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Li B, Liu S, Han W, Song P, Sun H, Cao X, Di G, Chen P. Aquaporin five deficiency suppresses fatty acid oxidation and delays liver regeneration through the transcription factor PPAR. J Biol Chem 2025; 301:108303. [PMID: 39947476 PMCID: PMC11930093 DOI: 10.1016/j.jbc.2025.108303] [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: 10/07/2024] [Revised: 02/03/2025] [Accepted: 02/07/2025] [Indexed: 03/09/2025] Open
Abstract
After 70% partial hepatectomy (PHx), the metabolic pathways leading to hepatocyte lipid droplet accumulation during liver regeneration remain unclear. Aquaporin 5 (Aqp5) is an aquaporin that facilitates the transport of both water and hydrogen peroxide (H2O2). In this study, we observed delayed liver regeneration following PHx in Aqp5 knockout (Aqp5-/-) mice. Considering the role of Aqp5 in H2O2 transport, we hypothesized that deficiency in Aqp5 may induce oxidative stress and hepatocyte injury. Through the measurement of reactive oxygen species (ROS) and redox-related indices, we observed significant alterations in ROS levels as well as malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) concentrations in regenerating livers lacking Aqp5 compared to wild-type controls. Oil Red O and 4-hydroxynonenal (4-HNE) staining results indicated that Aqp5 deficiency caused lipid accumulation during liver regeneration. The transcriptome sequencing results showed that the PPAR pathway is inhibited during the liver regeneration process in Aqp5 gene-knockout mice. The administration of the WY-14643 agonist, which targets the PPAR pathway, significantly mitigated delayed liver regeneration by enhancing hepatocyte proliferation and reducing lipid accumulation caused by Aqp5 deficiency. Our findings highlight the crucial role of Aqp5 in regulating H2O2 levels and lipid metabolism through the PPAR pathway during liver regeneration.
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Affiliation(s)
- Bin Li
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Shixu Liu
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Wenshuo Han
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Peirong Song
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Hetong Sun
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China
| | - Xin Cao
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China.
| | - Guohu Di
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China.
| | - Peng Chen
- School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; Institute of Stem Cell Regeneration Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong Province, China; Department of Ophthalmology, Qingdao Eighth People's Hospital, Qingdao, Shandong Province, China.
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Zhao Y, Cui R, Du R, Song C, Xie F, Ren L, Li J. Platelet-Derived Microvesicles Mediate Cardiomyocyte Ferroptosis by Transferring ACSL1 During Acute Myocardial Infarction. Mol Biotechnol 2025; 67:790-804. [PMID: 38466505 DOI: 10.1007/s12033-024-01094-w] [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: 07/23/2023] [Accepted: 01/21/2024] [Indexed: 03/13/2024]
Abstract
Acute myocardial infarction (AMI) is one of the critical health conditions often caused by the rupture of unstable coronary artery plaque, triggering a series of events, such as platelet activation, thrombus formation, coronary artery blockage, lasted severe ischemia, and hypoxia in cardiomyocytes, and culminating in cell death. Platelet-derived microvesicles (PMVs) act as intermediates for cellular communication. Nevertheless, the role of PMVs in myocardial infarction remains unclear. Initially, AMI-related messenger ribose nucleic acid (mRNA) and micro RNA (miRNA) datasets from the Gene Expression Omnibus (GEO) database were analyzed, specifically focusing on the expressed genes associated with Ferroptosis. Further, a miRNA-mRNA regulatory network specific to AMI was constructed. Then, the effect of PMVs on cardiomyocyte survival was further confirmed through in vitro experiments. High ACSL1 expression was observed in the platelets of AMI patients. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that ACSL1, located in the mitochondria, played a key role in the PPAR signaling pathway. The elevated ACSL1 expression in a co-culture model of PMVs and AC16 cardiomyocytes significantly increased the AC16 cell Ferroptosis. Further, we validated that the platelet ACSL1 expression could be regulated by hsa-miR-449a. Together, these findings suggested that platelet ACSL1 could trigger myocardial cell death via PMV transport. In addition, this research provided a theoretical framework for attenuating myocardial cell Ferroptosis in patients with acute myocardial infarction.
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Affiliation(s)
- Yunfeng Zhao
- Department of Cardiology, First Hospital of Qinhuangdao, No. 258, Wenhua Road, Haigang District, Qinhuangdao, 066099, China
| | - Rui Cui
- Department of Cardiology, First Hospital of Qinhuangdao, No. 258, Wenhua Road, Haigang District, Qinhuangdao, 066099, China
| | - Ran Du
- Department of Cardiology, First Hospital of Qinhuangdao, No. 258, Wenhua Road, Haigang District, Qinhuangdao, 066099, China
| | - Chunmei Song
- Department of Cardiology, First Hospital of Qinhuangdao, No. 258, Wenhua Road, Haigang District, Qinhuangdao, 066099, China
| | - Fei Xie
- Department of Cardiac Surgery, The Second Hospital Affiliated to Harbin Medical University, No.246, Xuefu Road, Nangang District, Harbin, 150001, Heilongjiang, China
| | - Lin Ren
- Department of Cardiology, First Hospital of Qinhuangdao, No. 258, Wenhua Road, Haigang District, Qinhuangdao, 066099, China.
| | - Junquan Li
- Department of Cardiac Surgery, The Second Hospital Affiliated to Harbin Medical University, No.246, Xuefu Road, Nangang District, Harbin, 150001, Heilongjiang, China.
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Zheng ZG, Zhang YP, Zhang XY, Qin MY, Xu YY, Wu H, Liu RQ, Wu QY, Wang MS, Zhang C, Zheng YQ, Dai JY, Li P, Yang H. Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1. Cell Rep 2025; 44:115203. [PMID: 39799570 DOI: 10.1016/j.celrep.2024.115203] [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: 06/20/2024] [Revised: 11/22/2024] [Accepted: 12/23/2024] [Indexed: 01/15/2025] Open
Abstract
Sterols target sterol-sensing domain (SSD) proteins to lower cholesterol and circulating and hepatic triglyceride levels, but the mechanism remains unclear. In this study, we identify acyl-coenzyme A (CoA) synthetase long-chain family member 1 (ACSL1) as a direct target of ergosterol (ES). The C-terminal domain of ACSL1 undergoes conformational changes from closed to open, and ES may target the drug-binding pocket in the acetyl-CoA synthetase-like domain 1 (ASLD1) of ACSL1 to stabilize the closed conformation and maintain its activity. Moreover, ES is mainly enriched in the mitochondria and promotes fatty acid β-oxidation through ACSL1 allosteric activation. Structure-activity relationship analysis reveals how different structural sterols interact with the sterol-sensing domain-containing protein (SCAP) and ACSL1, explaining their regulatory effects on lipid metabolism. Moreover, our findings reveal that the combination of SCAP inhibitor 25-hydroxycholesterol (25-HC) and ES has a stronger lipid-lowering effect than alone.
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Affiliation(s)
- Zu-Guo Zheng
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Yi-Ping Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xiao-Yu Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Meng-Yao Qin
- Collaborative Innovation Center for Northwestern Chinese Medicine & School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China
| | - Yin-Yue Xu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - He Wu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Run-Qing Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Qiu-Yi Wu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Ming-Su Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Chong Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yue-Qin Zheng
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Jian-Ye Dai
- Collaborative Innovation Center for Northwestern Chinese Medicine & School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China.
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Hua Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
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Dasso ME, Centola CL, Galardo MN, Riera MF, Meroni SB. FSH increases lipid droplet content by regulating the expression of genes related to lipid storage in Rat Sertoli cells. Mol Cell Endocrinol 2025; 595:112403. [PMID: 39490730 DOI: 10.1016/j.mce.2024.112403] [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: 09/16/2024] [Revised: 10/21/2024] [Accepted: 10/26/2024] [Indexed: 11/05/2024]
Abstract
Sertoli cells (SCs) are essential for appropriate spermatogenesis. From a metabolic standpoint, they catabolize glucose and provide germ cells with lactate, which is their main energy source. SCs also oxidize fatty acids (FAs), which are stored as triacylglycerides (TAGs) within lipid droplets (LDs), to fulfill their own energy requirements. On the other hand, it has been demonstrated that FSH regulates some of SCs functions, but little is known about its effect on lipid metabolism. In the present study, we aimed to analyze FSH-mediated regulation of (1) lipid storage in LDs and (2) the expression of genes involved in FAs activation and TAG synthesis and storage in SCs. SCs obtained from 20-day-old rats were cultured for different incubation periods with FSH (100 ng/ml). It was observed that FSH increased LD content and TAG levels in SCs. There were also increments in the expression of Plin1, Fabp5, Acsl1, Acsl4, Gpat3, and Dgat1, which suggests that these proteins may mediate the increase in TAGs and LDs elicited by FSH. Regarding the signaling involved in FSH actions, it was observed that dbcAMP increased LD, and H89, a PKA inhibitor, inhibited FSH stimulus. Also, dbcAMP increased Plin2, Fabp5, Acsl1, Acsl4, and Dgat1 mRNA levels, confirming a role of the cAMP/PKA pathway in the regulation of lipid storage in SCs. Altogether, these results suggest that FSH, via the cAMP/PKA pathway, regulates lipid storage in SCs ensuring the availability of substrates to satisfy their energy requirements.
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Affiliation(s)
- Marina Ercilia Dasso
- Centro de Investigaciones Endocrinológicas, "Dr César Bergadá", CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Argentina
| | - Cecilia Lucia Centola
- Centro de Investigaciones Endocrinológicas, "Dr César Bergadá", CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Argentina
| | - Maria Noel Galardo
- Centro de Investigaciones Endocrinológicas, "Dr César Bergadá", CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Argentina
| | - Maria Fernanda Riera
- Centro de Investigaciones Endocrinológicas, "Dr César Bergadá", CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Argentina
| | - Silvina Beatriz Meroni
- Centro de Investigaciones Endocrinológicas, "Dr César Bergadá", CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Argentina.
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Jiang Y, Wang W, Wang H, Zhang X, Kong Y, Chen YQ, Zhu S. ACSL1 positively regulates adipogenic differentiation. Biochem Biophys Res Commun 2024; 735:150865. [PMID: 39442449 DOI: 10.1016/j.bbrc.2024.150865] [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: 10/13/2024] [Revised: 10/16/2024] [Accepted: 10/19/2024] [Indexed: 10/25/2024]
Abstract
Aberrant adipogenic differentiation is strongly associated with obesity and related metabolic diseases. Elucidating the key factors driving adipogenesis is an effective strategy for identifying novel therapeutic targets for treating metabolic diseases represented by obesity. In this study, transcriptomic techniques were employed to investigate the functional genes that regulate adipogenic differentiation in OP9 cells and 3T3-L1 cells. The findings indicated a notable upregulation of Acsl1 expression throughout the adipogenic differentiation process. Knocking down Acsl1 led to a decrease in the expression of genes associated with adipogenesis and a reduction in triglyceride accumulation. Additionally, Acsl1 overexpression promoted adipocyte differentiation and adipose-specific overexpression of Acsl1 markedly aggravated steatosis induced by a high-fat diet. Mechanistically, Cyp2f2, Dusp23 and Gstm2 are the crucial genes implicated in Acsl1-induced adipogenic differentiation. The findings of this study indicate that Acsl1 promotes adipogenesis and could serve as a potential therapeutic target for treating obesity and related metabolic disorders.
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Affiliation(s)
- Yao Jiang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Wei Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China; The Second School of Clinical Medical, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hui Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Xiaoru Zhang
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Yuling Kong
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China
| | - Yong Q Chen
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China; MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, China.
| | - Shenglong Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214000, China.
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Yu Y, Wei R, Yi S, Teng Y, Ning R, Wei S, Bai L, Liu H, Li L, Xu H, Han C. Research Note: Integrative analysis of transcriptome and gut microbiome reveals foie gras capacity difference between cage and floor rearing systems. Poult Sci 2024; 103:104248. [PMID: 39217664 PMCID: PMC11402283 DOI: 10.1016/j.psj.2024.104248] [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: 04/09/2024] [Revised: 07/04/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024] Open
Abstract
To explore the differences in foie gras performance between geese raised in cages and on the ground, we conducted an integrative analysis of liver transcriptome and gut microbial metagenomes. The results showed extremely significant differences in the liver weight (P < 0.01) and liver lipid accumulation of FRS and CRS groups. The levels of triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) of CRS were significantly higher than those of FRS (P < 0.05). Transcriptome analysis showed that 3,917 upregulated and 1,395 downregulated genes were identified, and lipid metabolism pathway and fatty acid metabolism were significantly enriched. Analysis of cecum microbiota revealed that several inflammation-related bacteria (including Gallibacterium, Escherichia-Shigella, Desulfovibrio, Alistipes, and Fournierella) were enriched in CRS, while beneficial bacteria (including Lactobacillus, Limosilactobacillus, and Ligilactobacillus) were significantly enriched in FRS. In conclusion, CRS was better than FRS in foie gras production, which was more conducive to lipid deposition in the goose liver.
