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1
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Ježek P. Physiological Fatty Acid-Stimulated Insulin Secretion and Redox Signaling Versus Lipotoxicity. Antioxid Redox Signal 2025; 42:566-622. [PMID: 39834189 DOI: 10.1089/ars.2024.0799] [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] [Indexed: 01/22/2025]
Abstract
Significance: Type 2 diabetes as a world-wide epidemic is characterized by the insulin resistance concomitant to a gradual impairment of β-cell mass and function (prominently declining insulin secretion) with dysregulated fatty acids (FAs) and lipids, all involved in multiple pathological development. Recent Advances: Recently, redox signaling was recognized to be essential for insulin secretion stimulated with glucose (GSIS), branched-chain keto-acids, and FAs. FA-stimulated insulin secretion (FASIS) is a normal physiological event upon postprandial incoming chylomicrons. This contrasts with the frequent lipotoxicity observed in rodents. Critical Issues: Overfeeding causes FASIS to overlap with GSIS providing repeating hyperinsulinemia, initiates prediabetic states by lipotoxic effects and low-grade inflammation. In contrast the protective effects of lipid droplets in human β-cells counteract excessive lipids. Insulin by FASIS allows FATP1 recruitment into adipocyte plasma membranes when postprandial chylomicrons come late at already low glycemia. Future Directions: Impaired states of pancreatic β-cells and peripheral organs at prediabetes and type 2 diabetes should be revealed, including the inter-organ crosstalk by extracellular vesicles. Details of FA/lipid molecular physiology are yet to be uncovered, such as complex phenomena of FA uptake into cells, postabsorptive inactivity of G-protein-coupled receptor 40, carnitine carrier substrate specificity, the role of carnitine-O-acetyltransferase in β-cells, and lipid droplet interactions with mitochondria. Antioxid. Redox Signal. 42, 566-622.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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2
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Luong TVT, Yang S, Kim J. Lipotoxicity as a therapeutic target in the type 2 diabetic heart. J Mol Cell Cardiol 2025; 201:105-121. [PMID: 40020774 DOI: 10.1016/j.yjmcc.2025.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 01/07/2025] [Accepted: 02/24/2025] [Indexed: 03/03/2025]
Abstract
Cardiac lipotoxicity, characterized by excessive lipid accumulation in the cardiac tissue, is a critical contributor to the pathogenesis of diabetic heart. Recent research has highlighted the key mechanisms underlying lipotoxicity, including mitochondrial dysfunction, endoplasmic reticulum stress, inflammation, and cell apoptosis, which ultimately impair the cardiac function. Various therapeutic interventions have been developed to target these pathways, mitigate lipotoxicity, and improve cardiovascular outcomes in diabetic patients. Given the global escalation in the prevalence of diabetes and the urgent demand for effective therapeutic approaches, this review focuses on how targeting cardiac lipotoxicity may be a promising avenue for treating diabetes.
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Affiliation(s)
- Trang Van T Luong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Seonbu Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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3
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Cho CC, Yen GC, Lee HY, Tsai CT, Chang WT, Hsu CL. Protective role of Hsian-tsao ethanol extract against body fat, serum lipid profiles, and hepatic lipid profiles in high-fat diet-fed rats. J Food Drug Anal 2025; 33:48-60. [PMID: 40202407 PMCID: PMC12039537 DOI: 10.38212/2224-6614.3527] [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: 05/20/2024] [Accepted: 08/27/2024] [Indexed: 04/10/2025] Open
Abstract
This study investigated the preventive effects of a 40% ethanol extract of Hsian-tsao (40EEHT) on obesity in high-fat diet (HFD)-induced obese rats. Male Wistar rats were administered 0, 100, 200, or 500 mg/kg of 40EEHT, resulting in reduced body weight, total body fat, and hepatic tissue weight after 8 weeks. 40EEHT also decreased adipocyte size, improved lipid profiles, alleviated oxidative stress, and enhanced hepatic antioxidant enzyme activities. Additionally, it regulated fatty acid metabolism by reducing lipogenesis and increasing lipolysis and β-oxidation, suggesting its potential as an anti-obesity dietary supplement.
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Affiliation(s)
- Ching-Chang Cho
- Department of Nutrition, Chung Shan Medical University, Taichung,
Taiwan
| | - Gow-Chin Yen
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung,
Taiwan
| | - Hsin-Yi Lee
- Department of Nutrition, Chung Shan Medical University, Taichung,
Taiwan
| | - Chun-Tse Tsai
- Department of Nutrition, Chung Shan Medical University, Taichung,
Taiwan
| | - Wei-Tang Chang
- Department of Nutrition and Health Sciences, Chinese Culture University, Taipei,
Taiwan
| | - Chin-Lin Hsu
- Department of Nutrition, Chung Shan Medical University, Taichung,
Taiwan
- Department of Nutrition, Chung Shan Medical University Hospital, Taichung,
Taiwan
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4
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Zhang C, Yang X, Xue Y, Li H, Zeng C, Chen M. The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis. J Clin Transl Hepatol 2025; 13:233-252. [PMID: 40078199 PMCID: PMC11894391 DOI: 10.14218/jcth.2024.00348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/19/2024] [Accepted: 12/31/2024] [Indexed: 03/14/2025] Open
Abstract
Solute carrier (SLC) family transporters are crucial transmembrane proteins responsible for transporting various molecules, including amino acids, electrolytes, fatty acids, and nucleotides. To date, more than fifty SLC transporter subfamilies have been identified, many of which are linked to the progression of hepatic steatosis and fibrosis. These conditions are often caused by factors such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which are major contributors to the global liver disease burden. The activity of SLC members regulates the transport of substrates across biological membranes, playing key roles in lipid synthesis and metabolism, mitochondrial function, and ferroptosis. These processes, in turn, influence the function of hepatocytes, hepatic stellate cells, and macrophages, thereby contributing to the development of hepatic steatosis and fibrosis. Additionally, some SLC transporters are involved in drug transport, acting as critical regulators of drug-induced hepatic steatosis. Beyond substrate transport, certain SLC members also exhibit additional functions. Given the pivotal role of the SLC family in hepatic steatosis and fibrosis, this review aimed to summarize the molecular mechanisms through which SLC transporters influence these conditions.
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Affiliation(s)
| | | | - Yi Xue
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Huan Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Chuanfei Zeng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Zhong W, Chen C, Tan S, He X, Wen X, Wang S, Tocher DR, Waiho K, Chen C. Identification and Functional Characterization of the FATP1 Gene from Mud Crab, Scylla paramamosain. Animals (Basel) 2024; 14:2969. [PMID: 39457899 PMCID: PMC11506284 DOI: 10.3390/ani14202969] [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: 09/02/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
In mammals, fatty acid transport protein 1 (FATP1) plays important roles in cellular uptake and activation of long-chain fatty acid (LCFA), especially in processes of transportation, oxidation and triacylglycerol synthesis. However, the role of FATP1 in invertebrates, especially decapod crustaceans, is still poorly understood. In this study, the cDNA of a FATP1 gene from a decapod crustacean, mud crab Scylla paramamosain, was cloned and functionally characterized. The FATP1 gene encoded a polypeptide consisting of 643 amino acids that exhibits all the typical features of the FATP family and shares high homology with the other FATP orthologs of crustaceans. The relative mRNA expression levels of FATP1 were observed to be higher in metabolically active tissues such as hepatopancreas, stomach and gill than in other crab parts. Knockdown of the FATP1 mRNA in vivo significantly reduced triacylglycerols and total lipid levels in the hepatopancreas, accompanied by an increase in the expression of genes related to fatty acid transportation, allocation and hydrolysis, including long-chain acyl-CoA synthetase 3/4 (ACSL3/4) and carnitine palmitoyl transferase 1 (CPT1), and a decrease in the expression of genes related to fatty acid synthesis such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the hepatopancreas. Furthermore, increased dietary n-3 long-chain polyunsaturated fatty acid (LC-PUFA) levels resulted in the up-regulation of the FATP1 expression in the hepatopancreas, accompanied by an increase in LC-PUFA content, especially eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), in both polar (PLs) and neutral lipids (NLs) in the hepatopancreas and muscles of crabs. These findings suggested that the FATP1 gene identified in S. paramamosain might play important roles in regulating long-chain fatty acid metabolism and deposition in crustaceans.
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Affiliation(s)
- Wenjie Zhong
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Chuangsi Chen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Senyue Tan
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Xianda He
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Xiaobo Wen
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China;
| | - Shuqi Wang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Douglas R. Tocher
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK
| | - Khor Waiho
- Higher Institution Centre of Excellence (HICoE), Institute of Tropical Aquaculture and Fisheries, University Malaysia Terengganu, Kuala Terengganu 21300, Malaysia;
| | - Cuiying Chen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
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6
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Abdollahi A, Szramowski M, Tomoo K, Henderson GC. Metabolic responses to albumin deficiency differ distinctly between partial and full ablation of albumin expression in mice. Lipids Health Dis 2024; 23:242. [PMID: 39123208 PMCID: PMC11312229 DOI: 10.1186/s12944-024-02229-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
It had been observed that homozygous albumin knockout mice (Alb-/-) exhibit low plasma free fatty acid (FFA) concentration and improved blood glucose regulation. However, it was not yet known to what extent heterozygous albumin knockout (Alb+/-) mice would display a similar phenotype. Alb-/-, Alb+/-, and wild-type (WT) female mice were studied on a low-fat diet (LFD) or high-fat diet (HFD). On both diets, decreased plasma FFA concentration, and improved glucose tolerance test were observed in Alb-/-, but not in Alb+/-, compared to WT. Plasma adiponectin concentration showed greater elevation in Alb-/- than Alb+/-. Consistent with that, adiponectin gene expression was significantly higher in Alb-/- mice than in Alb+/- and WT mice. A dose-dependent response was observed for hepatic Acadl gene expression showing higher Acadl gene expression in Alb-/- mice than in Alb+/- and WT mice. In conclusion, although female Alb+/- mice exhibited some slight differences from WT mice (e.g., increased plasma adiponectin and hepatic Acadl gene expression), Alb+/- mice did not exhibit improved glucoregulation in comparison to WT mice, indicating that a minor suppression of albumin expression is not sufficient to improve glucoregulation. Furthermore, it is now clear that although the response of female mice to HFD might be unique from how males generally respond, still the complete albumin deficiency in Alb-/- mice and the associated FFA reduction is capable of improving glucoregulation in females on this diet. The present results have implications for the role of albumin and FFA in the regulation of metabolism.
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Affiliation(s)
- Afsoun Abdollahi
- Department of Nutrition Science, Purdue University, STON 208, 700 Mitch Daniels Blvd, West Lafayette, IN, 47907, USA
| | - Mirandia Szramowski
- Department of Nutrition Science, Purdue University, STON 208, 700 Mitch Daniels Blvd, West Lafayette, IN, 47907, USA
| | - Keigo Tomoo
- Department of Nutrition Science, Purdue University, STON 208, 700 Mitch Daniels Blvd, West Lafayette, IN, 47907, USA
| | - Gregory C Henderson
- Department of Nutrition Science, Purdue University, STON 208, 700 Mitch Daniels Blvd, West Lafayette, IN, 47907, USA.
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7
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Ma Y, Nenkov M, Chen Y, Gaßler N. The Role of Adipocytes Recruited as Part of Tumor Microenvironment in Promoting Colorectal Cancer Metastases. Int J Mol Sci 2024; 25:8352. [PMID: 39125923 PMCID: PMC11313311 DOI: 10.3390/ijms25158352] [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: 06/10/2024] [Revised: 07/15/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Adipose tissue dysfunction, which is associated with an increased risk of colorectal cancer (CRC), is a significant factor in the pathophysiology of obesity. Obesity-related inflammation and extracellular matrix (ECM) remodeling promote colorectal cancer metastasis (CRCM) by shaping the tumor microenvironment (TME). When CRC occurs, the metabolic symbiosis of tumor cells recruits adjacent adipocytes into the TME to supply energy. Meanwhile, abundant immune cells, from adipose tissue and blood, are recruited into the TME, which is stimulated by pro-inflammatory factors and triggers a chronic local pro-inflammatory TME. Dysregulated ECM proteins and cell surface adhesion molecules enhance ECM remodeling and further increase contractibility between tumor and stromal cells, which promotes epithelial-mesenchymal transition (EMT). EMT increases tumor migration and invasion into surrounding tissues or vessels and accelerates CRCM. Colorectal symbiotic microbiota also plays an important role in the promotion of CRCM. In this review, we provide adipose tissue and its contributions to CRC, with a special emphasis on the role of adipocytes, macrophages, neutrophils, T cells, ECM, and symbiotic gut microbiota in the progression of CRC and their contributions to the CRC microenvironment. We highlight the interactions between adipocytes and tumor cells, and potential therapeutic approaches to target these interactions.
