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Zeng F, Hu W, Xu H, Wang X, Zhao C, Wang Y, Wang J. Strontium regulating lipid metabolism of bovine hepatocytes via SIRT1/SREBPs pathway. J Steroid Biochem Mol Biol 2025; 252:106785. [PMID: 40403884 DOI: 10.1016/j.jsbmb.2025.106785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Accepted: 05/19/2025] [Indexed: 05/24/2025]
Abstract
Periparturient dairy cows are susceptible to negative energy balance (NEB), which triggers excessive adipose mobilization, leading to elevated plasma non-esterified fatty acids (NEFA) and hepatic lipid accumulation. While strontium (Sr) has shown metabolic regulatory potential, its role in hepatic lipid homeostasis remains unclear. Using an NEFA-induced lipid accumulation model in bovine hepatocytes, we demonstrated that Sr (5-20 μM) significantly reduced intracellular triglyceride (TG) and total cholesterol (TC) levels. Further mechanistic studies revealed that Sr enhances SIRT1 expression and suppresses the expression and nuclear translocation of SREBP-1C/SREBP2, thereby downregulating downstream lipogenic enzymes including ACC, FASN, SCD1, and HMGCR. Molecular docking indicated that Sr²⁺ binds with high affinity to Asp-481/483 of SIRT1, while SIRT1 inhibition with EX-527 abolished Sr-mediated lipid-lowering effects. Additionally, Sr promoted PPARα nuclear translocation to enhance β-oxidation and upregulated LDLR expression to facilitate lipid efflux. This study elucidated the multi-target molecular mechanism of Sr alleviating lipid metabolism disorders in bovine hepatocytes through the SIRT1/SREBPs pathway, providing a theoretical foundation for the application of Sr in preventing metabolic diseases in dairy cows.
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Affiliation(s)
- Fangyuan Zeng
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Wenjuan Hu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Haichuan Xu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xinxin Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chenxu Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yazhou Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Jianguo Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, China.
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André DCA, Oliveira PF, Alves MG, Martins AD. Caloric Restriction and Sirtuins as New Players to Reshape Male Fertility. Metabolites 2025; 15:303. [PMID: 40422880 DOI: 10.3390/metabo15050303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/25/2025] [Accepted: 04/30/2025] [Indexed: 05/28/2025] Open
Abstract
Over the years, caloric intake has remained a subject of profound scrutiny. Within the scientific community, there has been rigorous debate to ascertain which path is most ideal for enhancing quality of life and extending the human lifespan. Caloric restriction has been shown to be a promising contributor towards longevity and delaying the onset of age-related diseases. This diet consists of a reduction in caloric intake while maintaining essential energy and nutritional requirements to achieve optimal health while avoiding malnutrition. However, the effects of this nutritional regimen on male reproductive health have not yet been comprehensively studied. Nevertheless, such a complex process will certainly be regulated by a variety of metabolic sensors, likely sirtuins. Evidence has been gathered regarding this group of enzymes, and their ability to regulate processes such as chromatin condensation, the cell cycle, insulin signaling, and glucose and lipid metabolism, among many others. Concerning testicular function and male fertility, sirtuins can modulate certain metabolic processes through their interaction with the hypothalamic-pituitary-gonadal axis and mitochondrial dynamics, among many others, which remain largely unexplored. This review explores the impact of caloric restriction on male fertility, highlighting the emerging role of sirtuins as key regulators of male reproductive health through their influence on cellular metabolism.
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Affiliation(s)
- Diana C A André
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Pedro F Oliveira
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Marco G Alves
- Institute of Biomedicine, Department of Medical Sciences (iBiMED), University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ana D Martins
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
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Baik S, Qianshi Y, Park S, Lee H, Heo H, Lee J, Yuan C, Sung J. Flavonoid Derivatives Isolated from Hypericum monogynum Ameliorate Insulin Resistance via Modulation of IRS-1/PI3K/Akt/FOXO1 Pathway in HepG2 Cells. J Med Food 2025; 28:243-255. [PMID: 39711189 DOI: 10.1089/jmf.2024.k.0242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024] Open
Abstract
In this study, two high-content flavonoid derivatives [3-8 biapigenin (HM 104) and quercetin-3-O-β-d-galactopyranoside (HM 111)] were obtained through the bioactivity-guided isolation of antidiabetic compounds from Hypericum monogynum flowers. HM 104 and HM 111 exhibited good glucose consumption in fatty acid-induced insulin-resistant HepG2 cells. Moreover, both active compounds enhanced glucose uptake by restoring the expression of key regulators of glucose metabolism, including insulin receptor substrate 1, phosphoinositide 3-kinase, protein kinase B, and glucose transporter type 4, and by mitigating the expression of forkhead box O1 and the factors involved in gluconeogenesis. They upregulate the phosphorylation of glycogen synthase kinase-3β, which may affect glycogen synthesis. Furthermore, the production of reactive oxygen species was decreased by the two compounds. This study provides novel mechanistic insights into the protective effects of flavonoid derivatives isolated from H. monogynum flowers in preventing and managing insulin resistance and associated metabolic disorders.
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Affiliation(s)
- Seungjoo Baik
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Yunhua Qianshi
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, P.R. China
- Natural Products Research Center of Guizhou Province, Guiyang, P.R. China
| | - Samuel Park
- Department of Food Science and Biotechnology, Andong National University, Andong, Korea
| | - Hana Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Huijin Heo
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Junsoo Lee
- Department of Food Science and Biotechnology, Chungbuk National University, Cheongju, Korea
| | - Chunmao Yuan
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, P.R. China
| | - Jeehye Sung
- Department of Food Science and Biotechnology, Andong National University, Andong, Korea
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Fiorentino F, Fabbrizi E, Mai A, Rotili D. Activation and inhibition of sirtuins: From bench to bedside. Med Res Rev 2025; 45:484-560. [PMID: 39215785 PMCID: PMC11796339 DOI: 10.1002/med.22076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 09/04/2024]
Abstract
The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Antonello Mai
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
- Pasteur Institute, Cenci‐Bolognetti FoundationSapienza University of RomeRomeItaly
| | - Dante Rotili
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
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Amirkhizi F, Taghizadeh M, Khalese-Ranjbar B, Hamedi-Shahraki S, Asghari S. The clinical value of serum sirtuin-1 concentration in the diagnosis of metabolic dysfunction-associated steatotic liver disease. BMC Gastroenterol 2025; 25:27. [PMID: 39844087 PMCID: PMC11753077 DOI: 10.1186/s12876-025-03613-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 01/14/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease and can affect individuals without producing any symptoms. We aimed to explore the value of serum sirtuin-1 (Sirt-1) in the diagnosis of MASLD. METHODS This case-control study analyzed data collected from 190 individuals aged 20 to 60 years. Anthropometric parameters, demographic information, and serum biochemical variables-including glycemic parameters, lipid profiles, liver enzymes, and Sirt-1 levels-were assessed. The correlation between serum Sirt-1 and biochemical variables was examined using Pearson's correlation coefficient. Receiver operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic value of serum Sirt-1 in the context of MASLD. RESULTS Serum Sirt-1 levels was significantly lower in the MASLD group (p < 0.001) and was inversely correlated with serum insulin (r = -0.163, p = 0.025), HOMA-IR (r = -0.169, p = 0.020) and triglyceride (r = -0.190, p = 0.009) and positively correlated with serum levels of high-density lipoprotein cholesterol (HDL-C) (r = 0.214, p = 0.003). The area under the curve (AUC) of Sirt-1 to predict the presence of MASLD was 0.76 (p < 0.001, 95% CI: 0.69, 0.82) with a sensitivity of 78.9, specificity of 61.1, positive predictive value (PPV) of 67.0%, and negative predictive value (NPV) of 74.0%. The optimal cutoff, determined using Youden's index, was 23.75 ng/mL. This indicates that serum Sirt-1 levels below 23.75 ng/mL may be indicative of MASLD. CONCLUSIONS The present study demonstrated that serum Sirt-1 levels were significantly lower in patients with MASLD. Furthermore, these levels were correlated with various metabolic parameters, including insulin resistance and the serum lipid profile. A serum Sirt-1 level below the cutoff of 23.75 ng/mL exhibited a significant association with the presence of MASLD, suggesting its potential utility in identifying patients with this condition.
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Affiliation(s)
- Farshad Amirkhizi
- Department of Nutrition, School of Public Health, Zabol University of Medical Sciences, Zabol, Iran
| | - Mahdiyeh Taghizadeh
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd, Tehran, 141556117, Iran
| | - Banafshe Khalese-Ranjbar
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd, Tehran, 141556117, Iran
| | - Soudabeh Hamedi-Shahraki
- Department of Epidemiology and Biostatistics, School of Public Health, Zabol University of Medical Sciences, Zabol, Iran
| | - Somayyeh Asghari
- Department of Clinical Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, No#44, Hojjatdoust St., Naderi St., Keshavarz Blvd, Tehran, 141556117, Iran.
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An H, Jang Y, Choi J, Hur J, Kim S, Kwon Y. New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis. Biomol Ther (Seoul) 2025; 33:18-38. [PMID: 39702310 PMCID: PMC11704404 DOI: 10.4062/biomolther.2024.188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.
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Affiliation(s)
- Haeun An
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yerin Jang
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jungin Choi
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Juhee Hur
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seojeong Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
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Latifi Z, Nikanfar S, Khodavirdilou R, Beirami SM, Khodavirdilou L, Fattahi A, Oghbaei F. MicroRNAs as diagnostic biomarkers in diabetes male infertility: a systematic review. Mol Biol Rep 2024; 52:90. [PMID: 39739064 DOI: 10.1007/s11033-024-10197-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 12/20/2024] [Indexed: 01/02/2025]
Abstract
This study conducts an in-depth review of the correlation between testis tissue changes and circulating microRNAs (miRNA) in diabetes-induced male reproductive complications, drawing upon both animal and clinical studies. The original articles published in English that specifically investigate miRNAs linked to male infertility in humans or animals with either type I or ΙΙ diabetes mellitus were included. The relevant articles were gathered from the PubMed, Google Scholar, Cochrane Library, and ScienceDirect databases. The quality of study was assessed utilizing the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Prevalence Studies. We collected an overall number of 1989 citations relating to our research subject. Following the elimination of articles based on the criteria, a total of 20 papers were included in the study. Aberrant expression profiles of 25 miRNAs were identified in diabetes associated with male reproductive issues, with 15 miRNAs exhibiting increased expression and 10 miRNAs showing decreased expression. Among the chosen publications, eighteen were identified as low-risk and two were classed as moderate quality. The dysregulated miRNAs were linked to testicular injury, disrupted steroid production, decreased sperm development and quality, and erectile dysfunction. The results demonstrate that the miRNA-mRNA network is linked to the pathological progression of diabetic testicular damage or erectile dysfunction. From a therapeutic perspective, the identification of circulating miRNAs could be beneficial in the timely identification and prevention of diabetes problems, such as diabetes-induced male infertility. Among all signaling pathways influenced by modified miRNAs, the Bax-caspase-3, MAPK, PI3K-Akt, and eNOS-cGMP-PKC were the main deregulated pathways.