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Affiliation(s)
- Yin Yu
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Rongxue Wei
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Shuang Yi
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Yongqiang Teng
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Rong Ning
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Shouhai Wei
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Lili Bai
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Hehe Liu
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Liang Li
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Hengyong Xu
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Chunchun Han
- Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China; Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.
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Wu L, Li Z, Gao N, Deng H, Zhao Q, Hu Z, Chen J, Lei Z, Zhao J, Lin B, Gao Z. Interferon-α could induce liver steatosis to promote HBsAg loss by increasing triglyceride level. Heliyon 2024; 10:e32730. [PMID: 38975233 PMCID: PMC11226829 DOI: 10.1016/j.heliyon.2024.e32730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 06/07/2024] [Indexed: 07/09/2024] Open
Abstract
Background The correlation between metabolic syndrome (MetS) and hepatitis B surface antigen (HBsAg) loss remains to be further elucidated, particularly in patients receiving pegylated interferon-α (PEG-IFN) treatment. Methods 758 patients with low HBsAg quantification who had received nucleos(t)ide analog (NUC) therapy for at least one year and subsequently switched to or add on PEG-IFN therapy over an unfixed course were enrolled. 412 patients were obtained with baseline data matched. A total of 206 patients achieved HBsAg loss (cured group) within 48 weeks. Demographic and biochemical data associated with MetS were gathered for analysis. HepG2.2.15 cell line was used in vitro experiments to validate the efficacy of interferon-α (IFN-α). Results The proportion of patients with diabetes or hypertension in the uncured group was significantly higher than in the cured group. The levels of fasting blood glucose (FBG) and glycated albumin remained elevated in the uncured group over the 48 weeks. In contrast, the levels of blood lipids and uric acid remained higher in the cured group within 48 weeks. Triglycerides levels and liver steatosis of all patients increased after PEG-IFN therapy. Baseline elevated uric acid levels and hepatic steatosis may be beneficial for HBsAg loss. IFN-α could induce hepatic steatosis and indirectly promote HBsAg loss by increasing triglyceride level through upregulation of acyl-CoA synthetase long-chain family member 1(ACSL1). Conclusions IFN-α could induce liver steatosis to promote HBsAg loss by increasing triglyceride level through upregulation of ACSL1. Comorbid diabetes may be detrimental to obtaining HBsAg loss with PEG-IFN therapy in CHB patients.
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Affiliation(s)
- Lili Wu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhihui Li
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Na Gao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hong Deng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiyi Zhao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhaoxia Hu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junfeng Chen
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ziying Lei
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinhua Zhao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bingliang Lin
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zhiliang Gao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510080, China
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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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9
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Cao Z, Gao X, Meng J, Guo X, Xu J, Cui J, Zhou X. ACSL1: A preliminary study that provides a new target for the treatment of renal fibrosis could bring new insights in diabetic kidney disease. Nefrologia 2023; 43 Suppl 2:38-46. [PMID: 38245444 DOI: 10.1016/j.nefroe.2023.05.008] [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: 10/07/2022] [Accepted: 02/20/2023] [Indexed: 01/22/2024] Open
Abstract
BACKGROUND Renal fibrosis is the main cause of the development of diabetic kidney disease (DKD). ACSL1 plays an important role in colon cancer and liver fibrosis. METHODS We screened ACSL1 by proteomics analysis and then verified the expression of ACSL1 in the urine of diabetic nephropathy patients by WB and ELISA. Then, a total of 12db/m and db/db mice were used to verify the association between renal fibrosis and ACSL1. Periodic acid-Schiff (PAS) staining, Masson staining, and immunostaining were performed for histological studies. The relationship between ACSL1 and renal fibrosis was studied by knocking down ACSL1 in cell experiments. RESULTS The expression of ACSL1 was significantly increased in the exfoliated urine cells and urine supernatant of diabetic nephropathy patients and was closely related to renal function. In addition, the expression of ACSL1 was significantly increased in the renal tissues of db/db mice with fibrosis. Knocking down ACSL1 in HK-2 cells was shown to reverse renal fibrosis induced by high glucose. CONCLUSIONS We found a potential therapeutic target for preventing or ameliorating the progression of DKD fibrosis. Reducing ACSL1 expression may be a new strategy for the treatment of renal fibrosis caused by DKD, which provides an experimental theoretical basis for new drug research.
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Affiliation(s)
- Zhonghui Cao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China; Department of Pharmacy, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221004, China
| | - Xiao Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Jing Meng
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiaoli Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Jiahao Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Junchao Cui
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xueyan Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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10
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Singh A, Malla WA, Kumar A, Jain A, Thakur MS, Khare V, Tiwari SP. Review: genetic background of milk fatty acid synthesis in bovines. Trop Anim Health Prod 2023; 55:328. [PMID: 37749432 DOI: 10.1007/s11250-023-03754-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 09/12/2023] [Indexed: 09/27/2023]
Abstract
Milk fat composition is an important trait for the dairy industry as it directly influences the nutritional and technological properties of milk and other dairy products. The synthesis of milk fat is a complex process regulated by a network of genes. Thus, understanding the genetic variation and molecular mechanisms regulating milk fat synthesis will help to improve the nutritional quality of dairy products. In this review, we provide an overview of milk fat synthesis in bovines along with the candidate genes involved in the pathway. We also discuss de novo synthesis of fatty acids (ACSS, ACACA, FASN), uptake of FAs (FATP, FAT, LPL), intracellular activation and channelling of FAs (ACSL, FABP), elongation (EVOLV6), desaturation (SCD, FADS), formation of triglycerides (GPAM, AGPAT, LIPIN, DGAT), and milk lipid secretion (BTN1A1, XDH, PLIN2). The genetic variability of individual fatty acids will help to develop selection strategies for obtaining a healthier milk fat profile in bovines. Thus, this review will offer a potential understanding of the molecular mechanisms that regulate milk fat synthesis in bovines.
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Affiliation(s)
- Akansha Singh
- College of Veterinary Science and Animal Husbandry, NDVSU, Jabalpur, M.P, 482001, India.
| | - Waseem Akram Malla
- ICMR-National Institute of Malaria Research, Field Unit Guwahati, Assam, 781022, India
| | - Amit Kumar
- ICAR- Indian Veterinary Research Institute, Izatnagar, Bareilly, U.P, 243122, India
| | - Asit Jain
- College of Veterinary Science and Animal Husbandry, NDVSU, Jabalpur, M.P, 482001, India
| | - Mohan Singh Thakur
- College of Veterinary Science and Animal Husbandry, NDVSU, Jabalpur, M.P, 482001, India
| | - Vaishali Khare
- College of Veterinary Science and Animal Husbandry, NDVSU, Jabalpur, M.P, 482001, India
| | - Sita Prasad Tiwari
- College of Veterinary Science and Animal Husbandry, NDVSU, Jabalpur, M.P, 482001, India
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11
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Poppelreuther M, Lundsgaard A, Mensberg P, Sjøberg K, Vilsbøll T, Kiens B, Füllekrug J. Acyl-CoA synthetase expression in human skeletal muscle is reduced in obesity and insulin resistance. Physiol Rep 2023; 11:e15817. [PMID: 37726199 PMCID: PMC10509033 DOI: 10.14814/phy2.15817] [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: 07/12/2023] [Revised: 08/22/2023] [Accepted: 08/22/2023] [Indexed: 09/21/2023] Open
Abstract
Upon intramuscular entry, fatty acids are converted to amphiphatic fatty acyl-CoAs by action of the acyl-CoA synthetase (ACS) enzymes. While it has been reported that insulin resistant skeletal muscle shows an accumulation of fatty acyl-CoAs, the role of the enzymes which catalyze their synthesis is still sparsely studied in human muscle, in particular the influence of obesity, and insulin resistance. We analyzed muscle biopsies obtained from normal weight controls (n = 7, average BMI 24), males/females with obesity (n = 7, average BMI 31), and males/females with obesity and type 2 diabetes (T2D) (n = 7, average BMI 34), for relevant ACS (long-chain acyl-CoA synthetase 1 (ACSL1), -3 (ACSL3) and - 4 (ACSL4), fatty acid transport protein 1 (FATP1) and - 4 (FATP4)). The mRNA expression was determined by real-time PCR, and total oleoyl-CoA synthetase activity was measured. In the males/females with obesity and T2D, the response to 16 weeks of exercise training with minor weight loss was evaluated. ACSL1 is the dominantly expressed ACS isoform in human skeletal muscle. The content of total ACS mRNA, as well as ACSL1 mRNA, were lower in muscle of males/females with obesity and T2D. Exercise training in the males/females with obesity and T2D increased the total ACS enzyme activity, along with a lowering of the HOMA-IR index. The capacity for synthesis of fatty acyl-CoAs is lower in skeletal muscle of obese males/females with T2D. This suggests a decreased ability to convert fatty acids to fatty acyl-CoAs, which in turn may affect their entry into storage or metabolic pathways in muscle. Thus, the accumulation of fatty acyl-CoAs in the obese or insulin resistant state that has been shown in previous reports is not likely to result from increased fatty acid acylation. The upregulation of ACS activity by exercise training appears beneficial and occurred concomitantly with increased insulin sensitivity.
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Affiliation(s)
- Margarete Poppelreuther
- Molecular Cell Biology Laboratory, Internal Medicine IVUniversity of HeidelbergHeidelbergGermany
| | - Anne‐Marie Lundsgaard
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | | | - Kim Sjøberg
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Tina Vilsbøll
- Clinical ResearchSteno Diabetes Center CopenhagenHerlevDenmark
- Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Bente Kiens
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of ScienceUniversity of CopenhagenCopenhagenDenmark
| | - Joachim Füllekrug
- Molecular Cell Biology Laboratory, Internal Medicine IVUniversity of HeidelbergHeidelbergGermany
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12
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Al-Rashed F, Haddad D, Al Madhoun A, Sindhu S, Jacob T, Kochumon S, Obeid LM, Al-Mulla F, Hannun YA, Ahmad R. ACSL1 is a key regulator of inflammatory and macrophage foaming induced by short-term palmitate exposure or acute high-fat feeding. iScience 2023; 26:107145. [PMID: 37416456 PMCID: PMC10320618 DOI: 10.1016/j.isci.2023.107145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 04/29/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023] Open
Abstract
Foamy and inflammatory macrophages play pathogenic roles in metabolic disorders. However, the mechanisms that promote foamy and inflammatory macrophage phenotypes under acute-high-fat feeding (AHFF) remain elusive. Herein, we investigated the role of acyl-CoA synthetase-1 (ACSL1) in favoring the foamy/inflammatory phenotype of monocytes/macrophages upon short-term exposure to palmitate or AHFF. Palmitate exposure induced a foamy/inflammatory phenotype in macrophages which was associated with increased ACSL1 expression. Inhibition/knockdown of ACSL1 in macrophages suppressed the foamy/inflammatory phenotype through the inhibition of the CD36-FABP4-p38-PPARδ signaling axis. ACSL1 inhibition/knockdown suppressed macrophage foaming/inflammation after palmitate stimulation by downregulating the FABP4 expression. Similar results were obtained using primary human monocytes. As expected, oral administration of ACSL1 inhibitor triacsin-C in mice before AHFF normalized the inflammatory/foamy phenotype of the circulatory monocytes by suppressing FABP4 expression. Our results reveal that targeting ACSL1 leads to the attenuation of the CD36-FABP4-p38-PPARδ signaling axis, providing a therapeutic strategy to prevent the AHFF-induced macrophage foaming and inflammation.