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Affiliation(s)
| | | | | | - Nikolaus Gaßler
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany (M.N.)
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8
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Baldelli S, Aiello G, Mansilla Di Martino E, Campaci D, Muthanna FMS, Lombardo M. The Role of Adipose Tissue and Nutrition in the Regulation of Adiponectin. Nutrients 2024; 16:2436. [PMID: 39125318 PMCID: PMC11313710 DOI: 10.3390/nu16152436] [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: 06/14/2024] [Revised: 07/21/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Adipose tissue (AT), composed mainly of adipocytes, plays a critical role in lipid control, metabolism, and energy storage. Once considered metabolically inert, AT is now recognized as a dynamic endocrine organ that regulates food intake, energy homeostasis, insulin sensitivity, thermoregulation, and immune responses. This review examines the multifaceted role of adiponectin, a predominant adipokine released by AT, in glucose and fatty acid metabolism. We explore the regulatory mechanisms of adiponectin, its physiological effects and its potential as a therapeutic target for metabolic diseases such as type 2 diabetes, cardiovascular disease and fatty liver disease. Furthermore, we analyze the impact of various dietary patterns, specific nutrients, and physical activities on adiponectin levels, highlighting strategies to improve metabolic health. Our comprehensive review provides insights into the critical functions of adiponectin and its importance in maintaining systemic metabolic homeostasis.
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Affiliation(s)
- Sara Baldelli
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy (E.M.D.M.)
- IRCCS San Raffaele Roma, 00166 Rome, Italy
| | - Gilda Aiello
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy (E.M.D.M.)
| | - Eliana Mansilla Di Martino
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy (E.M.D.M.)
| | - Diego Campaci
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy (E.M.D.M.)
| | - Fares M. S. Muthanna
- Pharmacy Department, Faculty of Medicine and Health Sciences, University of Science and Technology-Aden, Alshaab Street, Enmaa City 22003, Yemen
| | - Mauro Lombardo
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Via di Val Cannuta, 247, 00166 Rome, Italy (E.M.D.M.)
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Huang MC, Chen PL, Hsu CL. Transcriptome Analysis of Mesenchymal Progenitor Cells Revealed Molecular Insights into Metabolic Dysfunction and Inflammation in Polycystic Ovary Syndrome. Int J Mol Sci 2024; 25:7948. [PMID: 39063189 PMCID: PMC11276887 DOI: 10.3390/ijms25147948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 07/13/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Polycystic ovary syndrome (PCOS) is a female endocrine disorder with metabolic issues. Hyperandrogenism combined with hyperinsulinemia exacerbates the reproductive, metabolic, and inflammatory problems in PCOS patients. The etiology of PCOS is unclear. Patient-specific induced pluripotent stem cells (iPSCs) offer a promising model for studying disease mechanisms and conducting drug screening. Here, we aim to use mesenchymal progenitor cells (MPCs) derived from PCOS iPSCs to explore the mechanism of PCOS. We compared the transcriptome profiles of PCOS and healthy control (HC) iPSC-derived MPCs (iPSCMs). Moreover, we assess the impact of androgens on iPSCMs. In the comparison between PCOS and HC, the expression levels of 1026 genes were significantly different. A gene set enrichment analysis (GSEA) revealed that adipogenesis- and metabolism-related genes were downregulated, whereas inflammation-related genes were upregulated in the PCOS iPSCMs. Dysregulation of the TGF-β1 and Wnt signaling pathways was observed in the PCOS iPSCMs. Furthermore, there was impaired adipogenesis and decreased lipolysis in the PCOS iPSCMs-derived adipocytes. With testosterone treatment, genes related to metabolism were upregulated in the HC iPSCMs but downregulated in the PCOS iPSCMs. The impact of testosterone varied among HCs and PCOS iPSCMs, possibly because of a genetic predisposition toward PCOS. This study found specific signaling pathways that could serve as therapeutic targets for PCOS.
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Affiliation(s)
- Mei-Chi Huang
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
| | - Pei-Lung Chen
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Chia-Lang Hsu
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
- Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan
- Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 100, Taiwan
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10
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Guo PP, Yao XR, Xu YN, Jin X, Li Q, Yan CG, Kim NH, Li XZ. Insulin interacts with PPARγ agonists to promote bovine adipocyte differentiation. Domest Anim Endocrinol 2024; 88:106848. [PMID: 38574690 DOI: 10.1016/j.domaniend.2024.106848] [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: 01/11/2024] [Revised: 02/29/2024] [Accepted: 03/19/2024] [Indexed: 04/06/2024]
Abstract
Insulin is a potent adipogenic hormone that triggers a series of transcription factors that regulate the differentiation of preadipocytes into mature adipocytes. Ciglitazone specifically binds to peroxisome proliferator-activated receptor-γ (PPARγ), thereby promoting adipocyte differentiation. As a natural ligand of PPARγ, oleic acid (OA) can promote the translocation of PPARγ into the nucleus, regulate the expression of downstream genes, and promote adipocyte differentiation. We hypothesized that ciglitazone and oleic acid interact with insulin to enhance bovine preadipocyte differentiation. Preadipocytes were cultured 96 h in differentiation medium containing 10 mg/L insulin (I), 10 mg/L insulin + 10 µM cycloglitazone (IC), 10 mg/L insulin + 100 µM oleic acid (IO), or 10 mg/L insulin + 10 µM cycloglitazone+100 µM oleic acid (ICO). Control preadipocytes (CON) were cultured in differentiation medium (containing 5% fetal calf serum). The effects on the differentiation of Yanbian cattle preadipocytes were examined using molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis. I, IC, IO, and ICO treatments produced higher concentrations of triglycerides (TAG) and lipid droplet accumulation in preadipocytes compared with CON treatment (P < 0.05). Co-treatment of insulin and PPARγ agonists significantly increased the expression of genes involved in regulating adipogenesis and fatty acid synthesis. (P < 0.05). Differential expression analysis identified 1488, 1764, 1974 and 1368 DEGs in the I, IC, IO and ICO groups, respectively. KEGG pathway analysis revealed DEGs mainly enriched in PPAR signalling, FOXO signaling pathway and fatty acid metabolism. These results indicate that OA, as PPARγ agonist, can more effectively promote the expression of bovine lipogenesis genes and the content of TAG and adiponectin when working together with insulin, and stimulate the differentiation of bovine preadipocytes. These findings provide a basis for further screening of relevant genes and transcription factors in intramuscular fat deposition and meat quality to enhance breeding programs.
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Affiliation(s)
- Pan Pan Guo
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; Healthcare International Innovation Institute, Jiangmen 529020, PR China; Guangdong University of Technology, Guangzhou 510000, PR China; Engineering Research Centre of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Department of Animal Science, College of Agriculture, Yanbian University, Yanji 133002, PR China
| | - Xue Rui Yao
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China; Healthcare International Innovation Institute, Jiangmen 529020, PR China; Guangdong University of Technology, Guangzhou 510000, PR China
| | - Yong Nan Xu
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China
| | - Xin Jin
- Engineering Research Centre of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Department of Animal Science, College of Agriculture, Yanbian University, Yanji 133002, PR China; Laboratory Animal Center, Yanbian University, Yanji 133002, PR China
| | - Qiang Li
- Engineering Research Centre of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Department of Animal Science, College of Agriculture, Yanbian University, Yanji 133002, PR China
| | - Chang Guo Yan
- Engineering Research Centre of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Department of Animal Science, College of Agriculture, Yanbian University, Yanji 133002, PR China; Yanbian Hongchao Wisdom Animal Husbandry Co., LTD, Yanji 133002, PR China
| | - Nam Hyung Kim
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, PR China
| | - Xiang Zi Li
- Engineering Research Centre of North-East Cold Region Beef Cattle Science & Technology Innovation, Ministry of Education, Department of Animal Science, College of Agriculture, Yanbian University, Yanji 133002, PR China.
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11
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Peeters R, Jellusova J. Lipid metabolism in B cell biology. Mol Oncol 2024; 18:1795-1813. [PMID: 38013654 PMCID: PMC11223608 DOI: 10.1002/1878-0261.13560] [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: 08/03/2023] [Revised: 10/30/2023] [Accepted: 11/24/2023] [Indexed: 11/29/2023] Open
Abstract
In recent years, the field of immunometabolism has solidified its position as a prominent area of investigation within the realm of immunological research. An expanding body of scientific literature has unveiled the intricate interplay between energy homeostasis, signalling molecules, and metabolites in relation to fundamental aspects of our immune cells. It is now widely accepted that disruptions in metabolic equilibrium can give rise to a myriad of pathological conditions, ranging from autoimmune disorders to cancer. Emerging evidence, although sometimes fragmented and anecdotal, has highlighted the indispensable role of lipids in modulating the behaviour of immune cells, including B cells. In light of these findings, this review aims to provide a comprehensive overview of the current state of knowledge regarding lipid metabolism in the context of B cell biology.
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Affiliation(s)
- Rens Peeters
- School of Medicine and Health, Institute of Clinical Chemistry and PathobiochemistryTechnical University of MunichGermany
- TranslaTUM, Center for Translational Cancer ResearchTechnical University of MunichGermany
| | - Julia Jellusova
- School of Medicine and Health, Institute of Clinical Chemistry and PathobiochemistryTechnical University of MunichGermany
- TranslaTUM, Center for Translational Cancer ResearchTechnical University of MunichGermany
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12
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Yang M, Liu S, Sui Y, Zhang C. Macrophage metabolism impacts metabolic dysfunction-associated steatotic liver disease and its progression. IMMUNOMETABOLISM 2024; 6:e00047. [DOI: 10.1097/in9.0000000000000047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), with a progressive form of metabolic dysfunction-associated steatohepatitis (MASH), is the leading chronic liver disease worldwide, which can progress to advanced liver disease and hepatocellular carcinoma. MASLD is tightly associated with metabolic disorders such as obesity, insulin resistance, and type 2 diabetes. Macrophages, as an innate immune component and a linker of adaptive immune response, play important roles in the pathogenesis and treatment of MASLD or MASH. Metabolic reprogramming can regulate macrophage activation and polarization to inhibit MASLD or MASH progression to advanced liver disease. Here, we summarize the underlying mechanisms of how different metabolites such as amino acids, glucose, and fatty acids can regulate macrophage function and phenotype, the factors that regulate macrophage metabolism, and potential treatment options to regulate macrophage function in MASLD or MASH, as well as other associated metabolic disorders.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Connecticut Health, School of Medicine, Farmington, CT, USA
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen, China
| | - Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
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Abdillah AM, Yun JW. Capsaicin induces ATP-dependent thermogenesis via the activation of TRPV1/β3-AR/α1-AR in 3T3-L1 adipocytes and mouse model. Arch Biochem Biophys 2024; 755:109975. [PMID: 38531438 DOI: 10.1016/j.abb.2024.109975] [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: 09/18/2023] [Revised: 03/22/2024] [Accepted: 03/22/2024] [Indexed: 03/28/2024]
Abstract
Capsaicin (CAP) is a natural bioactive compound in chili pepper that activates the transient receptor potential vanilloid subfamily 1 (TRPV1) and is known to stimulate uncoupling protein 1 (UCP1)-dependent thermogenesis. However, its effect on ATP-dependent thermogenesis remains unknown. In this study, we employed qRT-PCR, immunoblot, staining method, and assay kit to investigate the role of CAP on ATP-dependent thermogenesis and its modulatory roles on the TRPV1, β3-adrenergic receptor (β3-AR), and α1-AR using in vitro and in vivo models. The studies showed that CAP treatment in high-fat diet-induced obese mice resulted in lower body weight gain and elevated ATP-dependent thermogenic effectors' protein and gene expression through ATP-consuming calcium and creatine futile cycles. In both in vitro and in vivo experiments, CAP treatment elevated the protein and gene expressions of sarcoendoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), ryanodine receptor 2 (RYR2), creatine kinase B (CKB), and creatine kinase mitochondrial 2 (CKMT2) mediated by the activation of β3-AR, α1-AR, and TRPV1. Our study showed that CAP increased intracellular Ca2+ levels and the expression of voltage-dependent anion channel (VDAC) and mitochondrial calcium uniporter (MCU) which indicates that increased mitochondrial Ca2+ levels lead to increased expression of oxidative phosphorylation protein complexes as a result of ATP-futile cycle activation. A mechanistic study in 3T3-L1 adipocytes revealed that CAP induces UCP1- and ATP-dependent thermogenesis mediated by the β3-AR/PKA/p38MAPK/ERK as well as calcium-dependent α1-AR/TRPV1/CaMKII/AMPK/SIRT1 pathway. Taken together, we identified CAP's novel functional and modulatory roles in UCP1- and ATP-dependent thermogenesis, which is important for developing therapeutic strategies for combating obesity and metabolic diseases.
