertension.METHODS: Hypoxia-treated PASMCs were utilized for constructing an in-vitro pulmonary hypertension model. THP-1 cells were treated with PMA (320 nM) and LPS (10 μg/mL) + IFN-γ (20 ng/ml) for eliciting macrophage "M1" polarization. Exosomes derived from "M1" macrophages were isolated and added into PASMCs. The proliferation, inflammation, oxidative stress, and migration of PASMCs were evaluated. RT-PCR or Western blot examined the levels of miR-663b and the AMPK/Sirt1 pathway. Dual luciferase activity assay and RNA pull-down assay were carried out for confirming the targeted association between miR-663b and AMPK. An in-vivo PH model was built. Macrophage-derived exosomes with miR-663b inhibition were used for treating the rats, and alterations of pulmonary histopathology were monitored.
RESULTS: miR-663b was obviously up-regulated in hypoxia-elicited PASMCs and M1 macrophages. miR-663b overexpression boosted hypoxia-induced proliferation, inflammation, oxidative stress, and migration in PASMCs, whereas miR-663b low expression resulted in the opposite situation. AMPK was identified as a target of miR-663b, and miR-663b overexpression curbed the AMPK/Sirt1 pathway. AMPK activation ameliorated the damaging impact of miR-663b overexpression and "M1" macrophage exosomes on PASMCs. In vivo, "M1" macrophage exosomes with miR-663b low expression alleviated pulmonary vascular remodeling in pulmonary hypertension rats.
CONCLUSION: Exosomal miR-663b from "M1" macrophage facilitates PASMC dysfunctions and PH development by dampening the AMPK/Sirt1 axis.

Keywords:  AMPK pathway; exosomes; macrophages; miR-663b; pulmonary artery vascular smooth muscle cells

DOI:  https://doi.org/10.18632/aging.204690
Cell Commun Signal. 2023 May 04. 21(1): 95

Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity.

Qingsong Fu, Tiantian Li, Chen Zhang, Xiaotian Ma, Liying Meng, Limin Liu, Kai Shao, Guanzhao Wu, Xing Zhu, Xiaoyun Zhao.

  The higher prevalence of metabolic syndrome (MetS) in women after menopause is associated with a decrease in circulating 17β-oestradiol. To explore novel treatments for MetS in women with oestrogen deficiency, we studied the effect of exogenous butyrate on diet-induced obesity and metabolic dysfunctions using ovariectomized (OVX) mice as a menopause model. Oral administration of sodium butyrate (NaB) reduced the body fat content and blood lipids, increased whole-body energy expenditure, and improved insulin sensitivity. Additionally, NaB induced oestrogen receptor alpha (ERα) expression, activated the phosphorylation of AMPK and PGC1α, and improved mitochondrial aerobic respiration in cultured skeletal muscle cells. In conclusion, oral NaB improves metabolic parameters in OVX mice with diet-induced obesity. Oral supplementation with NaB might provide a novel therapeutic approach to treating MetS in women with menopause. Video Abstract.

Keywords:  Energy metabolism; Lipid metabolism; Metabolic syndrome; Mitochondrial function; Oestrogen receptor alpha; Sodium butyrate

DOI:  https://doi.org/10.1186/s12964-023-01119-y
Heliyon. 2023 May;9(5): e15316

Grain-sized moxibustion at Zusanli (ST36) promotes hepatic autophagy in rats with hyperlipidemia by regulating the ULK1 and TFEB expression through the AMPK/mTOR signaling pathway.

Qian Xu, Huanxi Wu, Haibin Zhu, Chengxuan Lu, Jiangjia Tao, Ziqiu Zhou, Jianbin Zhang.