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Affiliation(s)
- Fatema Al-Rashed
- Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Dania Haddad
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Ashraf Al Madhoun
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Sardar Sindhu
- Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Texy Jacob
- Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Shihab Kochumon
- Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Lina M. Obeid
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
| | - Yusuf A. Hannun
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Rasheed Ahmad
- Immunology & Microbiology Department, Dasman Diabetes Institute, Kuwait City, Dasman 15462, Kuwait
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13
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Yang X, Zhang X, Yang Z, Zhang Q, Hao W, Pang Y, Zhang D, Liu D. Transcriptional Regulation Associated with Subcutaneous Adipogenesis in Porcine ACSL1 Gene. Biomolecules 2023; 13:1057. [PMID: 37509093 PMCID: PMC10377008 DOI: 10.3390/biom13071057] [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: 04/24/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
Long-chain acyl-CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and fat deposition. The transcription of the ACSL1 gene is regulated specifically among cells and physiological processes, and transcriptional regulation of ACSL1 in adipogenesis remains elusive. Here, we characterize transcription factors (TFs) associated with adipogenesis in the porcine ACSL1 gene. CCAAT-enhancer binding protein (C/EBP)α, a well-known adipogenic marker, was found to enhance the expression of the ACSL1 gene via binding two tandem motifs in the promoter. Further, we demonstrate that ACSL1 mediates C/EBPα effects on adipogenesis in preadipocytes cultured from subcutaneous fat tissue of pigs via gain- and loss-of-function analyses. The cAMP-response element binding protein, another TF involved in adipogenesis, was also identified in the regulation of ACSL1 gene expression. Additionally, single nucleotide polymorphisms (SNPs) were screened in the promoter of ACSL1 among four breeds including the Chinese indigenous Min, and Duroc, Berkshire, and Yorkshire pigs through sequencing of PCR products. Two tightly linked SNPs, -517G>T and -311T>G, were found exclusively in Min pigs. The haplotype mutation decreases promoter activity in PK-15 and ST cells, and in vivo the expression of ACSL1, illustrating a possible role in adipogenesis regulated by C/EBPα/ACSL1 axis. Additionally, a total of 24 alternative splicing transcripts were identified, indicating the complexity of alternative splicing in the ACSL1 gene. The results will contribute to further revealing the regulatory mechanisms of ACSL1 during adipogenesis and to the characterization of molecular markers for selection of fat deposition in pigs.
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Affiliation(s)
- Xiuqin Yang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Xiaohan Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Zewei Yang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Qian Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Wanjun Hao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Yu Pang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Dongjie Zhang
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
| | - Di Liu
- Institute of Animal Husbandry, Heilongjiang Academy of Agricultural Sciences, Harbin 150086, China
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14
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Zhang J, Tian C, Zhu K, Liu Y, Zhao C, Jiang M, Zhu C, Li G. Effects of Natural and Synthetic Astaxanthin on Growth, Body Color, and Transcriptome and Metabolome Profiles in the Leopard Coral Grouper (Plectropomus leopardus). Animals (Basel) 2023; 13:ani13071252. [PMID: 37048508 PMCID: PMC10093260 DOI: 10.3390/ani13071252] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/31/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023] Open
Abstract
Natural and synthetic astaxanthin can promote pigmentation in fish. In this study, the effects of dietary astaxanthin on growth and pigmentation were evaluated in leopard coral grouper (Plectropomus leopardus). Fish were assigned to three groups: 0% astaxanthin (C), 0.02% natural astaxanthin (HP), and 0.02% synthetic astaxanthin (AS). Brightness (L*) was not influenced by astaxanthin. However, redness (a*) and yellowness (b*) were significantly higher for fish fed astaxanthin-containing diets than fish fed control diets and were significantly higher in the HP group than in the AS group. In a transcriptome analysis, 466, 33, and 32 differentially expressed genes (DEGs) were identified between C and HP, C and AS, and AS and HP, including various pigmentation-related genes. DEGs were enriched for carotenoid deposition and other pathways related to skin color. A metabolome analysis revealed 377, 249, and 179 differential metabolites (DMs) between C and HP, C and AS, and AS and HP, respectively. In conclusion, natural astaxanthin has a better coloration effect on P. leopardus, which is more suitable as a red colorant in aquaculture. These results improve our understanding of the effects of natural and synthetic astaxanthin on red color formation in fish.
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Affiliation(s)
- Junpeng Zhang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
| | - Changxu Tian
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
| | - Kecheng Zhu
- Key Laboratory of South China Sea Fishery Resources Exploitation and Utilization, Ministry of Agriculture and Rural Affairs, South China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510300, China
| | - Yong Liu
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
| | - Can Zhao
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
| | - Mouyan Jiang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
| | - Chunhua Zhu
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
| | - Guangli Li
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture, Zhanjiang 524088, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang 524088, China
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15
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Shafieipour N, Jafari Khamirani H, Kamal N, Tabei SMB, Dianatpour M, Dastgheib SA. The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review. Eur J Med Genet 2023; 66:104707. [PMID: 36709796 DOI: 10.1016/j.ejmg.2023.104707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/30/2022] [Accepted: 01/15/2023] [Indexed: 01/27/2023]
Abstract
Pathogenic variants in ACACA are the cause of acetyl-CoA carboxylase deficiency with an autosomal recessive inheritance that is identified by hypotonia, motor, and intellectual developmental delay. In this article, we describe a seven-year-old boy who is the child of consanguineous parents with a homozygous variant in ACACA (NM_198834.3:c.6641C > A, p.P2214H) that was detected by Whole-Exome Sequencing and confirmed by Sanger sequencing. This is the first reported patient of acetyl-CoA carboxylase deficiency that results from a homozygous pathogenic variant in the ACACA gene in the Iranian family. The proband presents with motor and intellectual developmental delay, muscle weakness, language disorder, facial dysmorphism, and poor growth. The patient discussed here is similar to other patients that were previously published; however, we were able to identify seizure that has hitherto not been reported. This paper describes the third person with a novel variant in the ACACA gene in the world that accounts for acetyl-CoA carboxylase deficiency and implicates the clinical spectrum of the disease. Finally, we describe an individual-based review of the symptoms associated with acetyl-CoA carboxylase deficiency. So far, only two acetyl-CoA carboxylase deficiency patients have been reviewed in the literature.
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Affiliation(s)
- Negin Shafieipour
- Department of Medical Genetics, Shiraz University of Medical Sciences, Iran
| | | | - Neda Kamal
- Department of Medical Genetics, Shiraz University of Medical Sciences, Iran
| | - Seyed Mohammad Bagher Tabei
- Department of Medical Genetics, Shiraz University of Medical Sciences, Iran; Maternal-fetal Medicine Research Center, Shiraz University of Medical Sciences, Iran
| | - Mehdi Dianatpour
- Department of Medical Genetics, Shiraz University of Medical Sciences, Iran; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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16
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Xu K, Xia P, Chen X, Ma W, Yuan Y. ncRNA-mediated fatty acid metabolism reprogramming in HCC. Trends Endocrinol Metab 2023; 34:278-291. [PMID: 36890041 DOI: 10.1016/j.tem.2023.02.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023]
Abstract
The challenges of hepatocellular carcinoma (HCC) pathogenesis, diagnosis, treatment, and prognosis evaluation are obvious. Hepatocyte-specific fatty acid (FA) metabolic reprogramming is an important marker of liver carcinogenesis and progression; elucidating its mechanism will help unravel the complexity of HCC pathogenesis. Noncoding RNAs (ncRNAs) play important roles in HCC development. Moreover, ncRNAs are important mediators of FA metabolism and are directly involved in the reprogramming of FA metabolism in HCC cells. Here we review significant new advances in understanding the mechanisms regulating HCC metabolism by focusing on ncRNA-mediated post-translational modifications of metabolic enzymes, metabolism-related transcription factors, and other proteins in associated signaling pathways. We also discuss the great therapeutic potential of targeting ncRNA-mediated FA metabolism reprogramming in HCC.
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Affiliation(s)
- Kequan Xu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Xi Chen
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China
| | - Weijie Ma
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China.
| | - Yufeng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, PR China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
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17
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Role of ACSL5 in fatty acid metabolism. Heliyon 2023; 9:e13316. [PMID: 36816310 PMCID: PMC9932481 DOI: 10.1016/j.heliyon.2023.e13316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 12/07/2022] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
Free fatty acids (FFAs) are essential energy sources for most body tissues. A fatty acid must be converted to fatty acyl-CoA to oxidize or be incorporated into new lipids. Acyl-CoA synthetase long-chain family member 5 (ACSL5) is localized in the endoplasmic reticulum and mitochondrial outer membrane, where it catalyzes the formation of fatty acyl-CoAs from long-chain fatty acids (C16-C20). Fatty acyl-CoAs are then used in lipid synthesis or β-oxidation mediated pathways. ACSL5 plays a pleiotropic role in lipid metabolism depending on substrate preferences, subcellular localization and tissue specificity. Here, we review the role of ACSL5 in fatty acid metabolism in multiple metabolic tissues, including the liver, small intestine, adipose tissue, and skeletal muscle. Given the increasing number of studies suggesting the role of ACSL5 in glucose and lipid metabolism, we also summarized the effects of ACSL5 on circulating lipids and insulin resistance.
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18
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Zhao Y, Chen S, Yuan J, Shi Y, Wang Y, Xi Y, Qi X, Guo Y, Sheng X, Liu J, Zhou L, Wang C, Xing K. Comprehensive Analysis of the lncRNA-miRNA-mRNA Regulatory Network for Intramuscular Fat in Pigs. Genes (Basel) 2023; 14:168. [PMID: 36672909 PMCID: PMC9859044 DOI: 10.3390/genes14010168] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/26/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Intramuscular fat (IMF) is an essential trait closely related to meat quality. The IMF trait is a complex quantitative trait that is regulated by multiple genes. In order to better understand the process of IMF and explore the key factors affecting IMF deposition, we identified differentially expressed mRNA, miRNA, and lncRNA in the longissimus dorsi muscle (LD) between Songliao Black (SL) pigs and Landrace pigs. We obtained 606 differentially expressed genes (DEGs), 55 differentially expressed miRNAs (DEMs), and 30 differentially expressed lncRNAs (DELs) between the SL pig and Landrace pig. Enrichment results from GO and KEGG indicate that DEGs are involved in fatty acid metabolism and some pathways related to glycogen synthesis. We constructed an lncRNA-miRNA-mRNA interaction network with 18 DELs, 11 DEMs, and 42 DEGs. Finally, the research suggests that ARID5B, CPT1B, ACSL1, LPIN1, HSP90AA1, IRS1, IRS2, PIK3CA, PIK3CB, and PLIN2 may be the key genes affecting IMF deposition. The LncRNAs MSTRG.19948.1, MSTRG.13120.1, MSTRG.20210.1, and MSTRG.10023.1, and the miRNAs ssc-miRNA-429 and ssc-miRNA-7-1, may play a regulatory role in IMF deposition through their respective target genes. Our research provides a reference for further understanding the regulatory mechanism of IMF.
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Affiliation(s)
- Yanhui Zhao
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Shaokang Chen
- Beijing Animal Husbandry Station, Beijing 100101, China
| | - Jiani Yuan
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Yumei Shi
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Yan Wang
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Yufei Xi
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Xiaolong Qi
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Yong Guo
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Xihui Sheng
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
| | - Jianfeng Liu
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Lei Zhou
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Chuduan Wang
- College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Kai Xing
- Animal Science and Technology College, Beijing University of Agriculture, Beijing 102206, China
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19
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Easton ZJW, Luo X, Li L, Regnault TRH. The impact of hyperglycemia upon BeWo trophoblast cell metabolic function: A multi-OMICS and functional metabolic analysis. PLoS One 2023; 18:e0283118. [PMID: 36930661 PMCID: PMC10022812 DOI: 10.1371/journal.pone.0283118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 02/23/2023] [Indexed: 03/18/2023] Open
Abstract
Pre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cell lines and ex vivo trophoblast preparations have highlighted hyperglycemia is an important independent regulator of placental function. However, it is poorly understood if hyperglycemia directly influences aspects of placental metabolic function, including nutrient storage and mitochondrial respiration, that are altered in term diabetic placentae. The current study examined metabolic and mitochondrial function as well as nutrient storage in both undifferentiated cytotrophoblast and differentiated syncytiotrophoblast BeWo cells cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the direct impacts of placental hyperglycemic exposure. Hyperglycemic-exposed BeWo trophoblasts displayed increased glycogen and triglyceride nutrient stores, but real-time functional readouts of metabolic enzyme activity and mitochondrial respiratory activity were not altered. However, specific investigation into mitochondrial dynamics highlighted increased expression of markers associated with mitochondrial fission that could indicate high glucose-exposed trophoblasts are transitioning towards mitochondrial dysfunction. To further characterize the impacts of independent hyperglycemia, the current study subsequently utilized a multi-omics approach and evaluated the transcriptomic and metabolomic signatures of BeWo cytotrophoblasts. BeWo cytotrophoblasts exposed to hyperglycemia displayed increased mRNA expression of ACSL1, HSD11B2, RPS6KA5, and LAP3 and reduced mRNA expression of CYP2F1, and HK2, concomitant with increased levels of: lactate, malonate, and riboflavin metabolites. These changes highlighted important underlying alterations to glucose, glutathione, fatty acid, and glucocorticoid metabolism in BeWo trophoblasts exposed to hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolism, nutrient storage, and mitochondrial function, and these data continue to expand our knowledge on mechanisms governing the development of placental dysfunction.