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Affiliation(s)
- Zeinab Latifi
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Saba Nikanfar
- Pôle de Recherche en Physiopathologie de la Reproduction, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Rasa Khodavirdilou
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA
| | - Sohrab Minaei Beirami
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Lida Khodavirdilou
- Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA
| | - Amir Fattahi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Farnaz Oghbaei
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Du T, Liu S, Yu H, Hu T, Huang L, Gao L, Jia L, Hu J, Yu Y, Sun Q. Chronic sleep deprivation disturbs energy balance modulated by suprachiasmatic nucleus efferents in mice. BMC Biol 2024; 22:296. [PMID: 39710657 DOI: 10.1186/s12915-024-02097-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/16/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Epidemiologic researches show that short sleep duration may affect feeding behaviors resulting in higher energy intake and increased risk of obesity, but the further mechanisms that can interpret the causality remain unclear. The circadian rhythm is fine-tuned by the suprachiasmatic nucleus (SCN) as the master clock, which is essential for driving rhythms in food intake and energy metabolism through neuronal projections to the arcuate nucleus (ARC) and paraventricular nucleus (PVN). RESULTS We showed that chronic SD-induced aberrant expressions of AgRP/NPY and POMC attributed to compromised JAK/STAT3 signals and reduced energy expenditure in the mice, which can be rescued with AAV-genetic overexpression of BMAL1 into SCN. The potential mechanism may be related to the disruptions of SCN efferent mediated by BMAL1. CONCLUSIONS Chronic SD impairs energy balance through directly dampening BMAL1 expression, probably in the transcription level, in the SCN, which in turn affects the neuron projections to ARC and PVN. Remarkably, we provide evidence that may explain the causal mechanisms associated with sleep curtailment and obesity in adolescents.
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Affiliation(s)
- Tingting Du
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
- Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Shuailing Liu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
- Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Honghong Yu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
- Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Tian Hu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
- Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Lina Huang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
- Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Lanyue Gao
- Experimental Center, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Lihong Jia
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China
| | - Jiajin Hu
- Institute of Health Sciences, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Yang Yu
- Institute of Health Sciences, China Medical University, Shenyang, Liaoning, People's Republic of China
| | - Qi Sun
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention Ministry of Education, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, People's Republic of China.
- Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China.
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Rahimi Naiini M, Shahouzehi B, Khaksari M, Azizi S, Naghibi N, Nazari-Robati M. Ellagic acid reduces hepatic lipid contents through regulation of SIRT1 and AMPK in old rats. Arch Physiol Biochem 2024; 130:686-693. [PMID: 37814948 DOI: 10.1080/13813455.2023.2262165] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 09/07/2023] [Indexed: 10/11/2023]
Abstract
OBJECTIVE Ellagic acid is used in traditional medicine for the treatment of lipid disorders. In this study, the effects of ellagic acid on key regulators of lipid metabolism, and histopathological alterations in aged liver were examined. METHODS A total of 21 male Wistar rats were divided into three groups, including young control, old control, and old ellagic acid. After one month of treatment with ellagic acid, the expression levels of hepatic SIRT1, AMPK, SREBP-1c, PPAR-α, and phosphorylated AMPK (p-AMPK) were evaluated. The levels of several serum biochemical factors, and hepatic triglyceride, and cholesterol contents were assessed. RESULTS Ellagic acid elevated the levels of SIRT1, p-AMPK, and PPAR-α and reduced SREBP-1c level in the liver of old rats. It decreased triglyceride and cholesterol contents in the aged liver and improved histopathological changes. CONCLUSIONS The results demonstrated that ellagic acid can exert protective effects against hepatic lipid metabolism disorders induced by ageing.
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Affiliation(s)
- Mahdis Rahimi Naiini
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Beydolah Shahouzehi
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Shahrzad Azizi
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Niloufar Naghibi
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mahdieh Nazari-Robati
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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10
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Biscetti F, Rando MM, Nicolazzi MA, Rossini E, Santoro M, Angelini F, Iezzi R, Eraso LH, Dimuzio PJ, Pitocco D, Massetti M, Gasbarrini A, Flex A. Evaluation of sirtuin 1 as a predictor of cardiovascular outcomes in diabetic patients with limb-threatening ischemia. Sci Rep 2024; 14:26940. [PMID: 39506067 PMCID: PMC11542011 DOI: 10.1038/s41598-024-78576-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 11/01/2024] [Indexed: 11/08/2024] Open
Abstract
Chronic limb-threatening ischemia (CLTI) significantly increases the risk of major adverse limb events (MALE) and major adverse cardiac events (MACE) after lower extremity revascularization (LER). This study aims to identify novel biomarkers that help to further reduce the risk of postoperative cardiovascular complications. In this prospective, nonrandomized, observational study, baseline serum levels of sirtuin 1 (SIRT1) were assessed in 147 diabetic patients scheduled for LER due to CLTI, and participants were followed for the occurrence of MALE and MACE over 12 months. Fifty-three patients experienced MALE, and 33 experienced MACE within the follow-up period. Lower baseline SIRT1 levels were significantly associated with an increased risk of MALE and MACE, independent of other risk factors. The ROC curve analysis identified a SIRT1 cutoff of 3.79 ng/mL for predicting the risk of MALE. Moreover, incorporating SIRT1 into predictive models significantly enhanced the accuracy of predicting adverse outcomes. Results suggest serum SIRT1 is a potential independent marker for predicting MALE and MACE in diabetic patients with CLTI undergoing LER. Further research is needed to clarify the mechanistic pathways in which SIRT1 may influence cardiovascular outcomes, and the role of this novel biomarker in the management of PAD and CLTI among patients with diabetes.
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Affiliation(s)
- Federico Biscetti
- Cardiovascular Internal Medicine , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, 00168, Roma, Italy.
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy.
| | - Maria Margherita Rando
- Cardiovascular Internal Medicine , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, 00168, Roma, Italy
| | - Maria Anna Nicolazzi
- Cardiovascular Internal Medicine , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, 00168, Roma, Italy
| | - Enrica Rossini
- Cardiovascular Internal Medicine , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, 00168, Roma, Italy
| | - Michele Santoro
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
| | - Flavia Angelini
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
| | - Roberto Iezzi
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
- Radiology Unit , Fondazione Policlinico Universitario A. Gemelli IRCCS , Roma, Italy
| | - Luis H Eraso
- Division of Vascular and Endovascular Surgery , Thomas Jefferson University , Philadelphia, PA, USA
| | - Paul J Dimuzio
- Division of Vascular and Endovascular Surgery , Thomas Jefferson University , Philadelphia, PA, USA
| | - Dario Pitocco
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
- Diabetology Unit , Fondazione Policlinico Universitario A. Gemelli IRCCS , Roma, Italy
| | - Massimo Massetti
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
- Department of Cardiovascular Sciences , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, Roma, 00168, Italy
| | - Antonio Gasbarrini
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
- Department of Medical and Surgical Sciences , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, Roma, 00168, Italy
| | - Andrea Flex
- Cardiovascular Internal Medicine , Fondazione Policlinico Universitario A. Gemelli IRCCS , Largo Agostino Gemelli 8, 00168, Roma, Italy
- Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168, Roma, Italy
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11
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Diab R, Dimachkie L, Zein O, Dakroub A, Eid AH. Intermittent Fasting Regulates Metabolic Homeostasis and Improves Cardiovascular Health. Cell Biochem Biophys 2024; 82:1583-1597. [PMID: 38847940 PMCID: PMC11445340 DOI: 10.1007/s12013-024-01314-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2024] [Indexed: 10/02/2024]
Abstract
Obesity is a leading cause of morbidity and mortality globally. While the prevalence of obesity has been increasing, the incidence of its related complications including dyslipidemia and cardiovascular disease (CVD) has also been rising. Recent research has focused on modalities aimed at reducing obesity. Several modalities have been suggested including behavioral and dietary changes, medications, and bariatric surgery. These modalities differ in their effectiveness and invasiveness, with dietary changes gaining more interest due to their minimal risks compared to other modalities. Specifically, intermittent fasting (IF) has been gaining interest in the past decade. IF is characterized by cycles of alternating fasting and eating windows, with several different forms practiced. IF has been shown to reduce weight and alleviate obesity-related complications. Our review of clinical and experimental studies explores the effects of IF on the lipid profile, white adipose tissue (WAT) dynamics, and the gut microbiome. Notably, IF corrects dyslipidemia, reduces WAT accumulation, and decreases inflammation, which reduces CVD and obesity. This comprehensive analysis details the protective metabolic role of IF, advocating for its integration into public health practices.
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Affiliation(s)
- Rawan Diab
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Lina Dimachkie
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar Zein
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali Dakroub
- St. Francis Hospital and Heart Center, Roslyn, NY, USA
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, Qatar University, QU Health, Doha, Qatar.
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12
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Kujawowicz K, Mirończuk-Chodakowska I, Witkowska AM. Sirtuin 1 as a potential biomarker of undernutrition in the elderly: a narrative review. Crit Rev Food Sci Nutr 2024; 64:9532-9553. [PMID: 37229564 DOI: 10.1080/10408398.2023.2214208] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Undernutrition and inflammatory processes are predictors of early mortality in the elderly and require a rapid and accurate diagnosis. Currently, there are laboratory markers for assessing nutritional status, but new markers are still being sought. Recent studies suggest that sirtuin 1 (SIRT1) has the potential to be a marker for undernutrition. This article summarizes available studies on the association of SIRT1 and undernutrition in older people. Possible associations between SIRT1 and the aging process, inflammation, and undernutrition in the elderly have been described. The literature suggests that low SIRT1 levels in the blood of older people may not be associated with physiological aging processes, but with an increased risk of severe undernutrition associated with inflammation and systemic metabolic changes.
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Affiliation(s)
- Karolina Kujawowicz
- Department of Food Biotechnology, Medical University of Bialystok, Bialystok, Poland
| | | | - Anna Maria Witkowska
- Department of Food Biotechnology, Medical University of Bialystok, Bialystok, Poland
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13
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Yang J, Félix-Soriano E, Martínez-Gayo A, Ibañez-Santos J, Sáinz N, Martínez JA, Moreno-Aliaga MJ. SIRT1 and FOXO1 role on MASLD risk: effects of DHA-rich n-3 PUFA supplementation and exercise in aged obese female mice and in post-menopausal overweight/obese women. J Physiol Biochem 2024; 80:697-712. [PMID: 39264516 PMCID: PMC11502560 DOI: 10.1007/s13105-024-01044-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 08/07/2024] [Indexed: 09/13/2024]
Abstract
Sirtuins 1 (SIRT1) and Forkhead box protein O1 (FOXO1) expression have been associated with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Exercise and/or docosahexaenoic acid (DHA) supplementation have shown beneficial effects on MASLD. The current study aims to assess the relationships between Sirt1, Foxo1 mRNA levels and several MASLD biomarkers, as well as the effects of DHA-rich n-3 PUFA supplementation and/or exercise in the steatotic liver of aged obese female mice, and in peripheral blood mononuclear cells (PBMCs) of postmenopausal women with overweight/obesity. In the liver of 18-month-old mice, Sirt1 levels positively correlated with the expression of genes related to fatty acid oxidation, and negatively correlated with lipogenic and proinflammatory genes. Exercise (long-term treadmill training), especially when combined with DHA, upregulated hepatic Sirt1 mRNA levels. Liver Foxo1 mRNA levels positively associated with hepatic triglycerides (TG) content and the expression of lipogenic and pro-inflammatory genes, while negatively correlated with the lipolytic gene Hsl. In PBMCs of postmenopausal women with overweight/obesity, FOXO1 mRNA expression negatively correlated with the hepatic steatosis index (HSI) and the Zhejiang University index (ZJU). After 16-weeks of DHA-rich PUFA supplementation and/or progressive resistance training (RT), most groups exhibited reduced MASLD biomarkers and risk indexes accompanying with body fat mass reduction, but no significant changes were found between the intervention groups. However, in PBMCs n-3 supplementation upregulated FOXO1 expression, and the RT groups exhibited higher SIRT1 expression. In summary, SIRT1 and FOXO1 could be involved in the beneficial mechanisms of exercise and n-3 PUFA supplementation related to MASLD manifestation.