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Affiliation(s)
- Alfin Mohammad Abdillah
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea
| | - Jong Won Yun
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk, 38453, Republic of Korea.
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Barbalho SM, de Alvares Goulart R, Minniti G, Bechara MD, de Castro MVM, Dias JA, Laurindo LF. Unraveling the rationale and conducting a comprehensive assessment of KD025 (Belumosudil) as a candidate drug for inhibiting adipogenic differentiation-a systematic review. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2681-2699. [PMID: 37966572 DOI: 10.1007/s00210-023-02834-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/02/2023] [Indexed: 11/16/2023]
Abstract
Rho-associated kinases (ROCKs) are crucial during the adipocyte differentiation process. KD025 (Belumosudil) is a newly developed inhibitor that selectively targets ROCK2. It has exhibited consistent efficacy in impeding adipogenesis across a spectrum of in vitro models of adipogenic differentiation. Given the novelty of this treatment, a comprehensive systematic review has not been conducted yet. This systematic review aims to fill this knowledge void by providing readers with an extensive examination of the rationale behind KD025 and its impacts on adipogenesis. Preclinical evidence was gathered owing to the absence of clinical trials. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the study's quality was assessed using the Joanna Briggs Institute (JBI) Checklist Critical Appraisal Tool for Systematic Reviews. In various in vitro models, such as 3T3-L1 cells, human orbital fibroblasts, and human adipose-derived stem cells, KD025 demonstrated potent anti-adipogenic actions. At a molecular level, KD025 had significant effects, including decreasing fibronectin (Fn) expression, inhibiting ROCK2 and CK2 activity, suppressing lipid droplet formation, and reducing the expression of proadipogenic genes peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Additionally, KD025 resulted in the suppression of fatty acid-binding protein 4 (FABP4 or AP2) expression, a decrease in sterol regulatory element binding protein 1c (SREBP-1c) and Glut-4 expression. Emphasis must be placed on the fact that while KD025 shows potential in preclinical studies and experimental models, extensive research is crucial to assess its efficacy, safety, and potential therapeutic applications thoroughly and directly in human subjects.
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Affiliation(s)
- Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília, São Paulo, 17500-000, Brazil
| | - Ricardo de Alvares Goulart
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
| | - Giulia Minniti
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
| | - Marcelo Dib Bechara
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
| | - Marcela Vialogo Marques de Castro
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
| | - Jefferson Aparecido Dias
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília, São Paulo, 17525-902, Brazil.
- Department of Biochemistry and Pharmacology, School of Medicine, Faculdade de Medicina de Marília (FAMEMA), Marília, São Paulo, 17519-030, Brazil.
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Chan MP, Takenaka N, Abe Y, Satoh T. Insulin-stimulated translocation of the fatty acid transporter CD36 to the plasma membrane is mediated by the small GTPase Rac1 in adipocytes. Cell Signal 2024; 117:111102. [PMID: 38365113 DOI: 10.1016/j.cellsig.2024.111102] [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: 12/31/2023] [Revised: 02/10/2024] [Accepted: 02/13/2024] [Indexed: 02/18/2024]
Abstract
Cluster of differentiation 36 (CD36) is a scavenger receptor (SR), recognizing diverse extracellular ligands in various types of mammalian cells. Long-chain fatty acids (FAs), which are important constituents of phospholipids and triglycerides, also utilize CD36 as a predominant membrane transporter, being incorporated from the circulation across the plasma membrane in several cell types, including cardiac and skeletal myocytes and adipocytes. CD36 is localized in intracellular vesicles as well as the plasma membrane, and its distribution is modulated by extracellular stimuli. Herein, we aimed to clarify the molecular basis of insulin-stimulated translocation of CD36, which leads to the enhanced uptake of long-chain FAs, in adipocytes. To this end, we developed a novel exofacial epitope-tagged reporter to specifically detect cell surface-localized CD36. By employing this reporter, we demonstrate that the small GTPase Rac1 plays a pivotal role in insulin-stimulated translocation of CD36 to the plasma membrane in 3T3-L1 adipocytes. Additionally, phosphoinositide 3-kinase and the protein kinase Akt2 are shown to be involved in the regulation of Rac1. Downstream of Rac1, another small GTPase RalA directs CD36 translocation. Collectively, these results suggest that CD36 is translocated to the plasma membrane by insulin through mechanisms similar to those for the glucose transporter GLUT4 in adipocytes.
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Affiliation(s)
- Man Piu Chan
- Laboratory of Cell Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Sakai 599-8531, Japan
| | - Nobuyuki Takenaka
- Laboratory of Cell Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Sakai 599-8531, Japan
| | - Yuki Abe
- Laboratory of Cell Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Sakai 599-8531, Japan
| | - Takaya Satoh
- Laboratory of Cell Biology, Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Sakai 599-8531, Japan.
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Acharya R, Shetty SS, Pavan G, Monteiro F, Munikumar M, Naresh S, Kumari NS. AI-Based Homology Modelling of Fatty Acid Transport Protein 1 Using AlphaFold: Structural Elucidation and Molecular Dynamics Exploration. Biomolecules 2023; 13:1670. [PMID: 38002353 PMCID: PMC10669040 DOI: 10.3390/biom13111670] [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: 09/23/2023] [Revised: 10/16/2023] [Accepted: 10/16/2023] [Indexed: 11/26/2023] Open
Abstract
Fatty acid transport protein 1 (FATP1) is an integral transmembrane protein that is involved in facilitating the translocation of long-chain fatty acids (LCFA) across the plasma membrane, thereby orchestrating the importation of LCFA into the cell. FATP1 also functions as an acyl-CoA ligase, catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and VLCFA (very-long-chain fatty acids) as substrates. It is expressed in various types of tissues and is involved in the regulation of crucial signalling pathways, thus playing a vital role in numerous physiological and pathological conditions. Structural insight about FATP1 is, thus, extremely important for understanding the mechanism of action of this protein and developing efficient treatments against its anomalous expression and dysregulation, which are often associated with pathological conditions such as breast cancer. As of now, there has been no prior prediction or evaluation of the 3D configuration of the human FATP1 protein, hindering a comprehensive understanding of the distinct functional roles of its individual domains. In our pursuit to unravel the structure of the most commonly expressed isoforms of FATP1, we employed the cutting-edge ALPHAFOLD 2 model for an initial prediction of the entire protein's structure. This prediction was complemented by molecular dynamics simulations, focusing on the most promising model. We predicted the structure of FATP1 in silico and thoroughly refined and validated it using coarse and molecular dynamics in the absence of the complete crystal structure. Their relative dynamics revealed the different properties of the characteristic FATP1.
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Affiliation(s)
- Ranjitha Acharya
- Department of Biochemistry, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, India; (R.A.); (F.M.); (S.N.)
| | - Shilpa S. Shetty
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, India; (S.S.S.); (G.P.)
| | - Gollapalli Pavan
- Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, India; (S.S.S.); (G.P.)
| | - Flama Monteiro
- Department of Biochemistry, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, India; (R.A.); (F.M.); (S.N.)
| | - Manne Munikumar
- Clinical Division, ICMR-National Institute of Nutrition, Jamai-Osmania (Post), Hyderabad 500007, India;
| | - Sriram Naresh
- Department of Biochemistry, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, India; (R.A.); (F.M.); (S.N.)
| | - Nalilu Suchetha Kumari
- Department of Biochemistry, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore 575018, India; (R.A.); (F.M.); (S.N.)
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Chong HW, Son J, Chae C, Jae C. The relationship between skeletal muscle mass and the KOSHA cardiovascular risk in obese male workers. Ann Occup Environ Med 2023; 35:e40. [PMID: 38029272 PMCID: PMC10654537 DOI: 10.35371/aoem.2023.35.e40] [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: 07/20/2023] [Revised: 09/08/2023] [Accepted: 09/17/2023] [Indexed: 12/01/2023] Open
Abstract
Background Efforts for the prevention and management of cardiovascular diseases (CVDs) in workers have been actively pursued. Obesity is one of the important risk factors related to CVDs. Obesity has various metabolic characteristics, and some individuals can be metabolically healthy. Body composition including skeletal muscle mass is known to have protective effect in obesity. The study aims to investigate the association between skeletal muscle mass and Korea Occupational Safety and Health Agency (KOSHA) CVD risk among obese male manufacturing workers in Korea and to identify appropriate indicators of skeletal muscle mass for predicting risk of CVDs. Methods The study was conducted on 2,007 obese male workers at a manufacturing industry aged more than 19 years. Skeletal muscle mass, skeletal muscle index (SMI), skeletal muscle mass percent (SMM%) and skeletal muscle to body fat ratio (MFR) were used to evaluate body composition and these indicators were divided into quartiles. The odds ratios (ORs) and 95% confidence intervals (CIs) for the KOSHA CVD risk groups according to quartiles of skeletal muscle mass indicators were estimated using ordinal logistic regression analysis. Results The OR for the KOSHA CVD risk groups in the highest quartile of SMI was 1.67 (95% CI: 1.42-1.92), while the ORs for the KOSHA CVD risk groups in the highest quartiles of SMM%, SMM/body mass index (BMI), and MFR were 0.47 (95% CI: 0.22-0.72), 0.51 (95% CI: 0.05-0.76), and 0.48 (95% CI: 0.23-0.74), respectively. Conclusions We found that high SMI increase the likelihood of high risk of CVDs, while high SMM%, SMM/BMI, and MFR lower the likelihood of high risk of CVDs. Accurate evaluation of skeletal muscle mass can help assess the cardiovascular risk in obese male workers.
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Affiliation(s)
- Hyo Won Chong
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - JunSeok Son
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Changho Chae
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Changho Jae
- Department of Occupational and Environmental Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
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Vámos A, Arianti R, Vinnai BÁ, Alrifai R, Shaw A, Póliska S, Guba A, Csősz É, Csomós I, Mocsár G, Lányi C, Balajthy Z, Fésüs L, Kristóf E. Human abdominal subcutaneous-derived active beige adipocytes carrying FTO rs1421085 obesity-risk alleles exert lower thermogenic capacity. Front Cell Dev Biol 2023; 11:1155673. [PMID: 37416800 PMCID: PMC10321670 DOI: 10.3389/fcell.2023.1155673] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/26/2023] [Indexed: 07/08/2023] Open
Abstract
Introduction: White adipocytes store lipids, have a large lipid droplet and few mitochondria. Brown and beige adipocytes, which produce heat, are characterized by high expression of uncoupling protein (UCP) 1, multilocular lipid droplets, and large amounts of mitochondria. The rs1421085 T-to-C single-nucleotide polymorphism (SNP) of the human FTO gene interrupts a conserved motif for ARID5B repressor, resulting in adipocyte type shift from beige to white. Methods: We obtained abdominal subcutaneous adipose tissue from donors carrying FTO rs1421085 TT (risk-free) or CC (obesity-risk) genotypes, isolated and differentiated their preadipocytes into beige adipocytes (driven by the PPARγ agonist rosiglitazone for 14 days), and activated them with dibutyryl-cAMP for 4 hours. Then, either the same culture conditions were applied for additional 14 days (active beige adipocytes) or it was replaced by a white differentiation medium (inactive beige adipocytes). White adipocytes were differentiated by their medium for 28 days. Results and Discussion: RNA-sequencing was performed to investigate the gene expression pattern of adipocytes carrying different FTO alleles and found that active beige adipocytes had higher brown adipocyte content and browning capacity compared to white or inactive beige ones when the cells were obtained from risk-free TT but not from obesity-risk CC genotype carriers. Active beige adipocytes carrying FTO CC had lower thermogenic gene (e.g., UCP1, PM20D1, CIDEA) expression and thermogenesis measured by proton leak respiration as compared to TT carriers. In addition, active beige adipocytes with CC alleles exerted lower expression of ASC-1 neutral amino acid transporter (encoded by SLC7A10) and less consumption of Ala, Ser, Cys, and Gly as compared to risk-free carriers. We did not observe any influence of the FTO rs1421085 SNP on white and inactive beige adipocytes highlighting its exclusive and critical effect when adipocytes were activated for thermogenesis.