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Affiliation(s)
- Zachary J W Easton
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
| | - Xian Luo
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Liang Li
- The Metabolomics Innovation Centre, University of Alberta, Edmonton, Alberta, Canada
- Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Timothy R H Regnault
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
- Department of Obstetrics and Gynaecology, London Health Science Centre-Victoria Hospital, London, Ontario, Canada
- Children's Health Research Institute, London, Ontario, Canada
- Lawson Health Research Institute, London, Ontario, Canada
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20
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Dong H, Zhong W, Zhang W, Hao L, Guo W, Yue R, Sun X, Sun Z, Bataller R, Zhou Z. Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis. Metabolism 2023; 138:155334. [PMID: 36349655 DOI: 10.1016/j.metabol.2022.155334] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/07/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Alcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD). METHODS We performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1Δhep) mice, hepatocyte-specific STAT5 knockout (STAT5Δhep) mice, and ACSL1Δhep based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal). RESULTS We found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients. CONCLUSIONS ACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.
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Affiliation(s)
- Haibo Dong
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Wei Zhong
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA; Department of Nutrition, the University of North Carolina at Greensboro, Greensboro, NC, USA
| | - Wenliang Zhang
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Liuyi Hao
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Wei Guo
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Ruichao Yue
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Xinguo Sun
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ramon Bataller
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, the University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA; Department of Nutrition, the University of North Carolina at Greensboro, Greensboro, NC, USA.
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Functional and miRNA regulatory characteristics of INSIG genes highlight the key role of lipid synthesis in the liver of chicken (Gallus gallus). Poult Sci 2022; 102:102380. [PMID: 36571872 PMCID: PMC9800209 DOI: 10.1016/j.psj.2022.102380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
The insulin-induced genes (INSIG1 and INSIG2) have been demonstrated to play a vital role in regulating lipid metabolism in mammals, however the function and regulation mechanism of them remains unknown in poultry. In this study, firstly the phylogenetic trees of INSIGs among various species were constructed and their subcellular locations were mapped in chicken LMH. Then the spatiotemporal expression profiles, over-expression and knockdown assays of chicken INSIGs were conducted. Furthermore, conservation of potential miRNA binding sites in INSIGs among species were analyzed, and the miRNA biological function and regulatory role were verified. The results showed that chicken INSIGs located in cellular endoplasmic reticulum, and were originated from the common ancestors of their mammalian counterparts. The INSIGs were widely expressed in all detected tissues, and their expression levels in the liver of chicken at 30 wk were significantly higher than that at 20 wk (P < 0.01). Over-expression of INSIGs led no significant increase in mRNA abundance of lipid metabolism-related genes and the contents of triacylglycerol (TG) and cholesterol (TC) in LMH cells. Knockdown of INSIG1 led to the decreased expressions of ACSL1, MTTP-L, ApoB, ApoVLDLII genes and TG, TC contents (P < 0.05). Knockdown of INSIG2 could significantly decrease the contents of TG and TC, and expressions of key genes related to the lipid metabolism (P < 0.05). Moreover, INSIG1 was directly targeted by both miR-130b-3p and miR-218-5p, and INSIG2 was directly targeted by miR-130b-3p. MiR-130b-3p mimic and miR-218-5p mimic treatment could significant decrease the mRNA and protein levels of INSIGs, mRNA levels of genes related to lipid metabolism, and the contents of TG and TC in LMH cells. The inhibition of miR-130b-3p and miR-218-5p on TG and TC contents could be restored by the overexpression of INSIGs, respectively. No significant alteration in expressions of sterol regulatory element binding protein (SREBPs) and SREBP cleavage-activating protein (SCAP) were observed when INSIGs were over-expressed. SCAP was down-regulated when INSIG1 was knocked down, while SREBP1 was down-regulated when INSIG2 was knocked down. Taken together, these results highlight the role of INSIG1 and INSIG2 in lipid metabolism and their regulatory mechanism in chicken.
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22
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Nishikai-Shen T, Hosono-Fukao T, Ariga T, Hosono T, Seki T. Cinnamon extract improves abnormalities in glucose tolerance by decreasing Acyl-CoA synthetase long-chain family 1 expression in adipocytes. Sci Rep 2022; 12:12574. [PMID: 35869105 PMCID: PMC9307619 DOI: 10.1038/s41598-022-13421-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 05/24/2022] [Indexed: 11/09/2022] Open
Abstract
AbstractWe previously demonstrated that cinnamon extract (CE) alleviates streptozotocin-induced type 1 diabetes in rats. The present study aimed to elucidate the detailed molecular target of cinnamon in cultured adipocytes and epididymal adipose tissue of type 2 diabetes model mice. Two-dimensional gel electrophoresis was employed to determine the molecular target of cinnamon in adipocytes. The function of Acyl-CoA synthetase long-chain family-1 (ACSL1), a molecular target of cinnamon that was identified in this study, was further investigated in 3T3-L1 adipocytes using specific inhibitors. Type 2 diabetes model mice (KK-Ay/TaJcl) were used to investigate the effect of CE on glucose tolerance, ACSL1 expression, and related signal molecules in vivo. CE decreased ACSL1 mRNA and protein expression in 3T3-L1 adipocytes but increased glucose uptake and AMPK signaling activation; moreover, a similar effect was observed with an ACSL1 inhibitor. CE improved glucose tolerance and downregulated ACSL1 in mice adipose tissue in vivo. ACSL1 was demonstrated as a molecular target of CE in type 2 diabetes both in a cell culture system and diabetic mouse model.
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Yuan X, Cui H, Jin Y, Zhao W, Liu X, Wang Y, Ding J, Liu L, Wen J, Zhao G. Fatty acid metabolism-related genes are associated with flavor-presenting aldehydes in Chinese local chicken. Front Genet 2022; 13:902180. [PMID: 36035160 PMCID: PMC9412053 DOI: 10.3389/fgene.2022.902180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/11/2022] [Indexed: 11/20/2022] Open
Abstract
Aldehydes are primary volatile organic compounds (VOCs) in local Chinese chicken meat and contribute green grass, fatty, citrus, and bitter almond aromas to chicken meat. To understand the genetic basis of these aldehyde VOC aromas, we used approximately 500 Chinese Jingxing Yellow (JXY) chickens to conduct genome-wide association studies (GWAS) on the flavor traits with the data of single nucleotide polymorphisms (SNPs) and insertions and deletions (INDELs). In total, 501 association variants (253 SNPs and 248 INDELs) were found to be suggestively (SNPs: p-value < 2.77e-06 and INDELs: p-value < 3.78e-05) associated with total aldehydes (the sum of nine aldehydes), hexanal, heptanal, benzaldehyde, (E,E)-2,4-nonadienal, octanal, (E)-2-decenal, nonanal, decanal, and octadecanal. Of them, six SNPs and 23 INDELs reached a genome-wide significance level (SNPs: p-value < 1.38e-07 and INDELs: p-value < 1.89e-06). Potential candidate aldehyde genes were functionally annotated for lipid metabolism, especially fatty acid-related pathways and phospholipid-related gene ontology (GO) terms. Moreover, the GWAS analysis of total aldehydes, hexanal, and nonanal generated the most significant signals, and phenotypic content differed between different genotypes at candidate gene-related loci. For total aldehydes and hexanal traits, candidate genes were annotated based on the significant and suggestive variants on chromosomes 3 and 8 with highly polymorphic linkage blocks. The following candidate genes were also identified: GALM, MAP4K3, GPCPD1, RPS6KA2, CRLS1, ASAP1, TRMT6, SDC1, PUM2, ALDH9A1, MGST3, GMEB1, MECR, LDLRAP1, GPAM and ACSL5. We also found that polyunsaturated fatty acids (PUFAs) (C18:2n6c linoleic acid and C18:3n3 linolenic acid) were significantly correlated with total aldehydes and hexanal contents. PUFAs are important aldehyde precursors, and consistently, our results suggested that candidate genes involved in fatty acid pathways and phospholipid GO terms were identified in association loci. This work provides an understanding of the genetic basis of aldehyde formation, which is a key flavor-forming compound.
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Li T, Jin M, Fei X, Yuan Z, Wang Y, Quan K, Wang T, Yang J, He M, Wei C. Transcriptome Comparison Reveals the Difference in Liver Fat Metabolism between Different Sheep Breeds. Animals (Basel) 2022; 12:ani12131650. [PMID: 35804549 PMCID: PMC9265030 DOI: 10.3390/ani12131650] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/09/2022] [Accepted: 06/23/2022] [Indexed: 11/16/2022] Open
Abstract
Hu sheep and Tibetan sheep are two commonly raised local sheep breeds in China, and they have different morphological characteristics, such as tail type and adaptability to extreme environments. A fat tail in sheep is the main adipose depot in sheep, whereas the liver is an important organ for fat metabolism, with the uptake, esterification, oxidation, and secretion of fatty acids (FAs). Meanwhile, adaptations to high-altitude and arid environments also affect liver metabolism. Therefore, in this study, RNA-sequencing (RNA-seq) technology was used to characterize the difference in liver fat metabolism between Hu sheep and Tibetan sheep. We identified 1179 differentially expressed genes (DEGs) (Q-value < 0.05) between the two sheep breeds, including 25 fat-metabolism-related genes. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 16 pathways were significantly enriched (Q-value < 0.05), such as the proteasome, glutamatergic synapse, and oxidative phosphorylation pathways. In particular, one of these pathways was enriched to be associated with fat metabolism, namely the thermogenesis pathway, to which fat-metabolism-related genes such as ACSL1, ACSL4, ACSL5, CPT1A, CPT1C, SLC25A20, and FGF21 were enriched. Then, the expression levels of ACSL1, CPT1A, and FGF21 were verified in mRNA and protein levels via qRT-PCR and Western blot analysis between the two sheep breeds. The results showed that the mRNA and protein expression levels of these three genes were higher in the livers of Tibetan sheep than those of Hu sheep. The above genes are mainly related to FAs oxidation, involved in regulating the oxidation of liver FAs. So, this study suggested that Tibetan sheep liver has a greater FAs oxidation level than Hu sheep liver. In addition, the significant enrichment of fat-metabolism-related genes in the thermogenesis pathway appears to be related to plateau-adaptive thermogenesis in Tibetan sheep, which may indicate that liver- and fat-metabolism-related genes have an impact on adaptive thermogenesis.
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Affiliation(s)
- Taotao Li
- Key Laboratory of Animal Genetics and Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (T.L.); (M.J.); (X.F.)
| | - Meilin Jin
- Key Laboratory of Animal Genetics and Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (T.L.); (M.J.); (X.F.)
| | - Xiaojuan Fei
- Key Laboratory of Animal Genetics and Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (T.L.); (M.J.); (X.F.)
| | - Zehu Yuan
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education, Yangzhou University, Yangzhou 225009, China;
| | - Yuqin Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China;
| | - Kai Quan
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China;
| | - Tingpu Wang
- College of Bioengineering and Biotechnology, Tianshui Normal University, Tianshui 741000, China;
| | - Junxiang Yang
- Gansu Institute of Animal Husbandry and Veterinary Medicine, Pingliang 744000, China; (J.Y.); (M.H.)
| | - Maochang He
- Gansu Institute of Animal Husbandry and Veterinary Medicine, Pingliang 744000, China; (J.Y.); (M.H.)
| | - Caihong Wei
- Key Laboratory of Animal Genetics and Breeding and Reproduction, Ministry of Agriculture, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (T.L.); (M.J.); (X.F.)