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Affiliation(s)
- Jinchunzi Yang
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Current Address: Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen, 518000, China
| | - Elisa Félix-Soriano
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Alejandro Martínez-Gayo
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - Javier Ibañez-Santos
- Studies, Research and Sports Medicine Centre (CEIMD), Government of Navarre, 31005, Pamplona, Spain
| | - Neira Sáinz
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
| | - J Alfredo Martínez
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain
| | - María J Moreno-Aliaga
- Center for Nutrition Research and Department of Nutrition, Food Science and Physiology, School of Pharmacy and Nutrition, University of Navarra, 31008, Pamplona, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
- IdISNA, Navarra Institute for Health Research, 31008, Pamplona, Spain.
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14
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Kumar KK, Aburawi EH, Ljubisavljevic M, Leow MKS, Feng X, Ansari SA, Emerald BS. Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues. Clin Epigenetics 2024; 16:78. [PMID: 38862980 PMCID: PMC11167878 DOI: 10.1186/s13148-024-01692-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024] Open
Abstract
Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the β-cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting β-cells and reducing T2DM-associated complications, among others.
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Affiliation(s)
- Kukkala Kiran Kumar
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, Abu Dhabi, United Arab Emirates
| | - Elhadi Husein Aburawi
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Milos Ljubisavljevic
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- Duke-NUS Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore
| | - Melvin Khee Shing Leow
- LKC School of Medicine, Nanyang Technological University, Singapore, Singapore
- Dept of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore
- Duke-NUS Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore
| | - Xu Feng
- Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore, Singapore
| | - Suraiya Anjum Ansari
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, Abu Dhabi, United Arab Emirates.
- Zayed Center for Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates.
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates.
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15
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Qian L, Zhu Y, Deng C, Liang Z, Chen J, Chen Y, Wang X, Liu Y, Tian Y, Yang Y. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases. Signal Transduct Target Ther 2024; 9:50. [PMID: 38424050 PMCID: PMC10904817 DOI: 10.1038/s41392-024-01756-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/13/2024] [Accepted: 01/23/2024] [Indexed: 03/02/2024] Open
Abstract
Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.
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Affiliation(s)
- Lu Qian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Yanli Zhu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Zhenxing Liang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East, Zhengzhou, 450052, China
| | - Junmin Chen
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Xue Wang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
| | - Yanqing Liu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Ye Tian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
| | - Yang Yang
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi'an, 710021, China.
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Faculty of Life Sciences and Medicine, Northwest University, 229 Taibai North Road, Xi'an, 710069, China.
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16
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Naiini MR, Shahouzehi B, Azizi S, Shafiei B, Nazari-Robati M. Trehalose-induced SIRT1/AMPK activation regulates SREBP-1c/PPAR-α to alleviate lipid accumulation in aged liver. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1061-1070. [PMID: 37581638 DOI: 10.1007/s00210-023-02644-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/24/2023] [Indexed: 08/16/2023]
Abstract
Aging is associated with a disturbance in the regulation of the metabolic function of the liver, which increases the risk of liver and systemic diseases. Trehalose, a natural disaccharide, has been identified to reduce dyslipidemia, hepatic steatosis, and glucose intolerance. However, the roles of trehalose on lipid metabolism in aged liver are unclear which was investigated in this study. Thirty-two male Wistar rats were randomly allocated into four groups (n = 8). Two groups of aged (24 months) and young (4 months) rats were administered 2% trehalose solution orally for 30 days. Control groups of aged and young rats did not receive any treatment. At the end of the treatment period, blood samples and liver tissues were collected. Then the expression of SIRT1, AMPK, SREBP-1c, and PPAR-α and the level of AMPK phosphorylation (p-AMPK) were quantified by real-time polymerase chain reaction and western blotting. Moreover, biochemical parameters and the histopathology of livers were evaluated. Trehalose supplementation increased the level of SIRT1, p-AMPK, and PPAR-α, whereas the level of SREBP-1c was diminished in the liver of old animals. In addition, treatment with trehalose improved histopathological features of senescent livers. Taken together, our results show that old rats developed lipogenesis in the liver which was alleviated with trehalose. Therefore, trehalose may be an effective intervention to reduce the progression of aging-induced liver diseases.
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Affiliation(s)
- Mahdis Rahimi Naiini
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Beydolah Shahouzehi
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Shahrzad Azizi
- Department of Pathobiology, Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Bentolhoda Shafiei
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Mahdieh Nazari-Robati
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
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17
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Guo J, Chen S, Zhang Y, Liu J, Jiang L, Hu L, Yao K, Yu Y, Chen X. Cholesterol metabolism: physiological regulation and diseases. MedComm (Beijing) 2024; 5:e476. [PMID: 38405060 PMCID: PMC10893558 DOI: 10.1002/mco2.476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 02/27/2024] Open
Abstract
Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.
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Affiliation(s)
- Jiarui Guo
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Silong Chen
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Ying Zhang
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
- Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Jinxia Liu
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Luyang Jiang
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Lidan Hu
- National Clinical Research Center for Child HealthThe Children's HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Ke Yao
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Yibo Yu
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Xiangjun Chen
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
- Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
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18
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Liu L, Liu L, Deng S, Zou L, He Y, Zhu X, Li H, Hu Y, Chu W, Wang X. Circadian Rhythm Alteration of the Core Clock Genes and the Lipid Metabolism Genes Induced by High-Fat Diet (HFD) in the Liver Tissue of the Chinese Soft-Shelled Turtle ( Trionyx sinensis). Genes (Basel) 2024; 15:157. [PMID: 38397147 PMCID: PMC10888015 DOI: 10.3390/genes15020157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024] Open
Abstract
Physiology disorders of the liver, as it is an important tissue in lipid metabolism, can cause fatty liver disease. The mechanism might be regulated by 17 circadian clock genes and 18 fat metabolism genes, together with a high-fat diet (HFD). Due to their rich nutritional and medicinal value, Chinese soft-shelled turtles (Trionyx sinensis) are very popular among the Chinese people. In the study, we aimed to investigate the influence of an HFD on the daily expression of both the core clock genes and the lipid metabolism genes in the liver tissue of the turtles. The two diets were formulated with 7.98% lipid (the CON group) and 13.86% lipid (the HFD group) to feed 180 juvenile turtles, which were randomly divided into two groups with three replicates per group and 30 turtles in each replicate for six weeks, and the diet experiment was administrated with a photophase regimen of a 24 h light/dark (12L:12D) cycle. At the end of the experiment, the liver tissue samples were collected from nine turtles per group every 3 h (zeitgeber time: ZT 0, 3, 6, 9, 12, 15, 18, 21 and 24) for 24 h to investigate the daily expression and correlation analysis of these genes. The results showed that 11 core clock genes [i.e., circadian locomotor output cycles kaput (Clock), brain and muscle arnt-like protein 1 and 2 (Bmal1/2), timeless (Tim), cryptochrome 1 (Cry2), period2 (Per2), nuclear factor IL-3 gene (Nfil3), nuclear receptor subfamily 1, treatment D, member 1 and 2 (Nr1d1/2) and retinoic acid related orphan receptor α/β/γ β and γ (Rorβ/γ)] exhibited circadian oscillation, but 6 genes did not, including neuronal PAS domain protein 2 (Npas2), Per1, Cry1, basic helix-loop-helix family, member E40 (Bhlhe40), Rorα and D-binding protein (Dbp), and 16 lipid metabolism genes including fatty acid synthase (Fas), diacylglycerol acyltransferase 1 (Dgat1), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), Low-density lipoprotein receptor-related protein 1-like (Ldlr1), Lipin 1 (Lipin1), Carnitine palmitoyltransferase 1A (Cpt1a), Peroxisome proliferator activation receptor α, β and γ (Pparα/β/γ), Sirtuin 1 (Sirt1), Apoa (Apoa1), Apolipoprotein B (Apob), Pyruvate Dehydrogenase kinase 4 (Pdk4), Acyl-CoA synthase long-chain1 (Acsl1), Liver X receptors α (Lxrα) and Retinoid X receptor, α (Rxra) also demonstrated circadian oscillations, but 2 genes did not, Scd and Acaca, in the liver tissues of the CON group. However, in the HFD group, the circadian rhythms' expressional patterns were disrupted for the eight core clock genes, Clock, Cry2, Per2, Nfil3, Nr1d1/2 and Rorβ/γ, and the peak expression of Bmal1/2 and Tim showed delayed or advanced phases. Furthermore, four genes (Cry1, Per1, Dbp and Rorα) displayed no diurnal rhythm in the CON group; instead, significant circadian rhythms appeared in the HFD group. Meanwhile, the HFD disrupted the circadian rhythm expressions of seven fat metabolism genes (Fas, Cpt1a, Sirt1, Apoa1, Apob, Pdk4 and Acsl1). Meanwhile, the other nine genes in the HFD group also showed advanced or delayed expression peaks compared to the CON group. Most importantly of all, there were remarkably positive or negative correlations between the core clock genes and the lipid metabolism genes, and their correlation relationships were altered by the HFD. To sum up, circadian rhythm alterations of the core clock genes and the lipid metabolism genes were induced by the high-fat diet (HFD) in the liver tissues of T. sinensis. This result provides experimental and theoretical data for the mass breeding and production of T. sinensis in our country.
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Affiliation(s)
- Li Liu
- School of Medical Technology, Shaoyang University, Shaoyang 422000, China;
| | - Lingli Liu
- Fisheries Research Institute of Hunan Province, Changsha 410153, China; (L.L.); (S.D.)
| | - Shiming Deng
- Fisheries Research Institute of Hunan Province, Changsha 410153, China; (L.L.); (S.D.)
| | - Li Zou
- Fisheries Research Institute of Hunan Province, Changsha 410153, China; (L.L.); (S.D.)
| | - Yong He
- Fisheries Research Institute of Hunan Province, Changsha 410153, China; (L.L.); (S.D.)
| | - Xin Zhu
- College of Biological and Chemical Engineering, Changsha University, Changsha 410003, China (H.L.)
| | - Honghui Li
- College of Biological and Chemical Engineering, Changsha University, Changsha 410003, China (H.L.)
| | - Yazhou Hu
- Fisheries College, Hunan Agriculture University, Changsha 410128, China;
| | - Wuying Chu
- College of Biological and Chemical Engineering, Changsha University, Changsha 410003, China (H.L.)
| | - Xiaoqing Wang
- Fisheries College, Hunan Agriculture University, Changsha 410128, China;
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Park J, Hall C, Hubbard B, LaMoia T, Gaspar R, Nasiri A, Li F, Zhang H, Kim J, Haeusler RA, Accili D, Shulman GI, Yu H, Choi E. MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis. Diabetes 2023; 72:1781-1794. [PMID: 37725942 PMCID: PMC10658066 DOI: 10.2337/db23-0314] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 09/12/2023] [Indexed: 09/21/2023]
Abstract
Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis on insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly. Disruption of the IR-MAD2 interaction increases serum fatty acid concentrations and hepatic fat accumulation in fasted male mice. Furthermore, disruption of the IR-MAD2 interaction distinctly changes metabolic and transcriptomic profiles in the liver and adipose tissues. Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis. ARTICLE HIGHLIGHTS The physiological role of IR endocytosis in insulin sensitivity remains unclear. Disruption of the IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling. IR-MAD2 controls insulin clearance and glucose metabolism. IR-MAD2 maintains energy homeostasis.