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Affiliation(s)
- Attila Vámos
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Rini Arianti
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Universitas Muhammadiyah Bangka Belitung, Pangkalanbaru, Indonesia
| | - Boglárka Ágnes Vinnai
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Rahaf Alrifai
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Abhirup Shaw
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szilárd Póliska
- Genomic Medicine and Bioinformatics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Andrea Guba
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Éva Csősz
- Proteomics Core Facility, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - István Csomós
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gábor Mocsár
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | | | - Zoltán Balajthy
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - László Fésüs
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Endre Kristóf
- Laboratory of Cell Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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Proteomic Analysis of Skeletal Muscle and White Adipose Tissue after Aerobic Exercise Training in High Fat Diet Induced Obese Mice. Int J Mol Sci 2023; 24:ijms24065743. [PMID: 36982812 PMCID: PMC10052314 DOI: 10.3390/ijms24065743] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/08/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Obesity is associated with excessive fat accumulation in adipose tissue and other organs, such as skeletal muscle, whereas aerobic exercise (AE) plays an important role in managing obesity through profound protein regulation. Our study aimed to investigate the impact of AE on proteomic changes in both the skeletal muscle and the epididymal fat pad (EFP) of high-fat-diet-induced obese mice. Bioinformatic analyses were performed on differentially regulated proteins using gene ontology enrichment analysis and ingenuity pathway analysis. Eight weeks of AE significantly reduced body weight, increased the serum FNDC5 level, and improved the homeostatic model assessment of insulin resistance. A high-fat diet caused alterations in a subset of proteins involved in the sirtuin signaling pathway and the production of reactive oxygen species in both skeletal muscle and EFP, leading to insulin resistance, mitochondrial dysfunction, and inflammation. On the other hand, AE upregulated skeletal muscle proteins (NDUFB5, NDUFS2, NDUFS7, ETFD, FRDA, and MKNK1) that enhance mitochondrial function and insulin sensitivity. Additionally, the upregulation of LDHC and PRKACA and the downregulation of CTBP1 in EFP can promote the browning of white adipose tissue with the involvement of FNDC5/irisin in the canonical pathway. Our study provides insights into AE-induced molecular responses and may help further develop exercise-mimicking therapeutic targets.
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Ren L, Cui H, Wang Y, Ju F, Cai Y, Gang X, Wang G. The role of lipotoxicity in kidney disease: From molecular mechanisms to therapeutic prospects. Biomed Pharmacother 2023; 161:114465. [PMID: 36870280 DOI: 10.1016/j.biopha.2023.114465] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/20/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Lipotoxicity is the dysregulation of the lipid environment and/or intracellular composition that leads to accumulation of harmful lipids and ultimately to organelle dysfunction, abnormal activation of intracellular signaling pathways, chronic inflammation and cell death. It plays an important role in the development of acute kidney injury and chronic kidney disease, including diabetic nephropathy, obesity-related glomerulopathy, age-related kidney disease, polycystic kidney disease, and the like. However, the mechanisms of lipid overload and kidney injury remain poorly understood. Herein, we discuss two pivotal aspects of lipotoxic kidney injury. First, we analyzed the mechanism of lipid accumulation in the kidney. Accumulating data indicate that the mechanisms of lipid overload in different kidney diseases are inconsistent. Second, we summarize the multiple mechanisms by which lipotoxic species affect the kidney cell behavior, including oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, dysregulated autophagy, and inflammation, highlighting the central role of oxidative stress. Blocking the molecular pathways of lipid accumulation in the kidney and the damage of the kidney by lipid overload may be potential therapeutic targets for kidney disease, and antioxidant drugs may play a pivotal role in the treatment of kidney disease in the future.
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Affiliation(s)
- Linan Ren
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China; Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Haiying Cui
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China; Institute of Translational Medicine, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Yao Wang
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Feng Ju
- Department of Orthopedics, Yuci District People's Hospital, Yuci 030600, Shanxi, China
| | - Yunjia Cai
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China.
| | - Guixia Wang
- Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun 130021, Jilin, China.
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Devereux CJ, Bayliss J, Keenan SN, Montgomery MK, Watt MJ. Investigating dual inhibition of ACC and CD36 for the treatment of nonalcoholic fatty liver disease in mice. Am J Physiol Endocrinol Metab 2023; 324:E187-E198. [PMID: 36629823 DOI: 10.1152/ajpendo.00161.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Dysregulation in hepatic lipid metabolism, including increased fatty acid uptake and de novo lipogenesis (DNL), is a hallmark of NAFLD. Here, we investigated dual inhibition of the fatty acid transporter fatty acid translocase (FAT/CD36), and acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in DNL, for the treatment of NAFLD in mice. Mice with hepatic CD36 deletion (Cd36LKO) and wild-type littermates were fed a high-fat diet for 12 wk and treated daily with either oral administration of an ACC inhibitor (GS-834356, Gilead Sciences; ACCi) or vehicle for 8 wk. Neither CD36 deletion or ACC inhibition impacted body composition, energy expenditure, or glucose tolerance. Cd36LKO mice had elevated fasting plasma insulin, suggesting mild insulin resistance. Whole body fatty acid oxidation was significantly decreased in Cd36LKO mice. Liver triglyceride content was significantly reduced in mice treated with ACCi; however, CD36 deletion caused an unexpected increase in liver triglycerides. This was associated with upregulation of genes and proteins of DNL, including ACC, and decreased liver triglyceride secretion ex vivo. Overall, these data confirm the therapeutic utility of ACC inhibition for steatosis resolution but indicate that inhibition of CD36 is not an effective treatment for NAFLD in mice.NEW & NOTEWORTHY Dysregulation of hepatic lipid metabolism is a hallmark of nonalcoholic fatty liver disease. Here, we show that dual inhibition of the de novo lipogenesis enzyme, ACC, and hepatic deletion of the fatty acid transporter, CD36, was ineffective for the treatment of NAFLD in mice. This was due to a paradoxical increase in liver triglycerides with CD36 deletion resulting from decreased hepatic triglyceride secretion and increased lipogenic gene expression.
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Affiliation(s)
- Camille J Devereux
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jacqueline Bayliss
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Stacey N Keenan
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Magdalene K Montgomery
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - Matthew J Watt
- Department of Anatomy and Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
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22
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I'Anson H, Archer HR, Choi HJ, Ko TB, Rodriguez CL, Samuel MA, Bezold KA, Whitworth GB. Resting metabolic rate, abdominal fat pad and liver metabolic gene expression in female rats provided a snacking diet from weaning to adulthood. Physiol Behav 2022; 256:113962. [PMID: 36100110 DOI: 10.1016/j.physbeh.2022.113962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/22/2022] [Accepted: 09/09/2022] [Indexed: 10/31/2022]
Abstract
Our female rat model with continuous, ad libitum access to snacks and chow from weaning to adulthood closely mimics human feeding behavior from childhood onwards. It causes weight gain, enlarged abdominal fat pads, reduced insulin sensitivity and leptin resistance without an increase in total caloric intake. Our current study investigated if this change in energy partitioning is due to a decrease in resting metabolic rate (RMR). In addition, we determined if carbohydrate and lipid metabolism changes in abdominal fat pads and liver. RMR, using indirect calorimetry, was determined in control and snacking rats every two weeks from Days 28-29 to Days 76-77. RMR decreased with age in both groups, but there was no difference between snacking and control rats at any age. At termination, abdominal fat pads (parametrial, retroperitoneal and mesenteric) and liver samples were collected for determination of gene expression for 21 genes involved in carbohydrate and lipid metabolism using RT-qPCR. Analysis of gene expression data showed a striking difference between metabolic profiles of control and snacking rats in abdominal fat pads and liver, with a distinct segregation of genes for both lipid and carbohydrate metabolism that correlated with an increase in body weight and fat pad weights. Genes involved in lipogenesis were upregulated in abdominal fat pads, while genes involved in adipogenesis, and lipid recycling were upregulated in the liver. In conclusion, snacking in addition to chow from weaning in female rats causes a repartitioning of energy that is not due to depressed RMR in snacking rats. Rather, snacking from weaning causes a shift in gene expression resulting in energy partitioning toward enhanced abdominal fat pad lipogenesis, and adipogenesis and lipid recycling in liver.
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Affiliation(s)
- Helen I'Anson
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States.
| | - Hannah R Archer
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
| | - Hannah J Choi
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
| | - Tiffany B Ko
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
| | - Carissa L Rodriguez
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
| | - Mariam A Samuel
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
| | - Kelly A Bezold
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
| | - Gregg B Whitworth
- Department of Biology, Washington & Lee University, Lexington VA 24450, United States
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23
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Liu Z, Zhang L, Qian C, Zhou Y, Yu Q, Yuan J, Lv Y, Zhang L, Chang X, Li Y, Liu Y. Recurrent hypoglycemia increases hepatic gluconeogenesis without affecting glycogen metabolism or systemic lipolysis in rat. Metabolism 2022; 136:155310. [PMID: 36063868 DOI: 10.1016/j.metabol.2022.155310] [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: 05/08/2022] [Revised: 08/29/2022] [Accepted: 08/31/2022] [Indexed: 11/26/2022]
Abstract
INTRODUCTION Recurrent hypoglycemia (RH) impairs secretion of counterregulatory hormones. Whether and how RH affects responses within metabolically important peripheral organs to counterregulatory hormones are poorly understood. OBJECTIVE To study the effects of RH on metabolic pathways associated with glucose counterregulation within liver, white adipose tissue and skeletal muscle. METHODS Using a widely adopted rodent model of 3-day recurrent hypoglycemia, we first checked expression of counterregulatory hormone G-protein coupled receptors (GPCRs), their inhibitory regulators and downstream enzymes catalyzing glycogen metabolism, gluconeogenesis and lipolysis by qPCR and western blot. Then, we examined epinephrine-induced phosphorylation of PKA substrates to validate adrenergic sensitivity in each organ. Next, we measured hepatic and skeletal glycogen content, degree of breakdown by epinephrine and abundance of phosphorylated glycogen phosphorylase under hypoglycemia and that of phosphorylated glycogen synthase during recovery to evaluate glycogen turnover. Further, we performed pyruvate and lactate tolerance tests to assess gluconeogenesis. Additionally, we measured circulating FFA and glycerol to check lipolysis. The abovementioned studies were repeated in streptozotocin-induced diabetic rat model. Finally, we conducted epinephrine tolerance test to investigate systemic glycemic excursions to counterregulatory hormones. Saline-injected rats served as controls. RESULTS RH increased counterregulatory hormone GPCR signaling in liver and epidydimal white adipose tissue (eWAT), but not in skeletal muscle. For glycogen metabolism, RH did not affect total content or epinephrine-stimulated breakdown in liver and skeletal muscle. Although RH decreased expression of phosphorylated glycogen synthase 2, it did not affect hepatic glycogen biosynthesis during recovery from hypoglycemia or after fasting-refeeding. For gluconeogenesis, RH upregulated fructose 1,6-bisphosphatase 1 and monocarboxylic acid transporter 1 that imports lactate as precursor, resulting in a lower blood lactate profile during hypoglycemia. In agreement, RH elevated fasting blood glucose and caused higher glycemic excursions during pyruvate tolerance test. For lipolysis, RH did not affect circulating levels of FFA and glycerol after overnight fasting or upon epinephrine stimulation. Interestingly, RH upregulated the trophic fatty acid transporter FATP1 and glucose transporter GLUT4 to increase lipogenesis in eWAT. These aforementioned changes of gluconeogenesis, lipolysis and lipogenesis were validated in streptozotocin-diabetic rats. Finally, RH increased insulin sensitivity to accelerate glucose disposal, which was attributable to upregulated visceral adipose GLUT4. CONCLUSIONS RH caused metabolic adaptations related to counterregulation within peripheral organs. Specifically, adrenergic signaling was enhanced in liver and visceral fat, but not in skeletal muscle. Glycogen metabolism remained unchanged. Hepatic gluconeogenesis was augmented. Systemic lipolysis was unaffected, but visceral lipogenesis was enhanced. Insulin sensitivity was increased. These findings provided insights into mechanisms underlying clinical problems associated with intensive insulin therapy, such as high gluconeogenic flux and body weight gain.