  Objective: Grain-sized moxibustion is an effective treatment for hyperlipidemia, but how it regulates dyslipidemia and liver lipid deposits still needs to be fully understood. This study explored the molecular biological mechanism of grain-sized moxibustion to regulate hepatic autophagy in hyperlipidemic rats by affecting ULK1 and TFEB through the AMPK/mTOR signaling pathway.Methods: Thirty male Sprague-Dawley (SD) rats were fed a high-fat diet for eight weeks to induce hyperlipidemia. Hyperlipidemic rats were divided into the HFD group, HFD + Statin group, HFD + CC + Moxi group, and grain-sized moxibustion intervention group (HFD + Moxi group). The control (Blank) group consisted of normal rats without any intervention. Grain-sized moxibustion and drug interventions were initiated eight weeks after high-fat diet induction and continued for ten weeks. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), as well as hepatic triglyceride (TG), were measured after treatment. Hepatic steatosis and the expression of LC3I, LC3II, p62, p-AMPK, AMPK, p-mTOR, mTOR, ULK1, p-ULK1, and TFEB in the liver were analyzed.
Results: Compared with the HFD group, grain-sized moxibustion improved hyperlipidemia and hepatocyte steatosis, increased the LC3, p-AMPK, p-ULK1, and nuclear TFEB expression in the liver, but decreased the p62 and p-mTOR expression.
Conclusion: Grain-sized moxibustion at ST36 acupoints could regulate the blood lipid level of SD rats with hyperlipidemia, increase the expression level of ULK1 and TFEB by activating the AMPK/mTOR signaling pathway in liver tissues, and initiate the transcription of autophagy genes such as LC3.

Keywords:  AMPK/mTOR; Grain-sized moxibustion; Hepatic autophagy; Hyperlipidemia; ST36

DOI:  https://doi.org/10.1016/j.heliyon.2023.e15316
Cell Commun Signal. 2023 May 04. 21(1): 98

Small heterodimer partner interacting leucine zipper protein (SMILE) ameliorates autoimmune arthritis via AMPK signaling pathway and the regulation of B cell activation.

JooYeon Jhun, Jeonghyeon Moon, Ji Ye Kwon, Keun-Hyung Cho, Seang Yoon Lee, Hyun Sik Na, Mi-La Cho, Jun-Ki Min.

  Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract.

Keywords:  AMPK/mTOR; B cell; BAFF receptor; Rheumatoid arthritis (RA); Small heterodimer partner-interacting leucine zipper protein (SMILE)

DOI:  https://doi.org/10.1186/s12964-023-01054-y
Food Res Int. 2023 06;pii: S0963-9969(23)00317-4. [Epub ahead of print]168 112772

Hypolipidemic effects of macadamia oil are related to AMPK activation and oxidative stress relief: In vitro and in vivo studies.

Xixiang Shuai, Taotao Dai, David Julian McClements, Roger Ruan, Liqing Du, Yuhuan Liu, Jun Chen.

  Macadamia oil is rich in monounsaturated fatty acids, especially a high level of palmitoleic acid, which may have beneficial health effects by lowering blood lipid levels. In our study, the hypolipidemic effects of macadamia oil and its potential mechanisms of action were investigated using a combination of in vitro and in vivo assays. The results showed that macadamia oil significantly reduced lipid accumulation, and improved triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels in oleic acid-induced high-fat HepG2 cells. The macadamia oil treatment also exhibited antioxidant effects, as seen by its ability to reduce reactive oxygen species and malondialdehyde (MDA) levels, and increase superoxide dismutase (SOD) activity. The effects of 1000 μg/mL of macadamia oil were comparable to that of 4.19 μg/mL simvastatin. The results of qRT-PCR and western blotting analyses indicated that macadamia oil effectively inhibited hyperlipidemia by reducing the expression levels of SREBP-1c, PPAR-γ, ACC and FAS and by enhancing the expression levels of HO-1, NRF2 and γ-GCS, via AMPK activation and oxidative stress relief, respectively. In addition, different doses of macadamia oil were found to significantly improve liver lipid accumulation, reduce serum and liver TC, TG, and LDL-C levels, increase HDL-C levels, increase antioxidant enzyme (SOD, GSH-Px, and T-AOC) activity, and decrease the MDA content of mice on a high-fat diet. These results indicated that macadamia oil had a hypolipidemic effect and provide insights that might facilitate the development of functional food and dietary supplements.

Keywords:  Hyperlipidemia; Macadamia oil; Molecular mechanism; Oxidative stress

DOI:  https://doi.org/10.1016/j.foodres.2023.112772