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Affiliation(s)
- Junhee Park
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Catherine Hall
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Brandon Hubbard
- Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
| | - Traci LaMoia
- Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
| | - Rafael Gaspar
- Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
| | - Ali Nasiri
- Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
| | - Fang Li
- Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Hanrui Zhang
- Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Jiyeon Kim
- Department of Urology and Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
| | - Rebecca A. Haeusler
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Domenico Accili
- Naomi Berrie Diabetes Center, Columbia University, New York, NY
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Gerald I. Shulman
- Departments of Internal Medicine and Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT
| | - Hongtao Yu
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China
| | - Eunhee Choi
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
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Ramezani M, Zobeiry M, Abdolahi S, Hatami B, Zali MR, Baghaei K. A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathol Res Pract 2023; 251:154809. [PMID: 37797383 DOI: 10.1016/j.prp.2023.154809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a major public health concern worldwide due to its rapidly rising prevalence and its potential to progress into end-stage liver disease. While the precise pathophysiology underlying NAFLD remains incompletely understood, it is strongly associated with various environmental triggers and other metabolic disorders. Epigenetics examines changes in gene expression that are not caused by alterations in the DNA sequence itself. There is accumulating evidence that epigenetics plays a key role in linking environmental cues to the onset and progression of NAFLD. Our understanding of how epigenetic mechanisms contribute to NAFLD pathophysiology has expanded considerably in recent years as research on the epigenetics of NAFLD has developed. This review summarizes recent insights into major epigenetic processes that have been implicated in NAFLD pathogenesis including DNA methylation, histone acetylation, and microRNAs that have emerged as promising targets for further investigation. Elucidating epigenetic mechanisms in NAFLD may uncover novel diagnostic biomarkers and therapeutic targets for this disease. However, many questions have remained unanswered regarding how epigenetics promotes NAFLD onset and progression. Additional studies are needed to further characterize the epigenetic landscape of NAFLD and validate the potential of epigenetic markers as clinical tools. Nevertheless, an enhanced understanding of the epigenetic underpinnings of NAFLD promises to provide key insights into disease mechanisms and pave the way for novel prognostic and therapeutic approaches.
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Affiliation(s)
- Meysam Ramezani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrokh Abdolahi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behzad Hatami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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21
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Miura M, Igarashi M, Isotani R, Nakagawa-Nagahama Y, Kuranami S, Naruse K, Kadowaki T, Yamauchi T. SIRT1 Controls Enteroendocrine Progenitor Cell Proliferation in High-Fat Diet-Fed Mice. Cell Mol Gastroenterol Hepatol 2023; 16:1040-1057. [PMID: 37598893 PMCID: PMC10685171 DOI: 10.1016/j.jcmgh.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND & AIMS We aimed to investigate how sirtuin 1 (SIRT1), a conserved mammalian Nicotinamide adenine dinucleotide+-dependent protein deacetylase, regulates the number of enteroendocrine cells (EECs). EECs benefit metabolism, and their increase potentially could treat type 2 diabetes and obesity. METHODS We used mice with specific Sirt1 disruption in the intestinal epithelium (VilKO, villin-Cre+, and Sirt1flox/flox mice) or enteroendocrine progenitor cells (EEPCs) (NgnKO, neurogenin 3-Cre+, Sirt1flox/flox mice) and mice with increased SIRT1 activity owing to overexpression (Sir2d mice) or 24-hour fasting. Mice were fed a high-fat diet (HFD), and blood glucagon-like peptide 1 (GLP-1) and glucose levels were measured. Intestinal tissues, EECs, and formed organoids were analyzed using quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In HFD-fed VilKO and NgnKO mice, an increase in EECs (42.3% and 37.2%), GLP-1- or GLP-2-producing L cells (93.0% and 61.4%), and GLP-1 (85.7% and 109.6%) was observed after glucose loading, explaining the improved metabolic phenotype of HFD-VilKO mice. These increases were associated with up-regulated expression of neurogenin 3 (EEPC marker) in crypts of HFD-VilKO and HFD-NgnKO mice, respectively. Conversely, Sir2d or 24-hour fasted mice showed a decrease in EECs (21.6%), L cells (41.6%), and proliferative progenitor cells. SIRT1 overexpression- or knockdown-mediated change in the progenitor cell proliferation was associated with Wnt/β-catenin activity changes. Notably, Wnt/β-catenin inhibitor completely suppressed EEC and L-cell increases in HFD-VilKO mice or organoids from HFD-VilKO and HFD-NgnKO mice. CONCLUSIONS Intestinal SIRT1 in EECs modulates the EEPC cycle by regulating β-catenin activity and can control the number of EECs in HFD-fed mice, which is a previously unknown role.
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Affiliation(s)
- Masaomi Miura
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaki Igarashi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Biology, Koch Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts.
| | - Ryosuke Isotani
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshiko Nakagawa-Nagahama
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Satoshi Kuranami
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kyoko Naruse
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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22
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Sohn JH, Mutlu B, Latorre-Muro P, Liang J, Bennett CF, Sharabi K, Kantorovich N, Jedrychowski M, Gygi SP, Banks AS, Puigserver P. Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism. Cell Metab 2023; 35:1356-1372.e5. [PMID: 37473754 PMCID: PMC10528355 DOI: 10.1016/j.cmet.2023.06.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 03/24/2023] [Accepted: 06/23/2023] [Indexed: 07/22/2023]
Abstract
Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
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Affiliation(s)
- Jee Hyung Sohn
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Beste Mutlu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Pedro Latorre-Muro
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Jiaxin Liang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Christopher F Bennett
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Kfir Sharabi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Noa Kantorovich
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Mark Jedrychowski
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Steven P Gygi
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Alexander S Banks
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Pere Puigserver
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
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You Y, Liang W. SIRT1 and SIRT6: The role in aging-related diseases. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166815. [PMID: 37499928 DOI: 10.1016/j.bbadis.2023.166815] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/26/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023]
Abstract
Aging is characterized by progressive functional deterioration with increased risk of mortality. It is a complex biological process driven by a multitude of intertwined mechanisms such as increased DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are a family of NAD+-dependent enzymes that regulate fundamental biological functions from genomic stability and lifespan to energy metabolism and tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 and SIRT6 are well-recognized for regulating signaling pathways related to aging. Herein, we review the protective role of SIRT1 and SIRT6 in aging-related diseases at molecular, cellular, tissue, and whole-organism levels. We also discuss the therapeutic potential of SIRT1 and SIRT6 modulators in the treatment of these diseases and challenges thereof.
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Affiliation(s)
- Yuzi You
- Department of General Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Wei Liang
- Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
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Yin JY, Lu XT, Hou ML, Cao T, Tian Z. Sirtuin1-p53: a potential axis for cancer therapy. Biochem Pharmacol 2023; 212:115543. [PMID: 37037265 DOI: 10.1016/j.bcp.2023.115543] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/12/2023]
Abstract
Sirtuin1 (SIRT1) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that plays key roles in a range of cellular events, including the maintenance of genome stability, gene regulation, cell proliferation, and apoptosis. P53 is one of the most studied tumor suppressors and the first identified non-histone target of SIRT1. SIRT1 deacetylates p53 in a NAD+-dependent manner and inhibits its transcriptional activity, thus exerting action on a series of pathways related to tissue homeostasis and various pathological states. The SIRT1-p53 axis is thought to play a central role in tumorigenesis. Although SIRT1 was initially identified as a tumor promoter, evidence now indicates that SIRT1 may also act as a tumor suppressor. This seemingly contradictory evidence indicates that the functionality of SIRT1 may be dictated by different cell types and intracellular localization patterns. In this review, we summarize recent evidence relating to the interactions between SIRT1 and p53 and discuss the relative roles of these two molecules with regards to cancer-associated cellular events. We also provide an overview of current knowledge of SIRT1-p53 signaling in tumorigenesis. Given the vital role of the SIRT1-p53 pathway, targeting this axis may provide promising strategies for the treatment of cancer.
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Affiliation(s)
- Jia-Yi Yin
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xin-Tong Lu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Meng-Ling Hou
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Ting Cao
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Zhen Tian
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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25
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Both prolonged high-fat diet consumption and calorie restriction boost hepatic NAD+ metabolism in mice. J Nutr Biochem 2023; 115:109296. [PMID: 36849030 DOI: 10.1016/j.jnutbio.2023.109296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 02/10/2023] [Accepted: 02/21/2023] [Indexed: 02/27/2023]
Abstract
Hepatic NAD+ homeostasis is essential to metabolic flexibility upon energy balance challenges. The molecular mechanism is unclear. This study aimed to determine how the enzymes involved in NAD+ salvage (Nampt, Nmnat1, Nrk1), clearance (Nnmt, Aox1, Cyp2e1), and consumption pathways (Sirt1, Sirt3, Sirt6, Parp1, Cd38) were regulated in the liver upon energy overload or shortage, as well as their relationships with glucose and lipid metabolism. Male C57BL/6N mice were fed ad libitum with the CHOW diet, high-fat diet (HFD), or subjected to 40% calorie restriction (CR) CHOW diet for 16 weeks respectively. HFD feeding increased hepatic lipids content and inflammatory markers, while lipids accumulation was not changed by CR. Both HFD feeding and CR elevated the hepatic NAD+ levels, as well as gene and protein levels of Nampt and Nmnat1. Furthermore, both HFD feeding and CR lowered acetylation of PGC-1α in parallel with the reduced hepatic lipogenesis and enhanced fatty acid oxidation, while CR enhanced hepatic AMPK activity and gluconeogenesis. Hepatic Nampt and Nnmt gene expression negatively correlated with fasting plasma glucose levels concomitant with positive correlations with Pck1 gene expression. Nrk1 and Cyp2e1 gene expression positively correlated with fat mass and plasma cholesterol levels, as well as Srebf1 gene expression. These data highlight that hepatic NAD+ metabolism will be induced for either the down-regulation of lipogenesis upon over nutrition or up-regulation of gluconeogenesis in response to CR, thus contributing to the hepatic metabolic flexibility upon energy balance challenges.
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26
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Moradi M, Farbood Y, Mard SA, Dianat M, Goudarzi G, Khorsandi L, Seyedian SS. p-Coumaric acid has pure anti-inflammatory characteristics against hepatopathy caused by ischemia-reperfusion in the liver and dust exposure. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:164-175. [PMID: 36742142 PMCID: PMC9869878 DOI: 10.22038/ijbms.2022.66192.14554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 11/30/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Studies show that chronic injuries like air pollution or acute damage such as hepatic ischemia-reperfusion (IR) cause various cellular pathologies such as oxidative stress, apoptosis, autophagy, and inflammation in hepatocytes. p-Coumaric acid (p-CA) is known as an antioxidant with many therapeutic impacts on inflammatory-related pathologies. In this experiment, we aimed to assess the hepatoprotective effects of p-CA on liver damage induced by dust and IR injury in adult male rats. MATERIALS AND METHODS Forty-eight adult male Wistar rats were divided into 6 groups; Control (CTRL); sham; DMSO+Dust+Laparotomy (LPT); DMSO+Dust+Ischemia-reperfusion (IR); p-CA+Dust+LPT; and p-CA+Dust+IR. Clean air, DMSO, p-CA, and dust were administrated 3 days a week for 6 consecutive weeks. Animals were sacrificed, the blood samples were aspirated and the liver sections were prepared for biochemical and histopathological assessments. RESULTS Significantly (P<0.05), the results represented that dust and IR can potentially increase the levels of ALT, AST, direct and total bilirubin, triglyceride, and cholesterol in serum. Also, MDA, TNF-α , NF-κB . HMGB-1 and ATG-7 levels were increased in hepatocytes. Gene expression of Nrf2, HOX-1, IL-6, HOTAIR, and miR-34a showed an incremental trend in the liver tissue. Total antioxidant capacity (TAC) in hepatocytes was decreased following dust exposure and IR induction. Also, miR-20b-5p, MEG3, and SIRT1 in the liver were decreased in dust and dust+IR groups. CONCLUSION p-CA alleviated pathological changes caused by dust exposure and IR injury. p-CA protected hepatic injury induced by dust and IR by inhibition of oxidative injury, inflammation, and autophagy.