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Affiliation(s)
- Zejian Liu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Lingyu Zhang
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Chen Qian
- Department of Endocrinology, Zhangjiagang Hospital Affiliated to Soochow University, Zhangjiagang, Suzhou, Jiangsu 215699, China
| | - Ying Zhou
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, China
| | - Qiuyu Yu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jiaqi Yuan
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yunfan Lv
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Leheng Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Yangyang Li
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, China.
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24
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Dysregulated transforming growth factor-beta mediates early bone marrow dysfunction in diabetes. Commun Biol 2022; 5:1145. [DOI: 10.1038/s42003-022-04112-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 10/14/2022] [Indexed: 12/15/2022] Open
Abstract
AbstractDiabetes affects select organs such as the eyes, kidney, heart, and brain. Our recent studies show that diabetes also enhances adipogenesis in the bone marrow and reduces the number of marrow-resident vascular regenerative stem cells. In the current study, we have performed a detailed spatio-temporal examination to identify the early changes that are induced by diabetes in the bone marrow. Here we show that short-term diabetes causes structural and molecular changes in the marrow, including enhanced adipogenesis in tibiae of mice, prior to stem cell depletion. This enhanced adipogenesis was associated with suppressed transforming growth factor-beta (TGFB) signaling. Using human bone marrow-derived mesenchymal progenitor cells, we show that TGFB pathway suppresses adipogenic differentiation through TGFB-activated kinase 1 (TAK1). These findings may inform the development of novel therapeutic targets for patients with diabetes to restore regenerative stem cell function.
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25
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Interplay between fat cells and immune cells in bone: Impact on malignant progression and therapeutic response. Pharmacol Ther 2022; 238:108274. [DOI: 10.1016/j.pharmthera.2022.108274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 08/11/2022] [Accepted: 08/23/2022] [Indexed: 11/20/2022]
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26
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Karl M, Hasselwander S, Zhou Y, Reifenberg G, Kim YO, Park KS, Ridder DA, Wang X, Seidel E, Hövelmeyer N, Straub BK, Li H, Schuppan D, Xia N. Dual roles of B lymphocytes in mouse models of diet-induced nonalcoholic fatty liver disease. Hepatology 2022; 76:1135-1149. [PMID: 35218234 DOI: 10.1002/hep.32428] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/08/2022] [Accepted: 02/19/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS Growing evidence suggests an important role of B cells in the development of NAFLD. However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking. APPROACH AND RESULTS In wild-type mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrovesicular steatosis, modest hepatic and adipose tissue inflammation, insulin resistance, and incipient fibrosis. Remarkably, Bnull (JHT) mice were partially protected whereas B cell harboring but antibody-deficient IgMi mice were completely protected from the development of hepatic steatosis, inflammation, and fibrosis. The common feature of JHT and IgMi mice is that they do not secrete antibodies, whereas HFD feeding in wild-type mice led to increased levels of serum IgG2c. Whereas JHT mice have no B cells at all, regulatory B cells were found in the liver of both wild-type and IgMi mice. HFD reduced the number of regulatory B cells and IL-10 production in the liver of wild-type mice, whereas these increased in IgMi mice. Livers of patients with advanced liver fibrosis showed abundant deposition of IgG and stromal B cells and low numbers of IL-10 expressing cells, compatible with our experimental data. CONCLUSIONS B lymphocytes have both detrimental and protective effects in HFD-induced NAFLD. The lack of secreted pathogenic antibodies protects partially from NAFLD, whereas the presence of certain B cell subsets provides additional protection. IL-10-producing regulatory B cells may represent such a protective B cell subset.
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Affiliation(s)
- Martin Karl
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Solveig Hasselwander
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Yawen Zhou
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Gisela Reifenberg
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
| | - Kyoung-Sook Park
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
| | - Dirk A Ridder
- Institute of PathologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Xiaoyu Wang
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
- Department of Basic MedicineShenyang Medical CollegeShenyangChina
| | - Eric Seidel
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Nadine Hövelmeyer
- Institute for Molecular Medicine and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
| | - Beate K Straub
- Institute of PathologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Huige Li
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for ImmunotherapyJohannes Gutenberg University Medical CenterMainzGermany
- Division of GastroenterologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMassachusettsUSA
| | - Ning Xia
- Department of PharmacologyJohannes Gutenberg University Medical CenterMainzGermany
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27
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Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37. Nat Commun 2022; 13:5371. [PMID: 36100608 PMCID: PMC9470561 DOI: 10.1038/s41467-022-33138-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/30/2022] [Indexed: 11/09/2022] Open
Abstract
The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma. Tetraspanin CD37 deficiency has been reported as a prognostic marker for aggressive B-cell lymphoma. Here, the authors show that CD37 interacts with the fatty acid transporter 1 to inhibit palmitate uptake and its deficiency leads to increased fatty acid metabolism which promotes tumorigenesis in B-cell lymphoma.
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28
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Lockridge A, Hanover JA. A nexus of lipid and O-Glcnac metabolism in physiology and disease. Front Endocrinol (Lausanne) 2022; 13:943576. [PMID: 36111295 PMCID: PMC9468787 DOI: 10.3389/fendo.2022.943576] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Although traditionally considered a glucose metabolism-associated modification, the O-linked β-N-Acetylglucosamine (O-GlcNAc) regulatory system interacts extensively with lipids and is required to maintain lipid homeostasis. The enzymes of O-GlcNAc cycling have molecular properties consistent with those expected of broad-spectrum environmental sensors. By direct protein-protein interactions and catalytic modification, O-GlcNAc cycling enzymes may provide both acute and long-term adaptation to stress and other environmental stimuli such as nutrient availability. Depending on the cell type, hyperlipidemia potentiates or depresses O-GlcNAc levels, sometimes biphasically, through a diversity of unique mechanisms that target UDP-GlcNAc synthesis and the availability, activity and substrate selectivity of the glycosylation enzymes, O-GlcNAc Transferase (OGT) and O-GlcNAcase (OGA). At the same time, OGT activity in multiple tissues has been implicated in the homeostatic regulation of systemic lipid uptake, storage and release. Hyperlipidemic patterns of O-GlcNAcylation in these cells are consistent with both transient physiological adaptation and feedback uninhibited obesogenic and metabolic dysregulation. In this review, we summarize the numerous interconnections between lipid and O-GlcNAc metabolism. These links provide insights into how the O-GlcNAc regulatory system may contribute to lipid-associated diseases including obesity and metabolic syndrome.
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Affiliation(s)
- Amber Lockridge
- Laboratory of Cell and Molecular Biology, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - John A. Hanover
- Laboratory of Cell and Molecular Biology, National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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29
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Li H, Herrmann T, Seeßle J, Liebisch G, Merle U, Stremmel W, Chamulitrat W. Role of fatty acid transport protein 4 in metabolic tissues: insights into obesity and fatty liver disease. Biosci Rep 2022; 42:BSR20211854. [PMID: 35583196 PMCID: PMC9160530 DOI: 10.1042/bsr20211854] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 11/28/2022] Open
Abstract
Fatty acid (FA) metabolism is a series of processes that provide structural substances, signalling molecules and energy. Ample evidence has shown that FA uptake is mediated by plasma membrane transporters including FA transport proteins (FATPs), caveolin-1, fatty-acid translocase (FAT)/CD36, and fatty-acid binding proteins. Unlike other FA transporters, the functions of FATPs have been controversial because they contain both motifs of FA transport and fatty acyl-CoA synthetase (ACS). The widely distributed FATP4 is not a direct FA transporter but plays a predominant function as an ACS. FATP4 deficiency causes ichthyosis premature syndrome in mice and humans associated with suppression of polar lipids but an increase in neutral lipids including triglycerides (TGs). Such a shift has been extensively characterized in enterocyte-, hepatocyte-, and adipocyte-specific Fatp4-deficient mice. The mutants under obese and non-obese fatty livers induced by different diets persistently show an increase in blood non-esterified free fatty acids and glycerol indicating the lipolysis of TGs. This review also focuses on FATP4 role on regulatory networks and factors that modulate FATP4 expression in metabolic tissues including intestine, liver, muscle, and adipose tissues. Metabolic disorders especially regarding blood lipids by FATP4 deficiency in different cell types are herein discussed. Our results may be applicable to not only patients with FATP4 mutations but also represent a model of dysregulated lipid homeostasis, thus providing mechanistic insights into obesity and development of fatty liver disease.
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Affiliation(s)
- Huili Li
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Thomas Herrmann
- Westkuesten Hospital, Esmarchstraße 50, 25746 Heide, Germany
| | - Jessica Seeßle
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
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30
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Prodanović R, Kirovski D, Vujanac I, Djordjevic A, Romić S, Pantelić M, Korićanac G. Obesity-related prepartal insulin resistance in dairy cows is associated with increased lipin 1 and decreased FATP 1 expression in skeletal muscle. Res Vet Sci 2022; 150:189-194. [DOI: 10.1016/j.rvsc.2022.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 04/10/2022] [Accepted: 04/16/2022] [Indexed: 11/26/2022]
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31
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Hu Q, Wang D, Lin H, Li H, Zhao J, Jiao H, Wang X. Adiponectin Reduces Lipid Content in Chicken Myoblasts by Activating AMPK Signaling Pathway. Biosci Rep 2022; 42:BSR20212549. [PMID: 35603780 PMCID: PMC9171728 DOI: 10.1042/bsr20212549] [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: 11/05/2021] [Revised: 05/03/2022] [Accepted: 05/20/2022] [Indexed: 12/03/2022] Open
Abstract
Studies in mammals have shown that adiponectin is secreted mainly by adipocytes, and it plays a crucial role in glucose and lipid metabolism in muscles. Clarifying the crosstalk role of adiponectin between adipose tissue and skeletal muscle tissue is very important for internal homeostasis. The glucose and lipid metabolism of chicken is different from that of mammals, and the role of adiponectin in chickens is unclear. Therefore, it is of great significance to study the effect and mechanism of adiponectin on lipid metabolism in chickens. In this study, the regulating effect of adiponectin on lipid metabolism in chicken myoblasts was explored by adding a certain concentration of exogenous recombinant adiponectin. Results showed that adiponectin reduced intracellular lipid content, increasing the mRNA expression of adiponectin receptor and cellular uptake of glucose and fatty acids. In addition, adiponectin activated the 5' adenosine monophosphate activated protein kinase (AMPK) signaling pathway. The above results suggested that adiponectin reduced intracellular lipid content, mainly by binding to adiponectin receptor, activating AMPK pathway, increasing cellular uptake of glucose and fatty acids, and promoting lipid oxidation.