- Correspondence:
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Gao J, Gu X, Zhang M, Zu X, Shen F, Hou X, Hao E, Bai G. Ferulic acid targets ACSL1 to ameliorate lipid metabolic disorders in db/db mice. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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26
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Shan B, Yan M, Yang K, Lin W, Yan J, Wei S, Wei W, Chen J, Zhang L. MiR-218-5p Affects Subcutaneous Adipogenesis by Targeting ACSL1, A Novel Candidate for Pig Fat Deposition. Genes (Basel) 2022; 13:genes13020260. [PMID: 35205304 PMCID: PMC8871969 DOI: 10.3390/genes13020260] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/21/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
As a centre enzyme in fatty acid activation, acyl-CoA synthetase long-chain family member 1 (ACSL1) plays an important role in body lipid homeostasis. However, the functions of ACSL1 in the subcutaneous adipogenesis of pigs are largely unknown. In the present study, we found that the expression of ACSL1 significantly increased during the process of porcine preadipocyte differentiation. Moreover, silencing of ACSL1 in preadipocytes decreased levels of triglyceride and adipogenic-related markers, including FABP4, APOE, and FASN (p < 0.01), and simultaneously increased levels of lipolytic-related markers, such as ATGL and HSL (p < 0.05). Conversely, overexpression of ACSL1 in preadipocytes increased levels of triglyceride and FABP4, APOE, and FASN (p < 0.01), and reduced levels of ATGL and HSL (p < 0.05). Luciferase reporter assays revealed that ACSL1 is a target of miR-218-5p, which can reduce the mRNA and protein levels of ACSL1 by directly binding the 3′ untranslated region of ACSL1. Furthermore, miR-218-5p has an inhibition role in porcine preadipocyte differentiation by suppressing ACSL1 expression. Taken together, these data provide insights into the mechanism of the miR-218-5p/ACSL1 axis in regulating subcutaneous fat deposition of pigs.
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27
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Nan J, Lee JS, Lee SA, Lee DS, Park KS, Chung SS. An Essential Role of the N-Terminal Region of ACSL1 in Linking Free Fatty Acids to Mitochondrial β-Oxidation in C2C12 Myotubes. Mol Cells 2021; 44:637-646. [PMID: 34511469 PMCID: PMC8490201 DOI: 10.14348/molcells.2021.0077] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/15/2021] [Accepted: 08/03/2021] [Indexed: 12/25/2022] Open
Abstract
Free fatty acids are converted to acyl-CoA by long-chain acyl-CoA synthetases (ACSLs) before entering into metabolic pathways for lipid biosynthesis or degradation. ACSL family members have highly conserved amino acid sequences except for their N-terminal regions. Several reports have shown that ACSL1, among the ACSLs, is located in mitochondria and mainly leads fatty acids to the β-oxidation pathway in various cell types. In this study, we investigated how ACSL1 was localized in mitochondria and whether ACSL1 overexpression affected fatty acid oxidation (FAO) rates in C2C12 myotubes. We generated an ACSL1 mutant in which the N-terminal 100 amino acids were deleted and compared its localization and function with those of the ACSL1 wild type. We found that ACSL1 adjoined the outer membrane of mitochondria through interaction of its N-terminal region with carnitine palmitoyltransferase-1b (CPT1b) in C2C12 myotubes. In addition, overexpressed ACSL1, but not the ACSL1 mutant, increased FAO, and ameliorated palmitate-induced insulin resistance in C2C12 myotubes. These results suggested that targeting of ACSL1 to mitochondria is essential in increasing FAO in myotubes, which can reduce insulin resistance in obesity and related metabolic disorders.
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Affiliation(s)
- Jinyan Nan
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Ji Seon Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Seung-Ah Lee
- Genomic Medicine Institute, Seoul National University Medical Research Center, Seoul 03080, Korea
| | - Dong-Sup Lee
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Sung Soo Chung
- Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea
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Song Q, Wang Z, Zhang H, Li X, Zhang Y, Xu Q, Chang G, Zhang H, Chen G. Single nucleotide polymorphism scanning and expression analysis of ACSL1 from different duck breeds. CANADIAN JOURNAL OF ANIMAL SCIENCE 2021. [DOI: 10.1139/cjas-2020-0131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Accumulating studies have indicated that the long-chain fatty acyl-CoA1 (ACSL1) gene is related to fat deposition and meat quality in mammals. However, few studies have investigated the relationship between ACSL1 and lipid deposition in ducks. To examine this, we assessed the physicochemical property, homologous alignment, and phylogenetic analyses of the ACSL1 amino acid sequence using bioinformatics tools. The analysis indicated that the ACSL1 amino acid sequence varies in animals, and the duck ACSL1 protein is most closely related to that of chicken. Two single nucleotide polymorphism (SNP) sites were identified at 1749 and 1905 bp of the coding region of ACSL1 by sequencing. Quantitative real-time PCR and western blotting were used to measure mRNA and protein levels in abdominal fat, breast muscle, and liver tissue of Pekin duck (BD) and Cherry Valley duck (CD). mRNA and protein expression were significantly higher in BD than in CD in abdominal fat and liver tissue (P < 0.05). In breast muscle, the mRNA level of ACSL1 was also significantly higher in BD than in CD (P < 0.05), and protein expression in BD tended to be higher than that of CD. These results suggest that ACSL1 may contribute to lipid deposition and meat quality in ducks.
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Affiliation(s)
- Qianqian Song
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, Yangzhou University, Yangzhou 225009, People’s Republic of China
| | - Zhixiu Wang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, Yangzhou University, Yangzhou 225009, People’s Republic of China
| | - Hongliang Zhang
- Bureau of Agriculture and Rural of the Lhasa, Lhasa 850000, People’s Republic of China
| | - Xiangxiang Li
- National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, People’s Republic of China
| | - Yang Zhang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, Yangzhou University, Yangzhou 225009, People’s Republic of China
| | - Qi Xu
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, Yangzhou University, Yangzhou 225009, People’s Republic of China
| | - Guobin Chang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, Yangzhou University, Yangzhou 225009, People’s Republic of China
| | - Hao Zhang
- National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, People’s Republic of China
| | - Guohong Chen
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, Yangzhou University, Yangzhou 225009, People’s Republic of China
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29
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Li B, Yang J, Gong Y, Xiao Y, Zeng Q, Xu K, Duan Y, He J, He J, Ma H. Integrated Analysis of Liver Transcriptome, miRNA, and Proteome of Chinese Indigenous Breed Ningxiang Pig in Three Developmental Stages Uncovers Significant miRNA-mRNA-Protein Networks in Lipid Metabolism. Front Genet 2021; 12:709521. [PMID: 34603377 PMCID: PMC8481880 DOI: 10.3389/fgene.2021.709521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/19/2021] [Indexed: 11/13/2022] Open
Abstract
Liver is an important metabolic organ of mammals. During each transitional period of life, liver metabolism is programmed by a complex molecular regulatory system for multiple physiological functions, many pathways of which are regulated by hormones and cytokines, nuclear receptors, and transcription factors. To gain a comprehensive and unbiased molecular understanding of liver growth and development in Ningxiang pigs, we analyzed the mRNA, microRNA (miRNA), and proteomes of the livers of Ningxiang pigs during lactation, nursery, and fattening periods. A total of 22,411 genes (19,653 known mRNAs and 2758 novel mRNAs), 1122 miRNAs (384 known miRNAs and 738 novel miRNAs), and 1123 unique proteins with medium and high abundance were identified by high-throughput sequencing and mass spectrometry. We show that the differences in transcriptional, post-transcriptional, or protein levels were readily identified by comparing different time periods, providing evidence that functional changes that may occur during liver development are widespread. In addition, we found many overlapping differentially expressed genes (DEGs)/differentially expressed miRNAs (DEMs)/differentially expressed proteins (DEPs) related to glycolipid metabolism in any group comparison. These overlapping DEGs/DEMs/DGPs may play an important role in functional transformation during liver development. Short Time-series Expression Miner (STEM) analysis revealed multiple expression patterns of mRNA, miRNA, and protein in the liver. Furthermore, several diverse key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including immune defense, glycolipid metabolism, protein transport and uptake, and cell proliferation and development, were identified by combined analysis of DEGs and DGPs. A number of predicted miRNA-mRNA-protein pairs were found and validated by qRT-PCR and parallel reaction monitoring (PRM) assays. The results provide new and important information about the genetic breeding of Ningxiang pigs, which represents a foundation for further understanding the molecular regulatory mechanisms of dynamic development of liver tissue, functional transformation, and lipid metabolism.
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Affiliation(s)
- Biao Li
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Jinzeng Yang
- Department of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, Honolulu, HI, United States
| | - Yan Gong
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Yu Xiao
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Qinghua Zeng
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Ningxiang Pig Farm of Dalong Livestock Technology Co., Ltd., Ningxiang, China
| | - Kang Xu
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agroecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences (CAS), Changsha, China
| | - Yehui Duan
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agroecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences (CAS), Changsha, China
| | - Jianhua He
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Jun He
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Haiming Ma
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
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30
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Qiao L, Wang HF, Xiang L, Ma J, Zhu Q, Xu D, Zheng H, Peng JQ, Zhang S, Lu HX, Chen WQ, Zhang Y. Deficient Chaperone-Mediated Autophagy Promotes Lipid Accumulation in Macrophage. J Cardiovasc Transl Res 2021; 14:661-669. [PMID: 32285315 PMCID: PMC8397667 DOI: 10.1007/s12265-020-09986-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/06/2020] [Indexed: 01/22/2023]
Abstract
Chaperone-mediated autophagy (CMA) serves as a critical upstream regulator of lipophagy and lipid metabolism in hepatocyte. However, the role of CMA in lipid metabolism of macrophage, the typical component of atherosclerotic plaque, remains unclear. In our study, LAMP-2A (L2A, a CMA marker) was reduced in macrophages exposed to high dose of oleate, and lipophagy was impaired in advanced atherosclerosis in ApoE (-/-) mice. Primary peritoneal macrophages isolated from macrophage-specific L2A-deficient mice exhibited pronounced intracellular lipid accumulation. Lipid regulatory enzymes, including long-chain-fatty-acid-CoA ligase 1 (ACSL1) and lysosomal acid lipase (LAL), were increased and reduced in L2A-KO macrophage, respectively. Other lipid-related proteins, such as SR-A, SR-B (CD36), ABCA1, or PLIN2, were not associated with increased lipid content in L2A-KO macrophage. In conclusion, deficient CMA promotes lipid accumulation in macrophage probably by regulating enzymes involved in lipid metabolism. CMA may represent a novel therapeutic target to alleviate atherosclerosis by promoting lipid metabolism. Graphical abstract.
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Affiliation(s)
- Lei Qiao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - He-Feng Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
- Qilu Hospital of Shandong University (Qingdao), No. 758 Hefei Road, Qingdao, 266035, China
| | - Lei Xiang
- Department of Cardiology, Sishui County People's Hospital, Sishui, 273200, Shandong, China
| | - Jing Ma
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Qiang Zhu
- Department of clinical laboratory, Sishui County People's Hospital, Sishui, 273200, Shandong, China
| | - Dan Xu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Hui Zheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Jie-Qiong Peng
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, China
| | - Sen Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
- Qilu Hospital of Shandong University (Qingdao), No. 758 Hefei Road, Qingdao, 266035, China
| | - Hui-Xia Lu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China
| | - Wen-Qiang Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China.
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wenhuaxi Road, 250012, Jinan, China.