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Affiliation(s)
- Mojtaba Moradi
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Yaghoob Farbood
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyyed Ali Mard
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahin Dianat
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Gholamreza Goudarzi
- Air Pollution and Respiratory Diseases Research Center, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
- Environmental Technologies Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Layasadat Khorsandi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Saeed Seyedian
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Chrononutrition-When We Eat Is of the Essence in Tackling Obesity. Nutrients 2022; 14:nu14235080. [PMID: 36501110 PMCID: PMC9739590 DOI: 10.3390/nu14235080] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/24/2022] [Accepted: 11/25/2022] [Indexed: 12/03/2022] Open
Abstract
Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on 'what to eat' or 'how much to eat' to reduce the obesity burden, but increasingly evidence indicates that 'when to eat' is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
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Jin M, Li X, Shen Y, Bao Y, Yang B, Wu Z, Jiao L, Zhou Q. The Benefit of Optimal Dietary Lipid Level for Black Seabream Acanthopagrus schlegelii Juveniles under Low-Salinity Environment. AQUACULTURE NUTRITION 2022; 2022:2222029. [PMID: 36860453 PMCID: PMC9973135 DOI: 10.1155/2022/2222029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/09/2022] [Accepted: 08/22/2022] [Indexed: 06/18/2023]
Abstract
The present study was aimed at evaluating the regulatory effects of dietary lipid levels on growth performance, osmoregulation, fatty acid composition, lipid metabolism, and physiological response in Acanthopagrus schlegelii under low salinity (5 psu). An 8-week feeding trial was conducted in juvenile A. schlegelii with an initial weight of 2.27 ± 0.05 g, and six isonitrogenous experimental diets were formulated with graded levels of lipid: 68.7 g/kg (D1), 111.7 g/kg (D2), 143.5 g/kg (D3), 188.9 g/kg (D4), 239.3 g/kg (D5), and 269.4 g/kg (D6), respectively. Results indicated that fish fed with diet containing 188.9 g/kg lipid significantly improved growth performance. Dietary D4 improved ion reabsorption and osmoregulation by increasing the concentrations of Na+, K+, and cortisol in serum and activities of Na+/K+-ATPase as well as expression levels of osmoregulation related to gene expression levels in the gill and intestine. The expression levels of long chain polyunsaturated fatty acid biosynthesis-related genes were dramatically upregulated when dietary lipid levels increased from 68.7 g/kg to 189.9 g/kg with levels of docosahexaenoic (DHA), eicosapentaenoic (EPA), and DHA/EPA ratio being highest in the D4 group. When fish fed dietary lipid levels from 68.7 g/kg to 188.9 g/kg, lipid homeostasis could be maintained by upregulating sirt1 and pparα expression levels, whereas lipid accumulation was observed in dietary lipid levels of 239.3 g/kg and over. Fish fed with high dietary lipid levels resulted in physiological stress related to oxidative stress and endoplasmic reticulum stress. In conclusion, based on weight gain, the optimal dietary lipid requirement of juvenile A. schlegelii reared at low-salinity water is 196.0 g/kg. These findings indicate that the optimal dietary lipid level can improve growth performance, n-3 LC-PUFA accumulation, and osmoregulatory ability and maintain lipid homeostasis and normal physiological functions of juvenile A. schlegelii.
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Affiliation(s)
- Min Jin
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Xuejiao Li
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Yuedong Shen
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Yangguang Bao
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Bingqian Yang
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Zhaoxun Wu
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Lefei Jiao
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
| | - Qicun Zhou
- Laboratory of Fish Nutrition, School of Marine Sciences, Ningbo University, Ningbo 315211, China
- Key Laboratory of Aquaculture Biotechnology Ministry of Education, Ningbo University, Ningbo 315211, China
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Yang B, Lu L, Zhou D, Fan W, Barbier-Torres L, Steggerda J, Yang H, Yang X. Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis. Front Endocrinol (Lausanne) 2022; 13:1007944. [PMID: 36267567 PMCID: PMC9578007 DOI: 10.3389/fendo.2022.1007944] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/05/2022] [Indexed: 11/29/2022] Open
Abstract
Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and culminating with the development of cirrhosis or hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is complex and diverse, and there is a lack of effective treatment measures. In this review, we address hepatokines identified in the pathogenesis of NAFLD and NASH, including the signaling of FXR/RXR, PPARα/RXRα, adipogenesis, hepatic stellate cell activation/liver fibrosis, AMPK/NF-κB, and type 2 diabetes. We also highlight the interaction between hepatokines, and cytokines or peptides secreted from muscle (myokines), adipose tissue (adipokines), and hepatic stellate cells (stellakines) in response to certain nutritional and physical activity. Cytokines exert autocrine, paracrine, or endocrine effects on the pathogenesis of NAFLD and NASH. Characterizing signaling pathways and crosstalk amongst muscle, adipose tissue, hepatic stellate cells and other liver cells will enhance our understanding of interorgan communication and potentially serve to accelerate the development of treatments for NAFLD and NASH.
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Affiliation(s)
- Bing Yang
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liqing Lu
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Dongmei Zhou
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wei Fan
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Lucía Barbier-Torres
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Justin Steggerda
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Heping Yang
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Xi Yang
- Department of Geriatric Endocrinology and Metabolism, Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, Guangxi Clinical Research Center for Cardio-cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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30
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Akan OD, Qin D, Guo T, Lin Q, Luo F. Sirtfoods: New Concept Foods, Functions, and Mechanisms. Foods 2022; 11:foods11192955. [PMID: 36230032 PMCID: PMC9563801 DOI: 10.3390/foods11192955] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/07/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Sirtfood is a new concept food that compounds diets that can target sirtuins (SIRTs). SIRTs are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases and ADP-ribosyltransferases (enzymes). SIRTs are mediators of calorie restriction (CR) and their activation can achieve some effects similar to CR. SIRTs play essential roles in ameliorating obesity and age-related metabolic diseases. Food ingredients such as resveratrol, piceatannol, anthocyanidin, and quinine are potential modulators of SIRTs. SIRT modulators are involved in autophagy, apoptosis, aging, inflammation, and energy homeostasis. Sirtfood proponents believe that natural Sirtfood recipes exert significant health effects.
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Affiliation(s)
- Otobong Donald Akan
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
- Microbiology Department, Faculty of Biological Science, Akwa-Ibom State University, Ikot Akpaden, Uyo 1167, Nigeria
| | - Dandan Qin
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Tianyi Guo
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Qinlu Lin
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Feijun Luo
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
- Correspondence: ; Tel.: +86-731-85623240
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31
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MiR-34a-5p promotes hepatic gluconeogenesis by suppressing SIRT1 expression. Exp Cell Res 2022; 420:113336. [PMID: 36058294 DOI: 10.1016/j.yexcr.2022.113336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 08/27/2022] [Accepted: 08/27/2022] [Indexed: 11/24/2022]
Abstract
Elevated hepatic gluconeogenesis is a major contributor of fasting hyperglycemia in diabetes. MicroRNAs (miRNAs) are tightly linked to glucose metabolism, but their role in hepatic gluconeogenesis remains largely unkown. In this current study, miR-34a-5p expression was significantly increased in liver tissues of db/db mice. Overexpression of miR-34a-5p promoted hepatic glucose production in mouse primary hepatocytes with increased expressions of gluconeogenic genes while miR-34a-5p inhibition displayed a contrary action. MiR-34a-5p overexpression in mouse primary hepatocytes repressed SIRT1 expression. SIRT1 inhibition by EX527 blocked phosphoenolpyruvate carboxykinase (PEPCK) protein degradation and enhanced hepatic gluconeogenesis. Treatment of A485 (a CBP/p300 inhibitor) decreased miR-34a-5p and PEPCK expressions in the livers of db/db mice, but elevated SIRT1 protein expression. In mouse primary hepatocytes, A485 exhibited a similar result. Overexpression of miR-34a-5p attenuated A485-inhibited gluconeogenic gene expressions and A485-induced SIRT1 protein expression. Finally, after miR-34a-5p was inhibited in the livers of db/db mice, hepatic glucose production and gluconeogenic gene expressions were markedly lowered. Our findings highlight a critical role of miR-34a-5p in the regulation of hepatic gluconeogenesis and miR-34a-5p may be a potential target in the treatment of type 2 diabetes.
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32
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Stress-Induced Premature Senescence Related to Oxidative Stress in the Developmental Programming of Nonalcoholic Fatty Liver Disease in a Rat Model of Intrauterine Growth Restriction. Antioxidants (Basel) 2022; 11:antiox11091695. [PMID: 36139771 PMCID: PMC9495674 DOI: 10.3390/antiox11091695] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
Metabolic syndrome (MetS) refers to cardiometabolic risk factors, such as visceral obesity, dyslipidemia, hyperglycemia/insulin resistance, arterial hypertension and non-alcoholic fatty liver disease (NAFLD). Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing metabolic/hepatic disorders later in life. Oxidative stress and cellular senescence have been associated with MetS and are observed in infants born following IUGR. However, whether these mechanisms could be particularly associated with the development of NAFLD in these individuals is still unknown. IUGR was induced in rats by a maternal low-protein diet during gestation versus. a control (CTRL) diet. In six-month-old offspring, we observed an increased visceral fat mass, glucose intolerance, and hepatic alterations (increased transaminase levels, triglyceride and neutral lipid deposit) in male rats with induced IUGR compared with the CTRL males; no differences were found in females. In IUGR male livers, we identified some markers of stress-induced premature senescence (SIPS) (lipofuscin deposit, increased protein expression of p21WAF, p16INK4a and Acp53, but decreased pRb/Rb ratio, foxo-1 and sirtuin-1 protein and mRNA expression) associated with oxidative stress (higher superoxide anion levels, DNA damages, decreased Cu/Zn SOD, increased catalase protein expression, increased nfe2 and decreased keap1 mRNA expression). Impaired lipogenesis pathways (decreased pAMPK/AMPK ratio, increased pAKT/AKT ratio, SREBP1 and PPARγ protein expression) were also observed in IUGR male livers. At birth, no differences were observed in liver histology, markers of SIPS and oxidative stress between CTRL and IUGR males. These data demonstrate that the livers of IUGR males at adulthood display SIPS and impaired liver structure and function related to oxidative stress and allow the identification of specific therapeutic strategies to limit or prevent adverse consequences of IUGR, particularly metabolic and hepatic disorders.