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Affiliation(s)
- Qingmei Hu
- Faculty of Animal Science and Technology, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
| | - Dan Wang
- Faculty of Animal Science and Technology, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
| | - Hai Lin
- Faculty of Animal Science and Technology, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
| | - Haifang Li
- Faculty of Life Sciences, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
| | - Jingpeng Zhao
- Faculty of Animal Science and Technology, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
| | - Hongchao Jiao
- Faculty of Animal Science and Technology, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
| | - Xiaojuan Wang
- Faculty of Animal Science and Technology, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong, P. R. China
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32
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Xu W, Hou L, Li P, Li L. Effect of nicotinamide N-methyltransferase on lipid accumulation in 3T3-L1 adipocytes. Bioengineered 2022; 13:12421-12434. [PMID: 35603729 PMCID: PMC9276046 DOI: 10.1080/21655979.2022.2074768] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Nicotinamide N-methyltransferase (NNMT) is a methylase, and its expression is positively correlated with obesity and insulin resistance. This study aims to detect the effects of NNMT on lipid accumulation, triglyceride content, adipocyte differentiation-related transcription factors, genes related to lipid metabolism, adipokine expression, and autophagy in adipocytes. Lentivirus vectors and eukaryotic expression plasmids were used to interfere with NNMT expression. The Oil Red O method was used to detect lipid accumulation, and colorimetry was used to detect triglyceride levels. The transcription of adipocyte differentiation-related transcription factors (PPARγ, C/EBPα, and SREBP1), lipid metabolism-related genes (FABP4, FAS, FATP1 [SLC27A1], and LPL), adipokines (ADIPOQ and LEP) and autophagy-related genes (Beclin1, ATG7, ATG12, and ATG14) was detected by quantitative real-time polymerase chain reaction (RT-qPCR), and the protein expressions of PPARγ, ADIPOQ, LC3I, LC3II, Beclin1, and P62 were detected by western blot analysis. Compared with the control group, the knockdown of NNMT expression reduced lipid accumulation and triglyceride content in 3T3-L1 cells. The transcription of PPARγ, C/EBPα, SREBP1, FABP4, FASN, FATP1, LPL, Beclin1, ATG7, ATG12, and ATG14 decreased, while ADIPOQ and LEP transcription increased. The expression of PPARγ, LC3I/II, and Beclin1 proteins also decreased, while ADIPOQ and P62 protein expression increased. The over-expression NNMT group showed experimental results opposite to those described above. Interference with the expression of NNMT affects lipid accumulation, triglyceride content after cell differentiation, adipocyte differentiation-related transcription factors, genes related to lipid metabolism, the expression of adipokines, and autophagy in adipocytes.
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Affiliation(s)
- Wanfeng Xu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ling Hou
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ping Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ling Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
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Wołosowicz M, Dajnowicz-Brzezik P, Łukaszuk B, Żebrowska E, Maciejczyk M, Zalewska A, Kasacka I, Chabowski A. Diverse impact of N-acetylcysteine or alpha-lipoic acid supplementation during high-fat diet regime on fatty acid transporters in visceral and subcutaneous adipose tissue. Adv Med Sci 2022; 67:216-228. [PMID: 35594763 DOI: 10.1016/j.advms.2022.05.001] [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: 12/14/2021] [Revised: 03/16/2022] [Accepted: 05/08/2022] [Indexed: 11/20/2022]
Abstract
PURPOSE Adipose tissue's (AT) structural changes accompanying obesity may alter lipid transport protein expression and, thus, the fatty acids (FAs) transport and lipid balance of the body. Metabolic abnormalities within AT contribute to the elevated production of reactive oxygen species and increased oxidative/nitrosative stress. Although compounds such as N-acetylcysteine (NAC) and α-lipoic acid (ALA), which restore redox homeostasis, may improve lipid metabolism in AT, the mechanism of action of these antioxidants on lipid metabolism in AT is still unknown. This study aimed to examine the impact of NAC and ALA on the level and FA composition of the lipid fractions, and the expression of FA transporters in the visceral and subcutaneous AT of high-fat diet-fed rats. MATERIALS AND METHODS Male Wistar rats were randomly divided into four groups. The mRNA levels and protein expression of FA transporters were assessed using real-time PCR and Western Blot analyses. The collected samples were subjected to histological evaluation. The level of lipids (FFA, DAG, and TAG) was measured using gas-liquid chromatography. RESULTS We found that antioxidants affect FA transporter expressions at both the transcript and protein levels, and, therefore, they promote changes in AT's lipid pools. One of the most remarkable findings of our research is that different antioxidant molecules may have a varying impact on AT phenotype. CONCLUSION NAC and ALA exert different influences on AT, which is reflected in histopathological images, FA transport proteins expression patterns, or even the lipid storage capacity of adipocytes.
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Affiliation(s)
- Marta Wołosowicz
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland.
| | | | - Bartłomiej Łukaszuk
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Ewa Żebrowska
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Bialystok, Poland
| | - Anna Zalewska
- Experimental Dentistry Laboratory, Medical University of Bialystok, Bialystok, Poland
| | - Irena Kasacka
- Department of Histology and Cytophysiology, Medical University of Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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Honecker J, Ruschke S, Seeliger C, Laber S, Strobel S, Pröll P, Nellaker C, Lindgren CM, Kulozik U, Ecker J, Karampinos DC, Claussnitzer M, Hauner H. Transcriptome and fatty-acid signatures of adipocyte hypertrophy and its non-invasive MR-based characterization in human adipose tissue. EBioMedicine 2022; 79:104020. [PMID: 35490555 PMCID: PMC9062743 DOI: 10.1016/j.ebiom.2022.104020] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/07/2022] [Accepted: 04/07/2022] [Indexed: 12/13/2022] Open
Abstract
Background The adipocyte-hypertrophy associated remodeling of fat cell function is considered causal for the development of metabolic disorders. A better understanding of transcriptome and fatty acid (FA) related alterations with adipocyte hypertrophy combined with less-invasive strategies for the detection of the latter can help to increase the prognostic and diagnostic value of adipocyte size and FA composition as markers for metabolic disease. Methods To clarify adipocyte-hypertrophy associated transcriptomic alterations, fat cell size was related to RNA-Seq data from white adipose tissue and size-separated adipocytes. The relationship between adipocyte size and adipose tissue FA composition as measured by GC-MS was investigated. MR spectroscopy (MRS) methods for clinical scanning were developed to characterize adipocyte size and FA composition in a fast and non-invasive manner. Findings With enlarged adipocyte size, substantial transcriptomic alterations of genes involved in mitochondrial function and FA metabolism were observed. Investigations of these two mechanisms revealed a reciprocal relationship between adipocyte size and estimated thermogenic adipocyte content as well as depot-specific correlations of adipocyte size and FA composition. MRS on a clinical scanner was suitable for the in-parallel assessment of adipose morphology and FA composition. Interpretation The current study provides a comprehensive overview of the adipocyte-hypertrophy associated transcriptomic and FA landscape in both subcutaneous and visceral adipose tissue. MRS represents a promising technique to translate the observed mechanistic, structural and functional changes in WAT with adipocyte hypertrophy into a clinical context for an improved phenotyping of WAT in the context of metabolic diseases. Funding Competence network for obesity (FKZ 42201GI1128), ERC (No 677661, ProFatMRI; No 875488, FatVirtualBiopsy), Else Kröner-Fresenius-Foundation.
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Serine Palmitoyltransferase Gene Silencing Prevents Ceramide Accumulation and Insulin Resistance in Muscles in Mice Fed a High-Fat Diet. Cells 2022; 11:cells11071123. [PMID: 35406688 PMCID: PMC8997855 DOI: 10.3390/cells11071123] [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: 02/23/2022] [Revised: 03/15/2022] [Accepted: 03/24/2022] [Indexed: 02/04/2023] Open
Abstract
Skeletal muscles account for ~80% of insulin-stimulated glucose uptake and play a key role in lipid metabolism. Consumption of a high-fat diet (HFD) contributes to metabolic changes in muscles, including the development of insulin resistance. The studies carried out to date indicate that the accumulation of biologically active lipids, such as long-chain acyl-CoA, diacylglycerols and ceramides, play an important role in the development of insulin resistance in skeletal muscles. Unfortunately, it has not yet been clarified which of these lipid groups plays the dominant role in inducing these disorders. In order to explore this topic further, we locally silenced the gene encoding serine palmitoyltransferase (SPT) in the gastrocnemius muscle of animals with HFD-induced insulin resistance. This enzyme is primarily responsible for the first step of de novo ceramide biosynthesis. The obtained results confirm that the HFD induces the development of whole-body insulin resistance, which results in inhibition of the insulin pathway. This is associated with an increased level of biologically active lipids in the muscles. Our results also demonstrate that silencing the SPT gene with the shRNA plasmid reduces the accumulation of ceramides in gastrocnemius muscle, which, in turn, boosts the activity of the insulin signaling pathway. Furthermore, inhibition of ceramide synthesis does not significantly affect the content of other lipids, which suggests the leading role of ceramide in the lipid-related induction of skeletal muscle insulin resistance.
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Palmer EA, Vedovatto M, Oliveira RA, Ranches J, Vendramini JMB, Poore MH, Martins T, Binelli M, Arthington JD, Moriel P. Effects of maternal winter vs. year-round supplementation of protein and energy on postnatal growth, immune function, and carcass characteristics of Bos indicus-influenced beef offspring. J Anim Sci 2022; 100:6539999. [PMID: 35230426 PMCID: PMC8886918 DOI: 10.1093/jas/skac003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/05/2022] [Indexed: 12/24/2022] Open
Abstract
This 2-yr study evaluated the effects of winter vs. year-round supplementation of Bos indicus-influenced beef cows on cow reproductive performance and impact on their offspring. On day 0 of each year (approximately day 122 ± 23 of gestation), 82 to 84 mature Brangus cows/yr were stratified by body weight (BW; 475 ± 67 kg) and body condition score (BCS; 4.85 ± 0.73) and randomly assigned to 1 of 6 bahiagrass (Paspalum notatum) pastures (13 to 14 cows/pasture). Treatments were randomly assigned to pastures consisting of winter supplementation with molasses + urea (WMOL), or year-round supplementation with molasses + urea (YMOL) or wheat middling-based range cubes (YCUB). Total yearly supplement DM amount was 272 kg/cow and supplements were formulated to be isocaloric and isonitrogenous (75% TDN and 20% CP). On day 421 (weaning; approximately 260 ± 24 d of age), 33 to 35 steers/yr were vaccinated against parainfluenza-3 (PI3) and bovine viral diarrhea virus type 1 (BVDV-1) and transported 1,193 km to a feedlot. Steers were penned according to maternal pasture and managed similarly until slaughter. Data were analyzed using the MIXED and GLIMMIX procedures of SAS. On day 217 (start of breeding season), BCS was greater (P = 0.01) for YMOL than WMOL cows, whereas BCS of YCUB did not differ (P ≥ 0.11) to both WMOL and YMOL cows. The percentage of cows that calved, calving date, birth BW, and preweaning BW of the first offspring did not differ (P ≥ 0.22) among maternal treatments. Plasma cortisol concentrations were greater (P ≤ 0.001) for YCUB steers at feedlot arrival (day 422) than WMOL and YMOL steers. Moreover, YCUB steers had greater (P = 0.02) and tended (P = 0.08) to have greater plasma concentrations of haptoglobin compared to WMOL and YMOL steers, respectively. Antibody titers against PI3 and BVDV-1 viruses did not differ (P ≥ 0.25) among maternal treatments. Steer BW at feedlot exit was greater (P ≤ 0.05) for YMOL and WMOL than YCUB steers. However, feedlot DMI did not differ (P ≥ 0.37) by maternal treatment. Hot carcass weight, yield grade, LMA, and marbling did not differ (P ≥ 0.14) among maternal treatments. Percentage of steers that graded low choice was enhanced (P ≤ 0.05) for WMOL and YCUB than YMOL steers. Maternal year-round supplementation of range cubes or molasses + urea either did not impact or decrease growth, immune function, and carcass characteristics of the offspring when compared with maternal supplementation of molasses + urea during winter only.