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31
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Echeverri-Peña OY, Salazar-Barreto DA, Rodríguez-Lopez A, González J, Alméciga-Díaz CJ, Verano-Guevara CH, Barrera LA. Use of a neuron-glia genome-scale metabolic reconstruction to model the metabolic consequences of the Arylsulphatase a deficiency through a systems biology approach. Heliyon 2021; 7:e07671. [PMID: 34381909 PMCID: PMC8340118 DOI: 10.1016/j.heliyon.2021.e07671] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/10/2021] [Accepted: 07/23/2021] [Indexed: 12/26/2022] Open
Abstract
Metachromatic leukodystrophy (MLD) is a human neurodegenerative disorder characterized by progressive damage on the myelin band in the nervous system. MLD is caused by the impaired function of the lysosomal enzyme Arylsulphatase A (ARSA). The physiopathology mechanisms and the biochemical consequences in the brain of ARSA deficiency are not entirely understood. In recent years, the use of genome-scale metabolic (GEM) models has been explored as a tool for the study of the biochemical alterations in MLD. Previously, we modeled the metabolic consequences of different lysosomal storage diseases using single GEMs. In the case of MLD, using a glia GEM, we previously predicted that the metabolism of glycosphingolipids and neurotransmitters was altered. The results also suggested that mitochondrial metabolism and amino acid transport were the main reactions affected. In this study, we extended the modeling of the metabolic consequences of ARSA deficiency through the integration of neuron and glial cell metabolic models. Cell-specific models were generated from Recon2, and these were used to create a neuron-glial bi-cellular model. We propose a workflow for the integration of this type of model and its subsequent study. The results predicted the impairment pathways involved in the transport of amino acids, lipids metabolism, and catabolism of purines and pyrimidines. The use of this neuron-glial GEM metabolic reconstruction allowed to improve the prediction capacity of the metabolic consequences of ARSA deficiency, which might pave the way for the modeling of the biochemical alterations of other inborn errors of metabolism with central nervous system involvement.
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Affiliation(s)
- Olga Y Echeverri-Peña
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - Diego A Salazar-Barreto
- Centro para la Optimización y Probabilidad Aplicada (COPA), Department of Industrial Engineering, Faculty of Engineering, Universidad de los Andes, Bogotá D.C., Colombia.,Grupo de Bioquímica Computacional, Estructural y Bioinformática, Department of Nutrition and Biochemistry, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Alexander Rodríguez-Lopez
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia.,Licenciatura en Química, Universidad Distrital Francisco Jose de Caldas, Bogota D.C., Colombia.,Molecular Biology and Immunology Department, Fundación Instituto de Inmunología de Colombia (FIDIC), Bogotá D.C., Colombia
| | - Janneth González
- Grupo de Bioquímica Computacional, Estructural y Bioinformática, Department of Nutrition and Biochemistry, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Carlos J Alméciga-Díaz
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | | | - Luis A Barrera
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C., Colombia.,Clínica de Errores Innatos del Metabolismo, Hospital Universitario San Ignacio, Bogotá D.C., Colombia
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32
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Li B, Liu J, Xin X, Zhang L, Zhou J, Xia C, Zhu W, Yu H. MiR-34c promotes hepatic stellate cell activation and Liver Fibrogenesis by suppressing ACSL1 expression. Int J Med Sci 2021; 18:615-625. [PMID: 33437196 PMCID: PMC7797556 DOI: 10.7150/ijms.51589] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/02/2020] [Indexed: 12/19/2022] Open
Abstract
Normally, there are multiple microRNAs involved in the pathogenesis of liver fibrosis. In our work, we aimed at identifying the role of miR-34c in the hepatic stellate cell (HSC) activation and liver fibrosis and its potential mechanism. Our results have shown that during natural activation of HSC, the level of miR-34c was increased significantly whereas acyl-CoA synthetase long-chain family member-1(ACSL1), which is a key enzyme can affect fatty acid(FA) synthesis, was decreased. A double fluorescence reporter assay further confirmed that ACSL1 is a direct target gene of miR-34c. Moreover, the inhibition of miR-34C can attenuate the synthesis of collagen in HSC-T6. In our rescue assay, ACSL1 expression was 1.49-fold higher compared to normal control cells which were transfected with the miR-34c inhibitor in a stable low expression ACSL1 cell line. While at the same time, α-SMA and Col1α expression decreased by 18.22% and 2.58%, respectively. Moreover, we performed an in vivo model using dimethylnitrosamine (DMN) in conjunction with the miR-34c agomir, combined with the treatment of DMN and the miR-34c agomir can increase liver fibrosis. Meanwhile, the degree of hepatic fibrosis was increased and lipid droplets reduced dramatically in rats and HSC-T6 cell treated with miR-34c mimics alone compared to untreated groups. Our results indicate that miR-34c plays an essential role in liver fibrosis by targeting ACSL1 closely associated with lipid droplets, and it might be used as a potential therapeutic target.
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Affiliation(s)
- Binbin Li
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Jiaxuan Liu
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Xuan Xin
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
- Department of Pathology, No. 960 Hospital of People' Liberation Army, Jinan 250031, China
| | - Lifen Zhang
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Jiaming Zhou
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
- Department of Pathological Anatomy, Nantong University, Nantong 226001, China
| | - Chunyan Xia
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Weijian Zhu
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Hongyu Yu
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
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33
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Luo Y, Tanigawa K, Kawashima A, Ishido Y, Ishii N, Suzuki K. The function of peroxisome proliferator-activated receptors PPAR-γ and PPAR-δ in Mycobacterium leprae-induced foam cell formation in host macrophages. PLoS Negl Trop Dis 2020; 14:e0008850. [PMID: 33075048 PMCID: PMC7595635 DOI: 10.1371/journal.pntd.0008850] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/29/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). In lepromatous leprosy (LL), skin macrophages, harboring extensive bacterial multiplication, gain a distinctive foamy appearance due to increased intracellular lipid load. To determine the mechanism by which M. leprae modifies the lipid homeostasis in host cells, an in vitro M. leprae infection system, using human macrophage precursor THP-1 cells and M. leprae prepared from the footpads of nude mice, was employed. RNA extracted from skin smear samples of patients was used to investigate host gene expressions before and after multidrug therapy (MDT). We found that a cluster of peroxisome proliferator-activated receptor (PPAR) target genes associated with adipocyte differentiation were strongly induced in M. leprae-infected THP-1 cells, with increased intracellular lipid accumulation. PPAR-δ and PPAR-γ expressions were induced by M. leprae infection in a bacterial load-dependent manner, and their proteins underwent nuclear translocalization after infection, indicating activation of PPAR signaling in host cells. Either PPAR-δ or PPAR-γ antagonist abolished the effect of M. leprae to modify host gene expressions and inhibited intracellular lipid accumulation in host cells. M. leprae-specific gene expressions were detected in the skin smear samples both before and after MDT, whereas PPAR target gene expressions were dramatically diminished after MDT. These results suggest that M. leprae infection activates host PPAR signaling to induce an array of adipocyte differentiation-associated genes, leading to accumulation of intracellular lipids to accommodate M. leprae parasitization. Certain PPAR target genes in skin lesions may serve as biomarkers for monitoring treatment efficacy. Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). Lipid-enriched intracellular environment is important for the parasitization of M. leprae. During anti-leprosy treatment, chemotherapy-killed bacilli can remain in host tissues for a long time, making it difficult to determine the treatment efficacy by Zeihl-Nelson’s staining-based bacterial index (BI) test. In this study, we found that host peroxisome proliferator-activated receptor (PPAR) signaling is responsible for modification of intracellular lipid homeostasis to accommodate M. leprae parasitization in host macrophages. In skin smear samples of patients, M. leprae-derived gene expressions were detected both before and after anti-leprosy treatment, whereas human PPAR target gene expressions were dramatically diminished after the treatment. These results further our understanding of M. leprae intracellular parasitization, and suggest that PPAR signaling may be a novel therapeutic target for treating M. leprae infection and monitoring the expressions of certain PPAR target genes in skin lesions may be helpful to evaluate the treatment efficacy and recurrent infection.
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Affiliation(s)
- Yuqian Luo
- Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Kazunari Tanigawa
- Department of Molecular Pharmaceutics, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan
| | - Akira Kawashima
- Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan
| | - Yuko Ishido
- Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan
| | - Norihisa Ishii
- Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koichi Suzuki
- Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan
- Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- * E-mail:
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34
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Lo B, Marty-Gasset N, Pichereaux C, Bravo C, Manse H, Domitile R, Rémignon H. Proteomic Analysis of Two Weight Classes of Mule Duck " foie gras" at the End of an Overfeeding Period. Front Physiol 2020; 11:569329. [PMID: 33041868 PMCID: PMC7528769 DOI: 10.3389/fphys.2020.569329] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/14/2020] [Indexed: 12/28/2022] Open
Abstract
The weight of the liver is one of the important selection criteria in the quality of “foie gras”. This factor is highly variable despite the fact that individuals are reared, overfed and slaughtered in the same way. In this study, we performed an analysis of the proteome profile of two weight classes of light (between 550 and 599 g) and heavy (more than 700 g) livers. For the analysis of the proteic extracts, a liquid chromatographic analysis coupled with mass spectrometry was carried out. In low-weight livers, aerobic energy metabolism, protein metabolism and lipid metabolism oriented toward export and beta-oxidation were overexpressed. On the contrary, high weight livers were characterized by anaerobic energy metabolism and a more active protein catabolism associated with cell apoptosis and reorganization of the cell structure.
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Affiliation(s)
- Bara Lo
- Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement, Ecole Nationale Vétérinaire de Toulouse, Université de Toulouse, GENétique PHYsiologie et Systèmes d'Elevage, Castanet-Tolosan, France
| | - Nathalie Marty-Gasset
- Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement, Ecole Nationale Vétérinaire de Toulouse, Université de Toulouse, GENétique PHYsiologie et Systèmes d'Elevage, Castanet-Tolosan, France
| | - Carole Pichereaux
- Centre National de la Recherche Scientifique, Fédération de Recherche (FR3450), Agrobiosciences, Interactions et Biodiversité, Toulouse, France.,Centre National de la Recherche Scientifique, Université de Toulouse - UPS, Institut de Pharmacologie et Biologie Structurale, Toulouse, France
| | - Céline Bravo
- Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement, Ecole Nationale Vétérinaire de Toulouse, Université de Toulouse, GENétique PHYsiologie et Systèmes d'Elevage, Castanet-Tolosan, France
| | - Hélène Manse
- Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement, Ecole Nationale Vétérinaire de Toulouse, Université de Toulouse, GENétique PHYsiologie et Systèmes d'Elevage, Castanet-Tolosan, France
| | | | - Hervé Rémignon
- Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement, Ecole Nationale Vétérinaire de Toulouse, Université de Toulouse, GENétique PHYsiologie et Systèmes d'Elevage, Castanet-Tolosan, France
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35
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Tian W, Wang D, Wang Z, Jiang K, Li Z, Tian Y, Kang X, Liu X, Li H. Evolution, expression profile, and regulatory characteristics of ACSL gene family in chicken (Gallus gallus). Gene 2020; 764:145094. [PMID: 32860898 DOI: 10.1016/j.gene.2020.145094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 08/21/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023]
Abstract
Long chain acyl-CoA synthetases (ACSLs), which drive the conversion of long chain fatty acid into acyl-CoA, an ingredient of lipid synthesis, have been well-acknowledged to exert an indispensable role in many metabolic processes in mammals, especially lipid metabolism. However, in chicken, the evolutionary characteristics, expression profiles and regulatory mechanisms of ACSL gene family are rarely understood. Here, we analyzed the genomic synteny, gene structure, evolutionary event and functional domains of the ACSL gene family members using bioinformatics methods. The spatiotemporal expression profiles of ACSL gene family, and their regulatory mechanism were investigated via bioinformatics analysis incorporated with in vivo and in vitro estrogen-treated experiments. Our results indicated that ACSL2 gene was indeed evolutionarily lost in the genome of chicken. Chicken ACSLs shared an AMP-binding functional domain, as well as highly conversed ATP/AMP and FACS signature motifs, and were clustered into two clades, ACSL1/5/6 and ACSL3/4, based on high sequence similarity, similar gene features and conversed motifs. Chicken ACSLs showed differential tissue expression distributions, wherein the significantly decreased expression level of ACSL1 and the significantly increased expression level of ACSL5 were found, respectively, the expression levels of the other ACSL members remained unchanged in the liver of peak-laying hens versus pre-laying hens. Moreover, the transcription activity of ACSL1, ACSL3 and ACSL4 was silenced and ACSL6 was activated by estrogen, but no response to ACSL5. In conclusion, though having highly conversed functional domains, chicken ACSL gene family is organized into two separate groups, ACSL1/5/6 and ACSL3/4, and exhibits varying expression profiles and estrogen effects. These results not only pave the way for better understanding the specific functions of ACSL genes in avian lipid metabolism, but also provide a valuable evidence for gene family characteristics.
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Affiliation(s)
- Weihua Tian
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China
| | - Dandan Wang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China
| | - Zhang Wang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China
| | - Keren Jiang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China
| | - Zhuanjian Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China; Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Yadong Tian
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China; Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Xiangtao Kang
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China; Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China
| | - Xiaojun Liu
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China; Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China.
| | - Hong Li
- College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou 450002, China; Henan Innovative Engineering Research Center of Poultry Germplasm Resource, Zhengzhou 450002, China; International Joint Research Laboratory for Poultry Breeding of Henan, Zhengzhou 450002, China.