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McGinnis CD, Jennings EQ, Harris PS, Galligan JJ, Fritz KS. Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction. Cells 2022; 11:cells11132045. [PMID: 35805129 PMCID: PMC9266223 DOI: 10.3390/cells11132045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 12/12/2022] Open
Abstract
Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer’s, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain. Acetylation provides a crucial connection between hepatic metabolism and mitochondrial function. Dysregulation of protein acetylation throughout the cell can alter mitochondrial function and is associated with numerous liver diseases, including non-alcoholic and alcoholic fatty liver disease, steatohepatitis, and hepatocellular carcinoma. This review introduces biochemical mechanisms of protein acetylation in the regulation of mitochondrial function and hepatic diseases and offers a viewpoint on the potential for targeted therapies.
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Affiliation(s)
- Courtney D. McGinnis
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
| | - Erin Q. Jennings
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; (E.Q.J.); (J.J.G.)
| | - Peter S. Harris
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
| | - James J. Galligan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; (E.Q.J.); (J.J.G.)
| | - Kristofer S. Fritz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; (C.D.M.); (P.S.H.)
- Correspondence:
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The Role of Insulin Resistance in Fueling NAFLD Pathogenesis: From Molecular Mechanisms to Clinical Implications. J Clin Med 2022; 11:jcm11133649. [PMID: 35806934 PMCID: PMC9267803 DOI: 10.3390/jcm11133649] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/09/2022] [Accepted: 06/21/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) represents a predominant hepatopathy that is rapidly becoming the most common cause of hepatocellular carcinoma worldwide. The close association with metabolic syndrome’s extrahepatic components has suggested the nature of the systemic metabolic-related disorder based on the interplay between genetic, nutritional, and environmental factors, creating a complex network of yet-unclarified pathogenetic mechanisms in which the role of insulin resistance (IR) could be crucial. This review detailed the clinical and pathogenetic evidence involved in the NAFLD–IR relationship, presenting both the classic and more innovative models. In particular, we focused on the reciprocal effects of IR, oxidative stress, and systemic inflammation on insulin-sensitivity disruption in critical regions such as the hepatic and the adipose tissue, while considering the impact of genetics/epigenetics on the regulation of IR mechanisms as well as nutrients on specific insulin-related gene expression (nutrigenetics and nutrigenomics). In addition, we discussed the emerging capability of the gut microbiota to interfere with physiological signaling of the hormonal pathways responsible for maintaining metabolic homeostasis and by inducing an abnormal activation of the immune system. The translation of these novel findings into clinical practice could promote the expansion of accurate diagnostic/prognostic stratification tools and tailored pharmacological approaches.
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35
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Vinnicombe KRT, Volkoff H. Possible role of transcription factors (BSX, NKX2.1, IRX3 and SIRT1) in the regulation of appetite in goldfish (Carassius auratus). Comp Biochem Physiol A Mol Integr Physiol 2022; 268:111189. [PMID: 35307341 DOI: 10.1016/j.cbpa.2022.111189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/13/2022] [Accepted: 03/13/2022] [Indexed: 12/17/2022]
Abstract
The homeobox genes play important roles in the embryonic development of animals. Recent evidence suggests they might also regulate feeding and act as transcription factors of appetite regulators. Examples of these genes are a brain-specific homeobox transcription factor (BSX), NK2 homeobox 1 (NKX2.1) and the Iroquois homeobox 3 (IRX3). Sirtuin1 (SIRT1) acts as a transcription factor for nutrient (e.g. lipid, glucose) homeostasis and responds to stress and nutrient availability, and has been shown to interact with appetite regulators. Very little is known about the role of these genes in the regulation of feeding and nutrient homeostasis in fish. In this study, we assessed the roles of BSX, NKX2.1, IRX3 and SIRT1 in the central regulation of feeding in goldfish by examining their mRNA brain distribution, assessing the effects of fasting on their brain expression and assessing the effects of peripheral injections of cholecystokinin (CCK, a brain-gut peptide), on their brain expression. All genes showed a widespread distribution in the brain, with high levels in the hypothalamus. In both hypothalamus and telencephalon, fasting induced increases in BSX, IRX3 and NKX2.1 expressions but had no effect on SIRT1 expression levels. CCK injections increased hypothalamic expression levels of IRX3 and SIRT1, and telencephalic expression levels of NKX2.1 and SIRT1, with no effect on either hypothalamic BSX or NKX2.1 expression levels or telencephalon BSX or IRX3 expression levels. Our results suggest that, in goldfish as in mammals, central BSX, NKX2.1, IRX3 and SIRT1 are present in regions of the brain regulating feeding, are sensitive to nutrient status and interact with appetite-regulating peptides.
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Affiliation(s)
- Kelsey R T Vinnicombe
- Department of Biology, Memorial University of Newfoundland, St. John's, NL A1B 3X9, Canada
| | - Helene Volkoff
- Department of Biology, Memorial University of Newfoundland, St. John's, NL A1B 3X9, Canada.
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36
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Palu RAS, Owings KG, Garces JG, Nicol A. A natural genetic variation screen identifies insulin signaling, neuronal communication, and innate immunity as modifiers of hyperglycemia in the absence of Sirt1. G3 (BETHESDA, MD.) 2022; 12:jkac090. [PMID: 35435227 PMCID: PMC9157059 DOI: 10.1093/g3journal/jkac090] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022]
Abstract
Variation in the onset, progression, and severity of symptoms associated with metabolic disorders such as diabetes impairs the diagnosis and treatment of at-risk patients. Diabetes symptoms, and patient variation in these symptoms, are attributed to a combination of genetic and environmental factors, but identifying the genes and pathways that modify diabetes in humans has proven difficult. A greater understanding of genetic modifiers and the ways in which they interact with metabolic pathways could improve the ability to predict a patient's risk for severe symptoms, as well as enhance the development of individualized therapeutic approaches. In this study, we use the Drosophila Genetic Reference Panel to identify genetic variation influencing hyperglycemia associated with loss of Sirt1 function. Through analysis of individual candidate functions, physical interaction networks, and gene set enrichment analysis, we identify not only modifiers involved in canonical glucose metabolism and insulin signaling, but also genes important for neuronal signaling and the innate immune response. Furthermore, reducing the expression of several of these candidates suppressed hyperglycemia, making them potential candidate therapeutic targets. These analyses showcase the diverse processes contributing to glucose homeostasis and open up several avenues of future investigation.
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Affiliation(s)
- Rebecca A S Palu
- Department of Biological Sciences, Purdue University-Fort Wayne, Fort Wayne, IN 46818, USA
| | - Katie G Owings
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - John G Garces
- Department of Biological Sciences, Purdue University-Fort Wayne, Fort Wayne, IN 46818, USA
| | - Audrey Nicol
- Department of Biological Sciences, Purdue University-Fort Wayne, Fort Wayne, IN 46818, USA
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37
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He L, Ma S, Zuo Q, Zhang G, Wang Z, Zhang T, Zhai J, Guo Y. An Effective Sodium-Dependent Glucose Transporter 2 Inhibition, Canagliflozin, Prevents Development of Hypertensive Heart Failure in Dahl Salt-Sensitive Rats. Front Pharmacol 2022; 13:856386. [PMID: 35370704 PMCID: PMC8964360 DOI: 10.3389/fphar.2022.856386] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/21/2022] [Indexed: 11/30/2022] Open
Abstract
Background: The aim of the study was to investigate the protective effect of canagliflozin (CANA) on myocardial metabolism and heart under stress overload and to further explore its possible molecular mechanism. Methods: High-salt diet was used to induce heart failure with preserved ejection fraction (HFpEF), and then, the physical and physiological indicators were measured. The cardiac function was evaluated by echocardiography and related indicators. Masson trichrome staining, wheat germ agglutinin, and immunohistochemical staining were conducted for histology analysis. Meanwhile, oxidative stress and cardiac ATP production were also determined. PCR and Western blotting were used for quantitative detection of related genes and proteins. Comprehensive metabolomics and proteomics were employed for metabolic analysis and protein expression analysis. Results: In this study, CANA showed diuretic, hypotensive, weight loss, and increased intake of food and water. Dahl salt-sensitive (DSS) rats fed with a diet containing 8% NaCl AIN-76A developed left ventricular remodeling and diastolic dysfunction caused by hypertension. After CANA treatment, cardiac hypertrophy and fibrosis were reduced, and the left ventricular diastolic function was improved. Metabolomics and proteomics data confirmed that CANA reduced myocardial glucose metabolism and increased fatty acid metabolism and ketogenesis in DSS rats, normalizing myocardial metabolism and reducing the myocardial oxidative stress. Mechanistically, CANA upregulated p-adenosine 5′-monophosphate-activated protein kinase (p-AMPK) and sirtuin 1 (SIRT1) and significantly induced the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a). Conclusion: CANA can improve myocardial hypertrophy, fibrosis, and left ventricular diastolic dysfunction induced by hypertension in DSS rats, possibly through the activation of the AMPK/SIRT1/PGC-1a pathway to regulate energy metabolism and oxidative stress.
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Affiliation(s)
- Lili He
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China.,Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Sai Ma
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China.,Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, China
| | - Qingjuan Zuo
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Guorui Zhang
- Department of Cardiology, The Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, China
| | - Zhongli Wang
- Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, China
| | - Tingting Zhang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Jianlong Zhai
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, China
| | - Yifang Guo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China.,Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, China
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38
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Miyahara H, Hasegawa K, Yashiro M, Ohara T, Fujisawa M, Yoshimura T, Matsukawa A, Tsukahara H. Thioredoxin interacting protein protects mice from fasting induced liver steatosis by activating ER stress and its downstream signaling pathways. Sci Rep 2022; 12:4819. [PMID: 35314758 PMCID: PMC8938456 DOI: 10.1038/s41598-022-08791-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Under normal conditions, fasting results in decreased protein disulfide isomerase (PDI) activity and accumulation of unfolded proteins, leading to the subsequent activation of the unfolded protein response (UPR)/autophagy signaling pathway to eliminate damaged mitochondria. Fasting also induces upregulation of thioredoxin-interacting protein (TXNIP) expression and mice deficient of this protein (TXNIP-KO mice) was shown to develop severe hypoglycemia, hyperlipidemia and liver steatosis (LS). In the present study, we aimed to determine the role of TXNIP in fasting-induced LS by using male TXNIP-KO mice that developed LS without severe hypoglycemia. In TXNIP-KO mice, fasting induced severe microvesicular LS. Examinations by transmission electron microscopy revealed mitochondria with smaller size and deformities and the presence of few autophagosomes. The expression of β-oxidation-associated genes remained at the same level and the level of LC3-II was low. PDI activity level stayed at the original level and the levels of p-IRE1 and X-box binding protein 1 spliced form (sXBP1) were lower. Interestingly, treatment of TXNIP-KO mice with bacitracin, a PDI inhibitor, restored the level of LC3-II after fasting. These results suggest that TXNIP regulates PDI activity and subsequent activation of the UPR/autophagy pathway and plays a protective role in fasting-induced LS.