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Affiliation(s)
- Elizabeth A Palmer
- IFAS – Range Cattle Research and Education Center, University of Florida, Ona, FL 33865, USA
| | - Marcelo Vedovatto
- Unidade Universitária de Aquidauana, Universidade Estadual de Mato Grosso do Sul, Aquidauana, MS, Brazil
| | - Rhaiza A Oliveira
- IFAS – Range Cattle Research and Education Center, University of Florida, Ona, FL 33865, USA
| | - Juliana Ranches
- Eastern Oregon Agricultural Research Center, Oregon State University, Burns, OR 97720, USA
| | - Joao M B Vendramini
- IFAS – Range Cattle Research and Education Center, University of Florida, Ona, FL 33865, USA
| | - Matthew H Poore
- Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA
| | - Thiago Martins
- Department of Animal Science, University of Florida, Gainesville, FL 32605, USA
| | - Mario Binelli
- Department of Animal Science, University of Florida, Gainesville, FL 32605, USA
| | - John D Arthington
- Department of Animal Science, University of Florida, Gainesville, FL 32605, USA
| | - Philipe Moriel
- IFAS – Range Cattle Research and Education Center, University of Florida, Ona, FL 33865, USA,Corresponding author:
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Fatty acid transport protein 2 interacts with ceramide synthase 2 to promote ceramide synthesis. J Biol Chem 2022; 298:101735. [PMID: 35181339 PMCID: PMC8931434 DOI: 10.1016/j.jbc.2022.101735] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 01/15/2023] Open
Abstract
Dihydroceramide is a lipid molecule generated via the action of (dihydro)ceramide synthases (CerSs), which use two substrates, namely sphinganine and fatty acyl-CoAs. Sphinganine is generated via the sequential activity of two integral membrane proteins located in the endoplasmic reticulum. Less is known about the source of the fatty acyl-CoAs, although a number of cytosolic proteins in the pathways of acyl-CoA generation modulate ceramide synthesis via direct or indirect interaction with the CerSs. In this study, we demonstrate, by proteomic analysis of immunoprecipitated proteins, that fatty acid transporter protein 2 (FATP2) (also known as very long-chain acyl-CoA synthetase) directly interacts with CerS2 in mouse liver. Studies in cultured cells demonstrated that other members of the FATP family can also interact with CerS2, with the interaction dependent on both proteins being catalytically active. In addition, transfection of cells with FATP1, FATP2, or FATP4 increased ceramide levels although only FATP2 and 4 increased dihydroceramide levels, consistent with their known intracellular locations. Finally, we show that lipofermata, an FATP2 inhibitor which is believed to directly impact tumor cell growth via modulation of FATP2, decreased de novo dihydroceramide synthesis, suggesting that some of the proposed therapeutic effects of lipofermata may be mediated via (dihydro)ceramide rather than directly via acyl-CoA generation. In summary, our study reinforces the idea that manipulating the pathway of fatty acyl-CoA generation will impact a wide variety of down-stream lipids, not least the sphingolipids, which utilize two acyl-CoA moieties in the initial steps of their synthesis.
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Ali H, Morito K, Hasi RY, Aihara M, Hayashi J, Kawakami R, Kanemaru K, Tsuchiya K, Sango K, Tanaka T. Characterization of uptake and metabolism of very long-chain fatty acids in peroxisome-deficient CHO cells. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159088. [PMID: 34848380 DOI: 10.1016/j.bbalip.2021.159088] [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: 08/21/2021] [Revised: 10/29/2021] [Accepted: 11/21/2021] [Indexed: 11/24/2022]
Abstract
Fatty acids (FAs) longer than C20 are classified as very long-chain fatty acids (VLCFAs). Although biosynthesis and degradation of VLCFAs are important for the development and integrity of the myelin sheath, knowledge on the incorporation of extracellular VLCFAs into the cells is limited due to the experimental difficulty of solubilizing them. In this study, we found that a small amount of isopropanol solubilized VLCFAs in aqueous medium by facilitating the formation of the VLCFA/albumin complex. Using this solubilizing technique, we examined the role of the peroxisome in the uptake and metabolism of VLCFAs in Chinese hamster ovary (CHO) cells. When wild-type CHO cells were incubated with saturated VLCFAs (S-VLCFAs), such as C23:0 FA, C24:0 FA, and C26:0 FA, extensive uptake was observed. Most of the incorporated S-VLCFAs were oxidatively degraded without acylation into cellular lipids. In contrast, in peroxisome-deficient CHO cells uptake of S-VLCFAs was marginal and oxidative metabolism was not observed. Extensive uptake and acylation of monounsaturated (MU)-VLCFAs, such as C24:1 FA and C22:1 FA, were observed in both types of CHO cells. However, oxidative metabolism was evident only in wild-type cells. Similar manners of uptake and metabolism of S-VLCFAs and MU-VLCFAs were observed in IFRS1, a Schwan cell-derived cell line. These results indicate that peroxisome-deficient cells limit intracellular S-VLCFAs at a low level by halting uptake, and as a result, peroxisome-deficient cells almost completely lose the clearance ability of S-VLCFAs accumulated outside of the cells.
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Affiliation(s)
- Hanif Ali
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Katsuya Morito
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Rumana Yesmin Hasi
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan
| | - Mutsumi Aihara
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan
| | - Junji Hayashi
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan
| | - Ryushi Kawakami
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan
| | - Kaori Kanemaru
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan
| | - Koichiro Tsuchiya
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
| | - Kazunori Sango
- Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan
| | - Tamotsu Tanaka
- Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan.
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Kent NL, Atluri SC, Cuffe JSM. Maternal Hypothyroidism in Rats Reduces Placental Lactogen, Lowers Insulin Levels, and Causes Glucose Intolerance. Endocrinology 2022; 163:6429715. [PMID: 34791119 DOI: 10.1210/endocr/bqab231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Indexed: 11/19/2022]
Abstract
Hypothyroidism increases the incidence of gestational diabetes mellitus (GDM) but the mechanisms responsible are unknown. This study aimed to assess the pathophysiological mechanisms by which hypothyroidism leads to glucose intolerance in pregnancy. Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from 1 week before pregnancy and throughout gestation. A nonpregnant cohort received the same dose for the same duration but were not mated. On gestational day 16 (GD16), or nonpregnant day 16 (NP16), animals were subjected to an intraperitoneal glucose tolerance test. Tissues and blood samples were collected 4 days later. Hypothyroidism induced a diabetic-like phenotype by GD16 in pregnant females only. Pregnant MOD and SEV females had reduced fasting plasma insulin, less insulin following a glucose load, and altered expression of genes involved in insulin signaling within skeletal muscle and adipose tissue. Hypothyroidism reduced rat placental lactogen concentrations, which was accompanied by reduced percentage β-cell cross-sectional area (CSA) relative to total pancreas CSA, and a reduced number of large β-cell clusters in the SEV hypothyroid group. Plasma triglycerides and free fatty acids were reduced by hypothyroidism in pregnant rats, as was the expression of genes that regulate lipid homeostasis. Hypothyroidism in pregnant rats results in a diabetic-like phenotype that is likely mediated by impaired β-cell expansion in pregnancy. This pregnancy-specific phenomenon is likely due to reduced placental lactogen secretion.
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Affiliation(s)
- Nykola Louise Kent
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Sharat Chandra Atluri
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
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Alleviative effects of total flavones of Glycyrrhiza uralensis Fisch on oxidative stress and lipid metabolism disorder induced by high-fat diet in intestines of Tilapia ( Oreochromis niloticus). 3 Biotech 2021; 11:348. [PMID: 34221818 DOI: 10.1007/s13205-021-02785-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/08/2021] [Indexed: 01/30/2023] Open
Abstract
Total flavones of Glycyrrhiza uralensis Fisch (GTF) are main components of Glycyrrhiza uralensis Fisch, which have anti-oxidation and lipid-lowering effects. However, its protective effects on the intestinal tissue of tilapia (Oreochromis niloticus) are unknown. The aims of the study were to evaluate the protective effects of GTF on the intestinal tissue of tilapia after high-fat diet (HFD) feeding. Tilapia (initial weight 30 ± 1 g) received diets containing four doses of GTF (0.05, 0.1, 0.5, and 1.0 g/kg diet) for 90 days. The intestinal tissues were collected to determine biochemical parameter, gene expression and protein level. The results showed that the HFD reduced antioxidant indexes and increased the fat level, lipid oxidation products in the intestinal tissue relative to the control. Adding GTF to the HFD resulted in an increase of antioxidant indexes, fat level and lipid oxidation products decreased after 60, 90 days. In the HFD group, mRNA level of fatty acid transport protein 1 (FATP1) was increased at 60 day and then decreased at 90 day. The mRNA levels of fatty acid binding protein 1 (FABP1) and sterol regulatory element binding protein 1c (SREBP 1c) were significantly increased at 60 or 90 day after HFD feeding. The mRNA levels of acetate coenzyme A carboxylase (ACCA) peroxisome proliferator-activated receptor γ (PPAR-γ) and PPAR-α were decreased significantly at 30, 60 and/or 90 days after HFD feeding. Western blotting results also showed that nuclear factor (NF)-κβ C-Rel (NF-κβ C-Rel) and mitogen-activated protein kinase 8 (MAPK8) protein expression in intestinal tissue increased after consumption of the HFD. However, adding GTF to the HFD reversed the changes of genes related to fatty acid synthesis and metabolism, and the level of NF-κβ c-Rel and MAPK8 at different degrees. Overall, these results indicated that GTF promoted decomposition and metabolism of fatty acids in intestinal tissue, alleviated oxidative stress damage caused by the HFD, and had certain protective effects on the intestinal tissue of tilapia.
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Hipólito A, Martins F, Mendes C, Lopes-Coelho F, Serpa J. Molecular and Metabolic Reprogramming: Pulling the Strings Toward Tumor Metastasis. Front Oncol 2021; 11:656851. [PMID: 34150624 PMCID: PMC8209414 DOI: 10.3389/fonc.2021.656851] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
Metastasis is a major hurdle to the efficient treatment of cancer, accounting for the great majority of cancer-related deaths. Although several studies have disclosed the detailed mechanisms underlying primary tumor formation, the emergence of metastatic disease remains poorly understood. This multistep process encompasses the dissemination of cancer cells to distant organs, followed by their adaptation to foreign microenvironments and establishment in secondary tumors. During the last decades, it was discovered that these events may be favored by particular metabolic patterns, which are dependent on reprogrammed signaling pathways in cancer cells while they acquire metastatic traits. In this review, we present current knowledge of molecular mechanisms that coordinate the crosstalk between metastatic signaling and cellular metabolism. The recent findings involving the contribution of crucial metabolic pathways involved in the bioenergetics and biosynthesis control in metastatic cells are summarized. Finally, we highlight new promising metabolism-based therapeutic strategies as a putative way of impairing metastasis.
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Affiliation(s)
- Ana Hipólito
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School
- Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
| | - Filipa Martins
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School
- Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
| | - Cindy Mendes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School
- Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
| | - Filipa Lopes-Coelho
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School
- Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
| | - Jacinta Serpa
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School
- Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal.,Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), Lisboa, Portugal
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Oviedo-Ojeda MF, Roque-Jiménez JA, Whalin M, Lee-Rangel HA, Relling AE. Effect of supplementation with different fatty acid profile to the dam in early gestation and to the offspring on the finishing diet on offspring growth and hypothalamus mRNA expression in sheep. J Anim Sci 2021; 99:6153448. [PMID: 33640974 DOI: 10.1093/jas/skab064] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/24/2021] [Indexed: 12/12/2022] Open
Abstract
Supplementation with omega-3 and omega-9 fatty acids (FA) during late gestation regulates offspring development; however, their effect in the first third of gestation is unknown in sheep. The objective of this experiment was to evaluate the effects of the maternal supplementation with an enriched source of monounsaturated FA (MUFA) or an enriched source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during the first third of gestation on productive performance on ewes and offspring, and hypothalamic neuropeptides on offspring. Seventy-nine post-weaning lambs, born of sheep supplemented in the first third of gestation with 1.61% Ca salts rich with MUFA or EPA+DHA (dam supplementation, DS), were distributed in a 2×2 factorial arrangement of treatments to finishing diets containing 1.48% of Ca salts of MUFA or EPA+DHA (lamb supplementation, LS). The finishing period of the offspring lasted for 56 d. During the finishing period dry matter intake (DMI, daily) and body weight (BW) were recorded. Plasma was collected for metabolites analysis. Twenty-four lambs were slaughtered, and hypothalamus was collected for mRNA expression of hormone receptors, neuropeptides, and lipid transport genes. The data were analyzed with a mixed model in SAS (9.4) using repeated measurements, when needed. There was a DS×LS interaction for BW (P = 0.10) where LS with EPA+DHA born from DS with MUFA were heavier than the other 3 treatments. Lambs born from DS with MUFA have a greater DMI (P < 0.01) than the offspring born from DS with EPA+DHA. Lambs born from MUFA supplemented dams had a greater (P ≤ 0.05) hypothalamus mRNA expression for cocaine and amphetamine regulated transcript, growth hormone receptor, metastasis suppressor 1, leptin receptor, pro-opiomelanocortin, and Neuropeptide Y. These results indicate that growth depends not on the type of FA during the finishing phase but the interaction of different sources of FA ad different stages. Also, supplementation with FA during early pregnancy changes productive performance and neuropeptides' mRNA expression of lambs independently of the finishing diet.