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Xie G, Wang Y, Xu Q, Hu M, Zhu J, Bai W, Lin Y. Knockdown of adiponectin promotes the adipogenesis of goat intramuscular preadipocytes. Anim Biotechnol 2020; 33:408-416. [PMID: 32755436 DOI: 10.1080/10495398.2020.1800484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Intramuscular fat (IMF) content determined by the intramuscular preadipocytes differentiation has a huge influence on the sensory quality traits of meats. It was reported that the adiponectin (ADIPOQ) gene could promote adipocytes differentiation, but the underlying molecular and functional characterization of the ADIPOQ for regulating goat IMF deposition remained unknown. Herein, the knockdown of ADIPOQ was mediated by siRNAs during goat intramuscular preadipocytes differentiation. Also, the qRT-PCR technique was performed to detect the mRNA levels of target genes in multiply experiment groups. These results showed that the ADIPOQ was expressed more than ∼400 folds in subcutaneous adipose tissue compared to that of heart tissue, and the mRNA level of ADIPOQ reached a peak at Hour 60 during the differentiation process, while at Hour 36 did ADIPOR1 and ADIPOR2. Moreover, the knockdown of ADIPOQ promoted the intramuscular preadipocytes differentiation and accelerated the lipid accumulation in the mature adipocytes with down-regulating the ADIPOR1 and preadipocyte factor 1 (Pref-1) mRNA levels and up-regulating the mRNA expression levels of the CAAT/enhancer-binding proteins (C/EBPs) and transcription factor peroxisomal proliferator-activated receptor γ (PPARγ), etc. Our study will provide a new opposite insight that the inhibition of ADIPOQ expression during intramuscular preadipocytes differentiation promotes goat IMF deposition.
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Affiliation(s)
- Guangjie Xie
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Chengdu, China.,College of Life Science and Technique, Southwest Minzu University, Chengdu, China
| | - Yong Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Chengdu, China
| | - Qing Xu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Chengdu, China.,College of Life Science and Technique, Southwest Minzu University, Chengdu, China
| | - Meng Hu
- College of Life Science and Technique, Southwest Minzu University, Chengdu, China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Chengdu, China
| | - Wenlin Bai
- College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang, China
| | - Yaqiu Lin
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Chengdu, China.,Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province, Chengdu, China.,College of Life Science and Technique, Southwest Minzu University, Chengdu, China
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Latorre J, Ortega FJ, Liñares-Pose L, Moreno-Navarrete JM, Lluch A, Comas F, Oliveras-Cañellas N, Ricart W, Höring M, Zhou Y, Liebisch G, Nidhina Haridas PA, Olkkonen VM, López M, Fernández-Real JM. Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes. EBioMedicine 2020; 53:102697. [PMID: 32143184 PMCID: PMC7056650 DOI: 10.1016/j.ebiom.2020.102697] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/03/2020] [Accepted: 02/16/2020] [Indexed: 12/12/2022] Open
Abstract
Background While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled β-oxidation, redirecting FA metabolism from energy storage to expenditure. Interpretation Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. Funding Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associació Catalana de Diabetis (ACD), Sociedad Española de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economía y Competitividad (MINECO), “La Caixa” Foundation, and CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN).
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Affiliation(s)
- Jèssica Latorre
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain
| | - Francisco J Ortega
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain.
| | - Laura Liñares-Pose
- Department of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - José M Moreno-Navarrete
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain
| | - Aina Lluch
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain
| | - Ferran Comas
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain
| | - Núria Oliveras-Cañellas
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain
| | - Wifredo Ricart
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain
| | - Marcus Höring
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - You Zhou
- Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
| | - P A Nidhina Haridas
- Minerva Foundation Institute for Medical Research, Biomedicum 2 U, Helsinki, Finland
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Biomedicum 2 U, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Miguel López
- Department of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.
| | - José M Fernández-Real
- Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona "Dr Josep Trueta", Girona, Spain.
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Chen Y, He L, Yang Y, Chen Y, Song Y, Lu X, Liang Y. The inhibition of Nrf2 accelerates renal lipid deposition through suppressing the ACSL1 expression in obesity-related nephropathy. Ren Fail 2020; 41:821-831. [PMID: 31488013 PMCID: PMC6735294 DOI: 10.1080/0886022x.2019.1655450] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background: Obesity has become a worldwide epidemic, and the incidence of obesity is increasing year by year. Obesity-related nephropathy (ORN) is a common kidney complication of obesity. Long-chain acyl-CoA synthetases-1, (ACSL1), is a key enzyme in the oxidative metabolism of fatty acids in mitochondria and ACSL1 may play a direct role in renal lipid deposition and promote the progress of ORN. In this study, we focus on the renoprotective role of ACSL1 in ORN. Methods: Electron microscopy, immunohistochemical (IHC) staining, Western blot, and real-time PCR were used to detect the expression of ACSL1and Nrf2 in ORN patients, ob/ob mice and palmitic acid (PA)-treated HK-2 cells. Oil red staining and Elisa Kit were used to detect the intracellular FFA and TG contents in ob/ob mice and PA-treated HK-2 cells. Dihydroethidium (DHE) staining and the MDA/SOD measurement were used to detect the ROS production. In order to demonstrate the role of ACSL1 and the interaction between ACSL1 and Nrf2 in ORN, related siRNA and plasmid were transfected into HK-2 cells. Results: More ROS production and renal lipid deposition have been found in ORN patients, ob/ob mice and PA-treated HK-2 cells. Compared with control, all the expression of ACSL1and Nrf2 were down-regulated in ORN patients, ob/ob mice and PA-treated HK-2 cells. The Nrf2 could regulate the expression of ACSL1 and the ACSL1 played the direct role in renal lipid deposition. Conclusions: The Nrf2 is inhibited in ORN, resulting more ROS production and oxidative stress. Increased oxidative stress will suppress the expression of ACSL1, which could increase the intracellular FFA and TG contents, ultimately leading to renal lipid deposition in renal tubulars and accelerating the development of ORN.
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Affiliation(s)
- Yinyin Chen
- Department of Nephrology, Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University , Changsha , Hunan , P.R. China
| | - Liyu He
- Key Lab of Kidney Disease and Blood Purification in Hunan, Department of Nephrology, The Second Xiangya Hospital Central South University , Changsha , Hunan , People's Republic of China
| | - Yiya Yang
- Department of Nephrology, Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University , Changsha , Hunan , P.R. China
| | - Ying Chen
- Department of Nephrology, Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University , Changsha , Hunan , P.R. China
| | - Yanran Song
- Department of Nephrology, Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University , Changsha , Hunan , P.R. China
| | - Xi Lu
- Department of Nephrology, Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University , Changsha , Hunan , P.R. China
| | - Yumei Liang
- Department of Nephrology, Laboratory of Kidney Disease, Hunan Provincial People's Hospital, Hunan Normal University , Changsha , Hunan , P.R. China
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Li T, Li X, Meng H, Chen L, Meng F. ACSL1 affects Triglyceride Levels through the PPARγ Pathway. Int J Med Sci 2020; 17:720-727. [PMID: 32218693 PMCID: PMC7085263 DOI: 10.7150/ijms.42248] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/18/2020] [Indexed: 12/14/2022] Open
Abstract
In clinical cohort studies, high expression of long-chain acyl-coenzyme A synthetases 1 (ACSL1 gene) in peripheral white blood cells of patients with acute myocardial infarction (AMI) has been utilized as molecular markers of myocardial infarction diagnosis. The plasma triglyceride level of AMI patients is significantly higher than that of healthy individuals. We hypothesized that the high expression of ACSL1 increases the level of triglyceride, which is one of the pathogenesis of AMI promoted by ACSL1. In this report, cell culture based methods were adopted to test the hypothesis and further investigate the effect and mechanism of ACSL1 on lipid metabolism. In this study, liver cells of healthy individuals were cultured, the overexpression and the knockdown vectors of ACSL1 were constructed and transfected into liver cells. The transfection was verified at the mRNA and protein level. Intracellular triglyceride content was quantitatively analyzed using ELISA. Changes of genes related to lipid metabolism were subsequently measured through PCR array. Overexpression of ACSL1 led to higher gene expression and protein levels compared to control and the triglyceride content was significantly increased in overexpressing cells. The expression level of fatty acid oxidation pathway PPARγ was significantly down-regulated compared with the control group, as were genes associated with fatty acid synthesis pathways: SREBP1, ACC, FAS, and SCD1. ACSL1 knockdown decreased the content of triglyceride whereas PPARγ was up-regulated and SREBP1, ACC, FAS, and SCD1 were down-regulated compared with the control group. In summary, high expression of ACSL1 reduced fatty acid β-oxidation through the PPARγ pathway, thereby increasing triglyceride levels.
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Affiliation(s)
- Tingting Li
- Department of Cardiology China-Japan Union Hospital of Jilin University, Changchun, China 130033
| | - Xiangdong Li
- Department of Cardiology China-Japan Union Hospital of Jilin University, Changchun, China 130033
| | - Heyu Meng
- Department of Cardiology China-Japan Union Hospital of Jilin University, Changchun, China 130033
| | - Lili Chen
- Department of Cardiology China-Japan Union Hospital of Jilin University, Changchun, China 130033
| | - Fanbo Meng
- Department of Cardiology China-Japan Union Hospital of Jilin University, Changchun, China 130033
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Han L, Bittner S, Dong D, Cortez Y, Dulay H, Arshad S, Shen WJ, Kraemer FB, Azhar S. Creosote bush-derived NDGA attenuates molecular and pathological changes in a novel mouse model of non-alcoholic steatohepatitis (NASH). Mol Cell Endocrinol 2019; 498:110538. [PMID: 31415794 PMCID: PMC7273809 DOI: 10.1016/j.mce.2019.110538] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 07/26/2019] [Accepted: 08/11/2019] [Indexed: 02/06/2023]
Abstract
Creosote bush (Larrea tridentata)-derived nordihydroguaiaretic acid (NDGA) was shown to have profound effects on the core components of metabolic syndrome. This study investigated the in vivo potential of NDGA for prevention or attenuation of the pathophysiologic abnormalities of NASH. A novel dietary NASH model with feeding C57BL/6J mice with a high trans-fat, high cholesterol and high fructose (HTF) diet, was used. The HTF diet fed mice exhibited obesity, insulin resistance, hepatic steatosis, fibrosis, inflammation, ER stress, oxidative stress, and liver injury. NDGA attenuated these metabolic abnormalities as well as hepatic steatosis and fibrosis together with attenuated expression of genes encoding fibrosis, progenitor and macrophage markers with no effect on the levels of mRNAs for lipogenic enzymes. NDGA increased expression of fatty acid oxidation genes. In conclusion, NDGA exerts anti-NASH/anti-fibrotic actions and raises the therapeutic potential of NDGA for treatment of NASH patients with fibrosis and other associated complications.
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Affiliation(s)
- Lu Han
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA
| | - Stefanie Bittner
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA
| | - Dachuan Dong
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA
| | - Yuan Cortez
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA
| | - Hunter Dulay
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA
| | - Sara Arshad
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA
| | - Wen-Jun Shen
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA.
| | - Fredric B Kraemer
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, USA
| | - Salman Azhar
- Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, CA, USA; Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, USA.
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Yu K, Zhang Y, Chen H, Zhu W. Hepatic Metabolomic and Transcriptomic Responses Induced by Cecal Infusion of Sodium Propionate in a Fistula Pig Model. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:13073-13081. [PMID: 31675219 DOI: 10.1021/acs.jafc.9b05070] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Short-chain fatty acids (SCFAs) are the major products of the microbial fermentation of indigestible carbohydrates. SCFAs are known to improve the host metabolism, but their underlying mechanism of action remains elusive. In this study, 16 growing pigs were infused with saline or sodium propionate solution (25 mL, 2 mol/L) through a cecal fistula twice a day during a 28 day experimental period. The results showed that the cecal infusion of the SCFA propionate decreased serum and liver triglyceride levels and increased serum PYY secretion in growing pigs. Hepatic metabolomics identified 12 metabolites that were significantly altered by propionate. These included decreased levels of lipid metabolism-related stearic acid and glycerol-2-phosphate; increased levels of TCA cycle components including malic acid, fructose-6-phosphate, and succinic acid; and decreased levels of the amino acid metabolism products aspartic acid and serine. Hepatic transcriptomics demonstrated that propionate inhibited fatty acid synthesis and promoted the lipid metabolic process. Pathway enrichment analysis showed that propionate accelerated gluconeogenesis and decreased glycolysis. Taken together, these data support a role of the SCFA propionate on host lipid and glucose metabolism.