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Affiliation(s)
- Hiroyuki Miyahara
- Department of Pediatrics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. .,Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
| | - Kosei Hasegawa
- Department of Pediatrics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masato Yashiro
- Department of Pediatrics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Toshiaki Ohara
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masayoshi Fujisawa
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirokazu Tsukahara
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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39
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Higgins CB, Mayer AL, Zhang Y, Franczyk M, Ballentine S, Yoshino J, DeBosch BJ. SIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase. Nat Commun 2022; 13:1074. [PMID: 35228549 PMCID: PMC8885655 DOI: 10.1038/s41467-022-28717-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 02/07/2022] [Indexed: 12/30/2022] Open
Abstract
Calorie restriction abates aging and cardiometabolic disease by activating metabolic signaling pathways, including nicotinamide adenine dinucleotide (NAD+) biosynthesis and salvage. Nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting in NAD+ salvage, yet hepatocyte NAMPT actions during fasting and metabolic duress remain unclear. We demonstrate that hepatocyte NAMPT is upregulated in fasting mice, and in isolated hepatocytes subjected to nutrient withdrawal. Mice lacking hepatocyte NAMPT exhibit defective FGF21 activation and thermal regulation during fasting, and are sensitized to diet-induced glucose intolerance. Hepatocyte NAMPT overexpression induced FGF21 and adipose browning, improved glucose homeostasis, and attenuated dyslipidemia in obese mice. Hepatocyte SIRT1 deletion reversed hepatocyte NAMPT effects on dark-cycle thermogenesis, and hepatic FGF21 expression, but SIRT1 was dispensable for NAMPT insulin-sensitizing, anti-dyslipidemic, and light-cycle thermogenic effects. Hepatocyte NAMPT thus conveys key aspects of the fasting response, which selectively dissociate through hepatocyte SIRT1. Modulating hepatocyte NAD+ is thus a potential mechanism through which to attenuate fasting-responsive disease.
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Affiliation(s)
- Cassandra B. Higgins
- grid.4367.60000 0001 2355 7002Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 USA
| | | | - Yiming Zhang
- grid.4367.60000 0001 2355 7002Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Michael Franczyk
- grid.26091.3c0000 0004 1936 9959Department of Medicine, Keio University School of Medicine, Minato, Tokyo, Japan
| | - Samuel Ballentine
- grid.4367.60000 0001 2355 7002Department of Anatomic and Molecular Pathology, Washington University School of Medicine, St. Louis, MO 63110 USA
| | - Jun Yoshino
- grid.26091.3c0000 0004 1936 9959Department of Medicine, Keio University School of Medicine, Minato, Tokyo, Japan
| | - Brian J. DeBosch
- grid.4367.60000 0001 2355 7002Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 USA ,grid.4367.60000 0001 2355 7002Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110 USA
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40
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Khawar MB, Sohail AM, Li W. SIRT1: A Key Player in Male Reproduction. Life (Basel) 2022; 12:318. [PMID: 35207605 PMCID: PMC8880319 DOI: 10.3390/life12020318] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 02/17/2022] [Accepted: 02/17/2022] [Indexed: 12/23/2022] Open
Abstract
Reproduction is the way to immortality for an individual, and it is essential to the continuation of the species. Sirtuins are involved in cellular homeostasis, energy metabolism, apoptosis, age-related problems, and sexual reproduction. Sirtuin 1 (SIRT1) belongs to the sirtuin family of deacetylases, and it is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. It removes the acetyl group from a variety of substrates. SIRT1 regulates endocrine/metabolic, reproductive, and placental development by deacetylating histone, different transcription factors, and signal transduction molecules in a variety of cellular processes. It also plays a very important role in the synthesis and secretion of sex hormones via regulating the hypothalamus-pituitary-gonadal (HPG) axis. Moreover, SIRT1 participates in several key stages of spermatogenesis and sperm maturation. The current review will give a thorough overview of SIRT1's functions in male reproductive processes, thus paving the way for more research on restorative techniques and their uses in reproductive medicine.
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Affiliation(s)
- Muhammad Babar Khawar
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
- Applied Molecular Biology and Biomedicine Laboratory, Department of Zoology, University of Narowal, Narowal 51600, Pakistan
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Abdullah Muhammad Sohail
- Molecular Medicine and Cancer Therapeutics Laboratory, Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore 54782, Pakistan
| | - Wei Li
- Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
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Potential of Polyphenols to Restore SIRT1 and NAD+ Metabolism in Renal Disease. Nutrients 2022; 14:nu14030653. [PMID: 35277012 PMCID: PMC8837945 DOI: 10.3390/nu14030653] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/18/2022] [Accepted: 01/29/2022] [Indexed: 11/17/2022] Open
Abstract
SIRT1 is an NAD+-dependent class III histone deacetylase that is abundantly expressed in the kidney, where it modulates gene expression, apoptosis, energy homeostasis, autophagy, acute stress responses, and mitochondrial biogenesis. Alterations in SIRT1 activity and NAD+ metabolism are frequently observed in acute and chronic kidney diseases of diverse origins, including obesity and diabetes. Nevertheless, in vitro and in vivo studies and clinical trials with humans show that the SIRT1-activating compounds derived from natural sources, such as polyphenols found in fruits, vegetables, and plants, including resveratrol, quercetin, and isoflavones, can prevent disease and be part of treatments for a wide variety of diseases. Here, we summarize the roles of SIRT1 and NAD+ metabolism in renal pathophysiology and provide an overview of polyphenols that have the potential to restore SIRT1 and NAD+ metabolism in renal diseases.
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López-Soldado I, Guinovart JJ, Duran J. Hepatic overexpression of protein targeting to glycogen attenuates obesity and improves hyperglycemia in db/db mice. Front Endocrinol (Lausanne) 2022; 13:969924. [PMID: 36157460 PMCID: PMC9500150 DOI: 10.3389/fendo.2022.969924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
Increased liver glycogen content has been shown to reduce food intake, attenuate obesity, and improve glucose tolerance in a mouse model of high-fat diet (HFD)-induced obesity. Here we studied the contribution of liver glycogen to the regulation of obesity and glucose metabolism in a model of type 2 diabetes and obesity, namely the db/db mouse. To this end, we crossed db/db mice with animals overexpressing protein targeting to glycogen (PTG) in the liver to generate db/db mice with increased liver glycogen content (db/db-PTG). Hepatic PTG overexpression reduced food intake and fat weight and attenuated obesity and hyperglycemia in db/db mice. Db/db-PTG mice showed similar energy expenditure and physical activity to db/db mice. PTG overexpression reduced liver phosphoenolpyruvate carboxykinase (PEPCK) protein levels and repressed hepatic glucose production in db/db mice. Moreover, increased liver glycogen elevated hepatic ATP content in these animals. However, lipid metabolism was not modified by PTG overexpression. In conclusion, increased liver glycogen content ameliorates the diabetic and obesity phenotype in db/db mice.
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Affiliation(s)
- Iliana López-Soldado
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain
- *Correspondence: Iliana López-Soldado,
| | - Joan J. Guinovart
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain
| | - Jordi Duran
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
- Institut Químic de Sarrià (IQS), Universitat Ramon Llull (URL), Barcelona, Spain
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain
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Liu D, Liu X, Ma X, Li C, Li J, Li Q, Zhang N, Cao Y, Li Z, Kang X, Tian Y, Li W. Two novel InDels within the Promoter of SIRT1 are associated with growth traits in chickens. Br Poult Sci 2021; 63:445-453. [PMID: 34923879 DOI: 10.1080/00071668.2021.2014400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
1. The objectives of the present study were to elucidate the relationship between novel variations of the SIRT1 gene and chicken growth traits. In total, 1,429 chickens, including six breeds and a Gushi ×Anka F2 resource population, were genotyped using PCR-RFLP. 2. Two novel InDels (c.-1552_-1553insCG and c.-450_-451delCG) in the promoter of the chicken SIRT1 gene were identified. An association study showed that c.-1552_-1553insCG was significantly correlated with growth traits and serum lipid indicators. 3. The insertion genotype was most highly associated with body weight at day old, two- and four-week-old chickens, and with shank circumference at four and eight weeks of age. The wild type genotype at this site was most highly associated with serum lipid indicators. 4. In contrast, c.-450_-451delCG was significantly correlated with muscle fibre diameter. The SIRT1 gene expression in chickens with different InDel genotypes was analysed and was significantly higher with heterozygous genotypes at both sites in muscle and fat tissue, relative to expression in chickens with the corresponding homozygous genotypes. 5. The effects of different haplotypes on SIRT1 promoter activity showed that promoter activity depends on haplotype, with haplotype HapII exhibiting the highest activity. 6. It was concluded that the SIRT1 gene is associated with chicken growth traits and that the two InDels influence SIRT1 promoter activity in chickens.
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Affiliation(s)
- Dandan Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Xuelian Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Xuejie Ma
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Chong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Jing Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Qi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Na Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Yanfang Cao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Zhuanjian Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
| | - Wenting Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450002, Henan, China.,Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002
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Hamidi-zad Z, Moslehi A, Rastegarpanah M. Attenuating effects of allantoin on oxidative stress in a mouse model of nonalcoholic steatohepatitis: role of SIRT1/Nrf2 pathway. Res Pharm Sci 2021; 16:651-659. [PMID: 34760013 PMCID: PMC8562413 DOI: 10.4103/1735-5362.327511] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/21/2021] [Accepted: 09/05/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Nonalcoholic steatohepatitis (NASH) is considered a common and serious liver disease, which develops into cirrhosis, fibrosis, and even hepatocellular carcinoma. Oxidative stress is identified as an important factor in the induction and promotion of NASH. Allantoin is a natural and safe compound and has notable effects on lipid metabolism, inflammation, and oxidative stress. Therefore, this study was aimed to assess the role of allantoin on the oxidative stress and SIRT1/Nrf2 pathway in a mouse model of NASH. EXPERIMENTAL APPROACH C57/BL6 male mice received saline and allantoin (saline as the control and allantoin as the positive control groups). NASH was induced by a methionine-choline deficient diet (MCD). In the NASH-allantoin (NASH-Alla) group, allantoin was injected for 4 weeks in the mice feeding on an MCD diet. Afterward, histopathological, serum, oxidative stress, and western blot evaluations were performed. FINDINGS/RESULTS We found NASH provided hepatic lipid accumulation and inflammation. Superoxide dismutase (SOD) and glutathione (GSH) levels decreased, lipid peroxidation increased, and the expression of SIRT1 and Nrf2 downregulated. However, allantoin-treatment decreased serum cholesterol, ALT, and AST. Liver steatosis and inflammation were improved. Protein expression of SIRT1 and Nrf2 were upregulated and SOD, CAT, and GSH levels increased and lipid peroxidation decreased. CONCLUSION AND IMPLICATIONS It seems that the antioxidant effects of allantoin might have resulted from the activation of SIRT1/Nrf2 pathway and increase of cellular antioxidant power.
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Affiliation(s)
- Zeinab Hamidi-zad
- Physiology Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, I.R. Iran
| | - Azam Moslehi
- Cellular & Molecular Research Center, Qom University of Medical Sciences, Qom, I.R. Iran
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Sousa G, de Carvalho SS, Atella GC. Trypanosoma cruzi Affects Rhodnius prolixus Lipid Metabolism During Acute Infection. FRONTIERS IN TROPICAL DISEASES 2021. [DOI: 10.3389/fitd.2021.737909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The interaction between Rhodnius prolixus and Trypanosoma cruzi has huge medical importance because it responds to the transmission of Chagas disease, a neglected tropical disease that affects about eight million people worldwide. It is known that trypanosomatid pathogens depend on active lipid endocytosis from the insect host to meet growth and differentiation requirements. However, until now, knowledge on how the parasite affects the lipid physiology of individual insect organs was largely unknown. Herein, the biochemical and molecular dynamics of the triatomine R. prolixus lipid metabolism in response to T. cruzi acute infection were investigated. A qRT-PCR approach was used to determine the expression profile of 12 protein-coding genes involved in R. prolixus lipid physiology. In addition, microscopic and biochemical assays revealed the lipid droplet profile and the levels of the different identified lipid classes. Finally, spectrometry analyses were used to determine fatty acid and sterol composition and their modulation towards the infection. T. cruzi infection downregulated the transcript levels of protein-coding genes for lipid biosynthetic and degrading pathways in individual triatomine organs. On the other hand, upregulation of lipid receptor transcripts indicates an attempt to capture more lipids from hemolymphatic lipoproteins. Consequently, several lipid classes (such as monoacylglycerol, diacylglycerol, triacylglycerol, cholesteryl ester, phosphatidylcholine, and phosphatidylethanolamine) were involved in the response to the parasite challenge, although modulating only the insect fat body. T. cruzi never leaves the insect gut and yet it modulates non-infected tissues, suggesting that the association between the parasite and the vector organs is reached by cell signaling molecules. This hypothesis raises several intriguing issues to inspire future studies in the parasite-vector interaction field.
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Rodrigues LGF, de Araujo LD, Roa SLR, Bueno AC, Uchoa ET, Antunes-Rodrigues J, Moreira AC, Elias LLK, de Castro M, Martins CS. Restricted feeding modulates peripheral clocks and nutrient sensing pathways in rats. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:549-561. [PMID: 34591411 PMCID: PMC10528573 DOI: 10.20945/2359-3997000000407] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 06/29/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVE Feeding restriction in rats alters the oscillators in suprachiasmatic, paraventricular, and arcuate nuclei, hypothalamic areas involved in food intake. In the present study, using the same animals and experimental protocol, we aimed to analyze if food restriction could reset clock genes (Clock, Bmal1) and genes involved in lipid metabolism (Pgc1a, Pparg, Ucp2) through nutrient-sensing pathways (Sirt1, Ampk, Nampt) in peripheral tissues. METHODS Rats were grouped according to food access: Control group (CG, food ad libitum), Restricted night-fed (RF-n, food access during 2 h at night), Restricted day-fed (RF-d, food access during 2 h in the daytime), and Day-fed (DF, food access during 12 h in the daytime). After 21 days, rats were decapitated at ZT3 (0900-1000 h), ZT11 (1700-1800 h), or ZT17 (2300-2400 h). Blood, liver, brown (BAT) and peri-epididymal (PAT) adipose tissues were collected. Plasma corticosterone and gene expression were evaluated by radioimmunoassay and qPCR, respectively. RESULTS In the liver, the expression pattern of Clock and Bmal1 shifted when food access was dissociated from rat nocturnal activity; this phenomenon was attenuated in adipose tissues. Daytime feeding also inverted the profile of energy-sensing and lipid metabolism-related genes in the liver, whereas calorie restriction induced a pre-feeding increased expression of these genes. In adipose tissues, Sirt1 expression was modified by daytime feeding and calorie restriction, with concomitant expression of Pgc1a, Pparg, and Ucp2 but not Ampk and Nampt. CONCLUSION Feeding restriction reset clock genes and genes involved in lipid metabolism through nutrient-sensing-related genes in rat liver, brown, and peri-epididymal adipose tissues.
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Affiliation(s)
- Luis Guilherme F Rodrigues
- Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Leonardo D de Araujo
- Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Silvia L R Roa
- Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Ana C Bueno
- Departamento de Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Ernane T Uchoa
- Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - José Antunes-Rodrigues
- Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Ayrton C Moreira
- Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Lucila L K Elias
- Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Margaret de Castro
- Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Clarissa S Martins
- Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil,
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Huang Y, Wang S, Meng X, Chen N, Li S. Molecular Cloning and Characterization of Sirtuin 1 and Its Potential Regulation of Lipid Metabolism and Antioxidant Response in Largemouth Bass ( Micropterus salmoides). Front Physiol 2021; 12:726877. [PMID: 34646155 PMCID: PMC8504536 DOI: 10.3389/fphys.2021.726877] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/06/2021] [Indexed: 12/24/2022] Open
Abstract
Sirtuin 1 (SIRT1) of largemouth bass (Micropterus salmoides) was cloned and characterized in the present study and the influence of SIRT1 activation induced by resveratrol inclusion on the expression of genes related to lipid metabolism and antioxidation was also investigated. The SIRT1 of largemouth bass, with full-length cDNA sequence of 3395bp encoding 695 amino acids, was mainly expressed in gonad, heart and liver. The analysis of multiple sequence alignment revealed that, in accordance with other species, SIRT1 of largemouth bass contained highly conserved substrate-binding site and NAD+ binding site. The result of subcellular localization displayed that SIRT1 of largemouth bass was mainly localized in the nucleus. The inclusion of 1.0 and 2.5‰ dietary RSV, a natural SIRT1 activator, significantly elevated the SIRT1 protein expression. Meanwhile, the phosphorylation of AKT1 and FoxO1 followed similar pattern with that of SIRT1, indicating the activation of insulin pathway, which may result in the inhibition of lipogenesis and activation of lipolysis, and reduced hepatic triglycerides content. Additionally, the activation of SIRT1 induced by dietary RSV elevated the antioxidant capacity at both transcriptional level and enzymatic level, which was probably mediated by the transcription factor Nrf2. In above, SIRT1 was suggested to be involved in improving antioxidant capacity and alleviating hepatic lipid deposition in largemouth bass.
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Affiliation(s)
- Yuting Huang
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, China
| | - Shilin Wang
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, China
| | - Xiaoxue Meng
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, China
| | - Naisong Chen
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, China.,National Demonstration Center on Experiment Teaching of Fisheries Science, Shanghai Ocean University, Shanghai, China
| | - Songlin Li
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, China.,National Demonstration Center on Experiment Teaching of Fisheries Science, Shanghai Ocean University, Shanghai, China
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Ding H, Li Y, Liu L, Hao N, Zou S, Jiang Q, Liang Y, Ma N, Feng S, Wang X, Wu J, Loor JJ. Sirtuin 1 is involved in oleic acid-induced calf hepatocyte steatosis via alterations in lipid metabolism-related proteins. J Anim Sci 2021; 99:6358199. [PMID: 34436591 DOI: 10.1093/jas/skab250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 08/24/2021] [Indexed: 11/14/2022] Open
Abstract
Sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase, plays a central role in the control of lipid metabolism in nonruminants. However, the role of SIRT1 in hepatic lipid metabolism in dairy cows with fatty liver is not well known. Thus, we used isolated primary bovine hepatocytes to determine the role of SIRT1 in protecting cells against oleic acid (OA)-induced steatosis. Recombinant adenoviruses to overexpress (AD-GFP-SIRT1-E) or knockdown (AD-GFP-SIRT1-N) SIRT1 were used for transduction of hepatocytes. Calf hepatocytes isolated from five female calves (1 d old, 30 to 40 kg) were used to determine both time required and the lowest dose of OA that could induce triacylglycerol (TAG) accumulation. Analyses indicated that 0.25 mM OA for 24 h was suitable to induce TAG accumulation. In addition, OA not only led to an increase in TAG, but also upregulated mRNA and protein abundance of sterol regulatory element-binding transcription factor 1 (SREBF1) and downregulated SIRT1 and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PPARGC1A). Thus, these in vitro conditions were deemed optimal for subsequent experiments. Calf hepatocytes were cultured and incubated with OA (0.25 mM) for 24 h, followed by adenoviral AD-GFP-SIRT1-E or AD-GFP-SIRT1-N transduction for 48 h. Overexpression of SIRT1 led to greater protein and mRNA abundance of SIRT1 along with fatty acid oxidation-related genes including PPARGC1A, peroxisome proliferator-activated receptor alpha (PPARA), retinoid X receptor α (RXRA), and ratio of phospho-acetyl-CoA carboxylase alpha (p-ACACA)/total acetyl-CoA carboxylase alpha (ACACA). In contrast, it resulted in lower protein and mRNA abundance of genes related to lipid synthesis including SREBF1, fatty acid synthase (FASN), apolipoprotein E (APOE), and low-density lipoprotein receptor (LDLR). The concentration of TAG decreased due to SIRT1 overexpression. In contrast, silencing SIRT1 led to lower protein and mRNA abundance of SIRT1, PPARGC1A, PPARA, RXRA, and greater protein and mRNA abundance of SREBF1, FASN, APOE, and LDLR. Further, those responses were accompanied by greater content of cellular TAG and total cholesterol (TC). Overall, data from these in vitro studies indicated that SIRT1 is involved in the regulation of lipid metabolism in calf hepatocytes subjected to an increase in the supply of OA. Thus, it is possible that alterations in SIRT1 abundance and activity in vivo contribute to development of fatty liver in dairy cows.
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Affiliation(s)
- Hongyan Ding
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Yu Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China.,Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Hefei 230036, Anhui, China
| | - Leihong Liu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Ning Hao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Suping Zou
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Qianming Jiang
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA
| | - Yusheng Liang
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA
| | - Nana Ma
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China
| | - Shibing Feng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Xichun Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Jinjie Wu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, Anhui, China
| | - Juan J Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801, USA
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Alidadi M, Banach M, Guest PC, Bo S, Jamialahmadi T, Sahebkar A. The effect of caloric restriction and fasting on cancer. Semin Cancer Biol 2021; 73:30-44. [PMID: 32977005 DOI: 10.1016/j.semcancer.2020.09.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 09/02/2020] [Accepted: 09/14/2020] [Indexed: 12/12/2022]
Abstract
Cancer is one of the most frequent causes of worldwide death and morbidity and is a major public health problem. Although, there are several widely used treatment methods including chemo-, immune- and radiotherapies, these mostly lack sufficient efficiency and induce toxicities in normal surrounding tissues. Thus, finding new approaches to mitigate side effects and potentially accelerate treatment is paramount. In line with this, increasing preclinical evidence indicates that caloric restriction (CR) and fasting might have anticancer effects by reducing tumor progression, enhancing death of cancer cells, and elevating the effectiveness and tolerability of chemo- and radiotherapies. Nonetheless, clinical studies assessing the potential of CR and fasting in cancer are scarce and inconsistent, and more investigations are still required to clarify their effect in different aspects of cancer treatment. In this review, we have summarized the findings of preclinical and clinical studies of CR and fasting with respect to efficacy and on the adverse effects of standard cancer treatments.
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Affiliation(s)
- Mona Alidadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland; Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - Simona Bo
- Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Torino, Italy
| | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Shahgaldi S, Kahmini FR. A comprehensive review of Sirtuins: With a major focus on redox homeostasis and metabolism. Life Sci 2021; 282:119803. [PMID: 34237310 DOI: 10.1016/j.lfs.2021.119803] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/24/2021] [Accepted: 07/02/2021] [Indexed: 01/01/2023]
Abstract
Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated under cellular stress conditions in which NAD+ levels are increased. Nevertheless, regulation of Sirtuins extends far beyond the influences of cellular NAD+/NADH ratio and a rapidly expanding body of evidence currently suggests that their expression and catalytic activity are highly kept under control at multiple levels by various factors and processes. Owing to their intrinsic ability to enzymatically target various intracellular proteins, Sirtuins are prominently involved in the regulation of fundamental biological processes including inflammation, metabolism, redox homeostasis, DNA repair and cell proliferation and senescence. In fact, Sirtuins are well established to regulate and reprogram different redox and metabolic pathways under both pathological and physiological conditions. Therefore, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several disorders. This review first highlights the mechanisms involved in the regulation of Sirtuins and further summarizes the current findings on the major functions of Sirtuins in cellular redox homeostasis and bioenergetics (glucose and lipid metabolism).
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Affiliation(s)
- Shahab Shahgaldi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Fatemeh Rezaei Kahmini
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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