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42
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Li N, Saitou M, Atilla-Gokcumen GE. The Role of p38 MAPK in Triacylglycerol Accumulation during Apoptosis. Proteomics 2019; 19:e1900160. [PMID: 31099964 DOI: 10.1002/pmic.201900160] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/14/2019] [Indexed: 12/21/2022]
Abstract
Lipids are emerging as key regulators of apoptosis. Specific lipid species are associated with apoptosis with important functional roles, but the understanding of the regulation of these lipid species is still limited. It has been previously shown by our laboratory that polyunsaturated triacylglycerols accumulate and get stored within lipid droplets during apoptosis via activated glycerolipid biosynthesis. In this work, the biochemical mechanisms that result in the activation of glycerolipid biosynthesis and, consequently, triacylglycerol and lipid droplet accumulation during apoptosis are investigated. The transcriptomes of control and apoptotic HCT-116 cells are compared and gene enrichment analysis revealed the upregulation of p38 mitogen-activated protein kinase (MAPK). It is shown that p38 MAPK regulates triacylglycerol biosynthesis through diacylglycerol acyltransferase1 during apoptosis. Perilipin 2 and cytosolic phospholipase A2delta are also shown to be involved in lipid droplet and polyunsaturated triacylglycerol accumulation in this process. Overall, the results provide new insights into the upregulation of glycerolipid synthesis during apoptosis.
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Affiliation(s)
- Nasi Li
- Department of Chemistry, State University of New York at Buffalo, Buffalo, NY, 14260, USA
| | - Marie Saitou
- Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY, 14260, USA
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Dongiovanni P, Meroni M, Longo M, Fargion S, Fracanzani AL. miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis. Int J Mol Sci 2018; 19:E3966. [PMID: 30544653 PMCID: PMC6320931 DOI: 10.3390/ijms19123966] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/03/2018] [Accepted: 12/06/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD.
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Affiliation(s)
- Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
| | - Silvia Fargion
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy.
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano 20122, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy.
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Madureira TV, Malhão F, Simões T, Pinheiro I, Lopes C, Gonçalves JF, Urbatzka R, Castro LFC, Lemos MFL, Rocha E. Sex-steroids and hypolipidemic chemicals impacts on brown trout lipid and peroxisome signaling - Molecular, biochemical and morphological insights. Comp Biochem Physiol C Toxicol Pharmacol 2018; 212:1-17. [PMID: 29885532 DOI: 10.1016/j.cbpc.2018.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 05/31/2018] [Accepted: 06/03/2018] [Indexed: 01/08/2023]
Abstract
Lipid metabolism involves complex pathways, which are regulated in a similar way across vertebrates. Hormonal and hypolipidemic deregulations cause lipid imbalance from fish to humans, but the underlying mechanisms are far from understood. This study explores the potential of using juvenile brown trout to evaluate the in vivo interferences caused by estrogenic (17α-ethinylestradiol - EE2), androgenic (testosterone - T), and hypolipidemic (clofibrate - CLF) compounds in lipidic and/or peroxisomal pathways. Studied endpoints were from blood/plasma biochemistry, plasma fatty acid profile, ultrastructure of hepatocytes and abundance of their peroxisomes to mRNA expression in the liver. Both T and CLF caused minimal effects when compared to EE2. Estrogenized fish had significantly higher hepatosomatic indexes, increased triglycerides and very-low density lipoproteins (VLDL) in plasma, compared with solvent control. Morphologically, EE2 fish showed increased lipid droplets in hepatocytes, and EE2 and T reduced volume density of peroxisomes in relation to the hepatic parenchyma. Polyunsaturated fatty acids (PUFA) in plasma, namely n-3 PUFA, increased with EE2. EE2 animals had increased mRNA levels of vitellogenin A (VtgA), estrogen receptor alpha (ERα), peroxisome proliferator-activated receptor alpha (PPARα), PPARαBa and acyl-CoA long chain synthetase 1 (Acsl1), while ERβ-1, acyl-CoA oxidase 1-3I (Acox1-3I), Acox3, PPARγ, catalase (Cat), urate oxidase (Uox), fatty acid binding protein 1 (Fabp1) and apolipoprotein AI (ApoAI) were down-regulated. In summary, in vivo EE2 exposure altered lipid metabolism and peroxisome dynamics in brown trout, namely by changing the mRNA levels of several genes. Our model can be used to study possible organism-level impacts, viz. in gonadogenesis.
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Affiliation(s)
- Tânia Vieira Madureira
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal.
| | - Fernanda Malhão
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - Tiago Simões
- MARE - Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, 2520-641 Peniche, Portugal
| | - Ivone Pinheiro
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - Célia Lopes
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - José F Gonçalves
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Aquatic Production Department, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
| | - Ralph Urbatzka
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal
| | - L Filipe C Castro
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Faculty of Sciences (FCUP), University of Porto (U.Porto), Department of Biology, Rua do Campo Alegre, P 4169-007 Porto, Portugal
| | - Marco F L Lemos
- MARE - Marine and Environmental Sciences Centre, ESTM, Instituto Politécnico de Leiria, 2520-641 Peniche, Portugal
| | - Eduardo Rocha
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U.Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos, Portugal; Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto, Portugal
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Steensels S, Ersoy BA. Fatty acid activation in thermogenic adipose tissue. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1864:79-90. [PMID: 29793055 DOI: 10.1016/j.bbalip.2018.05.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 03/10/2018] [Accepted: 05/17/2018] [Indexed: 02/07/2023]
Abstract
Channeling carbohydrates and fatty acids to thermogenic tissues, including brown and beige adipocytes, have garnered interest as an approach for the management of obesity-related metabolic disorders. Mitochondrial fatty acid oxidation (β-oxidation) is crucial for the maintenance of thermogenesis. Upon cellular fatty acid uptake or following lipolysis from triglycerides (TG), fatty acids are esterified to coenzyme A (CoA) to form active acyl-CoA molecules. This enzymatic reaction is essential for their utilization in β-oxidation and thermogenesis. The activation and deactivation of fatty acids are regulated by two sets of enzymes called acyl-CoA synthetases (ACS) and acyl-CoA thioesterases (ACOT), respectively. The expression levels of ACS and ACOT family members in thermogenic tissues will determine the substrate availability for β-oxidation, and consequently the thermogenic capacity. Although the role of the majority of ACS and ACOT family members in thermogenesis remains unclear, recent proceedings link the enzymatic activities of ACS and ACOT family members to metabolic disorders and thermogenesis. Elucidating the contributions of specific ACS and ACOT family members to trafficking of fatty acids towards thermogenesis may reveal novel targets for modulating thermogenic capacity and treating metabolic disorders.
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Affiliation(s)
- Sandra Steensels
- Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA
| | - Baran A Ersoy
- Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA.
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Analysis of meat quality traits and gene expression profiling of pigs divergent in residual feed intake. Meat Sci 2018; 137:265-274. [DOI: 10.1016/j.meatsci.2017.11.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 09/08/2017] [Accepted: 11/16/2017] [Indexed: 11/19/2022]
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Yang L, Yang Y, Si D, Shi K, Liu D, Meng H, Meng F. High expression of long chain acyl-coenzyme A synthetase 1 in peripheral blood may be a molecular marker for assessing the risk of acute myocardial infarction. Exp Ther Med 2017; 14:4065-4072. [PMID: 29104625 PMCID: PMC5658692 DOI: 10.3892/etm.2017.5091] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 06/22/2017] [Indexed: 01/10/2023] Open
Abstract
The current study aimed to investigate whether the increased expression of long chain acyl-coenzymeA synthetase 1 (ACSL1) in peripheral blood leukocytes (PBL) may be a molecular marker for the genetic evaluation of acute myocardial infarction (AMI). The mechanism of action of ACSL1 in the pathogenesis of AMI was also investigated. A total of 75 patients with AMI and 70 individuals without coronary heart disease were selected to participate in the present study. The demographic and clinical information of the enrolled subjects was recorded. Reverse transcription quantitative polymerase chain reaction and western blot analysis were applied to measure the expression of ACSL1 at the mRNA and protein levels. It was demonstrated that the expression of ACSL1 mRNA and protein in PBL was increased in patients with AMI compared with controls. Logistic regression analysis indicated that ACSL1 expression in PBL was an independent risk factor of AMI. There was a significant positive association between the level of ACSL1 expression and the degree of atherosclerosis in the coronary artery. Furthermore, patients with AMI exhibited an increased risk of atherosclerosis due to increased fasting blood glucose, total cholesterol, triglyceride and lipoprotein levels and decreased high-density lipoprotein levels, compared with controls. Therefore, the current study demonstrated that ACSL1 expression was increased in the PBLs of patients with AMI. The elevated expression of ACSL1 acts an independent risk factor of AMI and may act as a potential biomarker when determining the risk of AMI.
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Affiliation(s)
- Liping Yang
- Department of Cardiology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yushuang Yang
- Department of Cardiology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Daoyuan Si
- Department of Cardiology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Kaiyao Shi
- Department of Cardiology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Dongna Liu
- Department of Cardiology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Heyu Meng
- Medical College, Yanbian University, Yanji, Jilin 130002, P.R. China
| | - Fanbo Meng
- Department of Cardiology, The China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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48
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Pre- and post-prandial expression of genes involved in lipid metabolism at the end of the overfeeding period of mule ducks. Mol Cell Biochem 2017; 438:111-121. [DOI: 10.1007/s11010-017-3118-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 07/15/2017] [Indexed: 01/23/2023]
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CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation. Proc Natl Acad Sci U S A 2017; 114:E6556-E6565. [PMID: 28739932 DOI: 10.1073/pnas.1703791114] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a "low-lipid" phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1's interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.
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50
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Jiang XP, Ai WB, Wan LY, Zhang YQ, Wu JF. The roles of microRNA families in hepatic fibrosis. Cell Biosci 2017; 7:34. [PMID: 28680559 PMCID: PMC5496266 DOI: 10.1186/s13578-017-0161-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 06/26/2017] [Indexed: 12/17/2022] Open
Abstract
When hepatocytes are damaged severely, a variety of signaling pathways will be triggered by inflammatory factors and cytokines involving in the process of hepatic fibrosis. The microRNA (miRNA) family consists of several miRNAs which have the potential for synergistic regulation of these signaling pathways. However, it is poor to understand the roles of miRNA family as a whole in hepatic fibrosis. Increasing studies have suggested several miRNA families are related with activation of hepatic stellate cells and hepatic fibrosis through cooperatively regulating certain signaling pathways. During the process of hepatic fibrosis, miR-29 family primarily induces cell apoptosis by modulating phosphatidylinositol 3-kinase/AKT signaling pathway and regulates extracellular matrix accumulation. miR-34 family promotes the progression of hepatic fibrosis by inducing activation of hepatic stellate cells, while miR-378 family suppresses the process in Glis dependent manner. miR-15 family mainly promotes cell proliferation and induces apoptosis. The miR-199 family and miR-200 family are responsible for extracellular matrix deposition and the release of pro-fibrotic cytokines. These miRNA family members play pro-fibrotic or anti-fibrotic roles by targeting genes collectively or respectively which involve in hepatic fibrosis related signaling pathways and hepatic stellate cell activation. Thus, good understandings of molecular mechanisms which are based on miRNA families may provide new ideas for the molecular targeted therapy of hepatic fibrosis in the future.
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Affiliation(s)
- Xue-Ping Jiang
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China
| | - Wen-Bing Ai
- The Yiling Hospital of Yichang, 31 Donghu Road, Yi Ling District, Yichang, 443100 Hubei China
| | - Lin-Yan Wan
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China.,The RenMin Hospital, China Three Gorges University, 31 Huti Subdistrict, Xi Ling District, Yichang, 443000 Hubei China
| | - Yan-Qiong Zhang
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China
| | - Jiang-Feng Wu
- Institute of Organ Fibrosis and Targeted Drug Delivery, China Three Gorges University, 8 Daxue Road, Xiling District, Yichang, 443002 China
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