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Affiliation(s)
- Mario Francisco Oviedo-Ojeda
- Department of Animal Sciences, The Ohio State University, Ohio Agricultural Research and Development Center (OARDC), Wooster, OH 44691, USA.,Universidad Autónoma de San Luis Potosí, Facultad de Agronomía y Veterinaria, San Luis Potosí 78175, México
| | - José Alejandro Roque-Jiménez
- Department of Animal Sciences, The Ohio State University, Ohio Agricultural Research and Development Center (OARDC), Wooster, OH 44691, USA.,Universidad Autónoma de San Luis Potosí, Facultad de Agronomía y Veterinaria, San Luis Potosí 78175, México
| | - Megan Whalin
- Department of Animal Sciences, The Ohio State University, Ohio Agricultural Research and Development Center (OARDC), Wooster, OH 44691, USA
| | - Héctor Aarón Lee-Rangel
- Universidad Autónoma de San Luis Potosí, Facultad de Agronomía y Veterinaria, San Luis Potosí 78175, México
| | - Alejandro Enrique Relling
- Department of Animal Sciences, The Ohio State University, Ohio Agricultural Research and Development Center (OARDC), Wooster, OH 44691, USA
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Jang Y, Park YK, Lee JE, Wan D, Tran N, Gavrilova O, Ge K. MED1 is a lipogenesis coactivator required for postnatal adipose expansion. Genes Dev 2021; 35:713-728. [PMID: 33888555 PMCID: PMC8091974 DOI: 10.1101/gad.347583.120] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/16/2021] [Indexed: 12/28/2022]
Abstract
In this study, Jang et al. investigated the role of MED1 in adipose development and expansion in vivo, and they show that MED1 is not generally required for transcription during adipogenesisin culture and that MED1 is dispensable for adipose development in mice. Instead, MED1 is required for postnatal adipose expansion and the induction of fatty acid and triglyceride synthesis genes after pups switch diet from high-fat maternal milk to carbohydrate-based chow. Their findings identify a cell- and gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion. MED1 often serves as a surrogate of the general transcription coactivator complex Mediator for identifying active enhancers. MED1 is required for phenotypic conversion of fibroblasts to adipocytes in vitro, but its role in adipose development and expansion in vivo has not been reported. Here, we show that MED1 is not generally required for transcription during adipogenesis in culture and that MED1 is dispensable for adipose development in mice. Instead, MED1 is required for postnatal adipose expansion and the induction of fatty acid and triglyceride synthesis genes after pups switch diet from high-fat maternal milk to carbohydrate-based chow. During adipogenesis, MED1 is dispensable for induction of lineage-determining transcription factors (TFs) PPARγ and C/EBPα but is required for lipid accumulation in the late phase of differentiation. Mechanistically, MED1 controls the induction of lipogenesis genes by facilitating lipogenic TF ChREBP- and SREBP1a-dependent recruitment of Mediator to active enhancers. Together, our findings identify a cell- and gene-specific regulatory role of MED1 as a lipogenesis coactivator required for postnatal adipose expansion.
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Affiliation(s)
- Younghoon Jang
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.,Department of Biology and Chemistry, Changwon National University, Changwon 51140, Korea
| | - Young-Kwon Park
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Ji-Eun Lee
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Danyang Wan
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Nhien Tran
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Oksana Gavrilova
- Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Kai Ge
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
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André S, Pinto AE, Silva GL, Silva F, Serpa J, Félix A. Male Breast Cancer-Immunohistochemical Patterns and Clinical Relevance of FASN, ATF3, and Collagen IV. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2021; 15:11782234211002496. [PMID: 33888988 PMCID: PMC8040573 DOI: 10.1177/11782234211002496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/24/2021] [Indexed: 11/16/2022]
Abstract
Background Male breast carcinoma (male BC) is an uncommon neoplasia without individualized strategies for diagnosis and therapeutics. Low overall survival (OS) rates have been reported, mostly associated with patients' advanced stage and older age. Intratumoral heterogeneity versus homogeneity of malignant epithelial cells seems to be an important factor to consider for the development of combination therapies with curative intention. Objective In this preliminary study, we aim to provide valuable insight into the distinct clinicopathologic features of male BC. Material and methods In a series of 40 male BC patients, we evaluated by immunohistochemistry androgen receptor; activating transcription factor 3 (ATF3); p16; cyclin D1; fatty acid synthase (FASN); fatty acid transport protein 1 (FATP1); β1, β3, β4, and β6 integrins; collagen I and collagen IV; and their interactions. Kaplan-Meier survival curves and log-rank tests were assessed for statistical analysis. Results Homogeneous epithelial staining of p16, ATF3, β6 integrin, FASN, and FATP1 was found to be significantly intercorrelated, and associated with high Ki67. These markers also stained tumor stromal fibroblasts. The prognostic analysis showed statistically significant associations of FASN with disease-free survival (DFS) and OS, as well as of ATF3 with OS and collagen IV with DFS. Conclusions This study highlights, as a novel finding, the relevance of FASN, ATF3, and collagen IV immunophenotypes, which may have innovative application in the clinical management of male BC.
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Affiliation(s)
- Saudade André
- Department of Pathology, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal
| | - António E Pinto
- Department of Pathology, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal
| | - Giovani L Silva
- Department of Mathematics of Higher Technical Institute (Instituto Superior Técnico), Faculty of Sciences (Faculdade de Ciências), University of Lisbon, Lisbon, Portugal.,Statistics and Applications Center of University of Lisbon (CEAUL), Lisbon, Portugal
| | - Fernanda Silva
- CEDOC, NOVA Medical School, NOVA University, Lisbon, Portugal
| | - Jacinta Serpa
- CEDOC, NOVA Medical School, NOVA University, Lisbon, Portugal
| | - Ana Félix
- Department of Pathology, Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal.,CEDOC, NOVA Medical School, NOVA University, Lisbon, Portugal
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Abstract
As the principal tissue for insulin-stimulated glucose disposal, skeletal muscle is a primary driver of whole-body glycemic control. Skeletal muscle also uniquely responds to muscle contraction or exercise with increased sensitivity to subsequent insulin stimulation. Insulin's dominating control of glucose metabolism is orchestrated by complex and highly regulated signaling cascades that elicit diverse and unique effects on skeletal muscle. We discuss the discoveries that have led to our current understanding of how insulin promotes glucose uptake in muscle. We also touch upon insulin access to muscle, and insulin signaling toward glycogen, lipid, and protein metabolism. We draw from human and rodent studies in vivo, isolated muscle preparations, and muscle cell cultures to home in on the molecular, biophysical, and structural elements mediating these responses. Finally, we offer some perspective on molecular defects that potentially underlie the failure of muscle to take up glucose efficiently during obesity and type 2 diabetes.
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Zhang L, Xiu X, Wang Z, Jiang Y, Fan H, Su J, Sui S, Wang S, Wang R, Li J, Wang J, Li N, Wang J. Increasing Long-Chain Dicarboxylic Acid Production in Candida tropicalis by Engineering Fatty Transporters. Mol Biotechnol 2021; 63:544-555. [PMID: 33786739 DOI: 10.1007/s12033-021-00319-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/20/2021] [Indexed: 01/03/2023]
Abstract
Candida tropicalis can metabolize alkanes or fatty acids to produce long-chain dicarboxylic acids (DCAs). Fatty acid transporters located on the cell or peroxisome membrane may play an important role in this process. Using amino acid sequence homologous alignment, two putative proteins, CtFat1p and CtPxa1p, located on the cell and peroxisome membrane were found, respectively. Moreover, single- and double-knockout homologous recombination technology was used to study ctfat1p and ctpxa1p gene effects on DCA synthesis. In comparison to the wild-type strain, long-chain DCA yield decreased by 65.14%, 88.38% and 56.19% after single and double-copy knockout of ctfat1p genes and double-copy knockout of ctpxa1p genes, respectively, indicating that the knockout of ctfat1p and ctpxa1p genes had a significant effect on the conversion of oils and fats into long-chain DCAs by C. tropicalis. However, the yield of long-chain DCAs increased by 21.90% after single-knockout of the ctpxa1p gene, indicating that the single-knockout of the ctpxa1p gene may reduce fatty acid transport to peroxisome for further oxidation. Moreover, to improve the intracellular transport rate of fatty acids, ctfat1p copy number increased, increasing DCA yield by 30.10%. These results may provide useful information for enhancing the production of long-chain DCAs by C. tropicalis.
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Affiliation(s)
- Lihua Zhang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China
| | - Xiang Xiu
- School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu, 214122, People's Republic of China
| | - Zirui Wang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China
| | - Yanjun Jiang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China
| | - Han Fan
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China
| | - Jing Su
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China
| | - Songsen Sui
- Zhucheng Dongxiao Biotechnology Co., Ltd, Xinxing Town, Zhucheng, Shandong, 262200, People's Republic of China
| | - Songjiang Wang
- Zhucheng Dongxiao Biotechnology Co., Ltd, Xinxing Town, Zhucheng, Shandong, 262200, People's Republic of China
| | - Ruiming Wang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China
| | - Junlin Li
- Zhucheng Dongxiao Biotechnology Co., Ltd, Xinxing Town, Zhucheng, Shandong, 262200, People's Republic of China
| | - Junqing Wang
- State Key Laboratory of Biobased Material and Green Papermaking (LBMP), Qilu University of Technology, Jinan, 250353, Shandong, People's Republic of China.
| | - Nan Li
- Collage of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, People's Republic of China.
| | - Jianbin Wang
- Zhucheng Dongxiao Biotechnology Co., Ltd, Xinxing Town, Zhucheng, Shandong, 262200, People's Republic of China
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Parikh HM, Elgzyri T, Alibegovic A, Hiscock N, Ekström O, Eriksson KF, Vaag A, Groop LC, Ström K, Hansson O. Relationship between insulin sensitivity and gene expression in human skeletal muscle. BMC Endocr Disord 2021; 21:32. [PMID: 33639916 PMCID: PMC7912896 DOI: 10.1186/s12902-021-00687-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 02/03/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood. METHODS To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g. PPARGC1A. CONCLUSIONS The muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g. SIRT2, and genes regulating autophagy and mTOR signaling, e.g. FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.
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Affiliation(s)
- Hemang M Parikh
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, 3650 Spectrum Blvd, Tampa, FL, 33612, USA.
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden.
| | - Targ Elgzyri
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden
| | | | - Natalie Hiscock
- Unilever Discover R & D, Colworth Science Park, Sharnbrook, Bedfordshire, MK44 1LQ, UK
| | - Ola Ekström
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden
| | - Karl-Fredrik Eriksson
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden
| | - Allan Vaag
- Steno Diabetes Center, DK-2820, Gentofte, Denmark
| | - Leif C Groop
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden
- Finnish Institute of Molecular Medicine, FI-00014, University of Helsinki, Helsinki, Finland
| | - Kristoffer Ström
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden
- Swedish Winter Sports Research Centre, Mid Sweden University, SE-83125, Östersund, Sweden
| | - Ola Hansson
- Department of Clinical Sciences, Diabetes & Endocrinology, Lund University, University Hospital Malmö, SE-20502, Malmö, Sweden
- Finnish Institute of Molecular Medicine, FI-00014, University of Helsinki, Helsinki, Finland
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Irvin MR, Aggarwal P, Claas SA, de las Fuentes L, Do AN, Gu CC, Matter A, Olson BS, Patki A, Schwander K, Smith JD, Srinivasasainagendra V, Tiwari HK, Turner AJ, Nickerson DA, Rao DC, Broeckel U, Arnett DK. Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP, TRAPPC11, and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population. Front Genet 2021; 12:588452. [PMID: 33679876 PMCID: PMC7933688 DOI: 10.3389/fgene.2021.588452] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 01/11/2021] [Indexed: 11/18/2022] Open
Abstract
Background: Indices of left ventricular (LV) structure and geometry represent useful intermediate phenotypes related to LV hypertrophy (LVH), a predictor of cardiovascular (CV) disease (CVD) outcomes. Methods and Results: We conducted an exome-wide association study of LV mass (LVM) adjusted to height2.7, LV internal diastolic dimension (LVIDD), and relative wall thickness (RWT) among 1,364 participants of African ancestry (AAs) in the Hypertension Genetic Epidemiology Network (HyperGEN). Both single-variant and gene-based sequence kernel association tests were performed to examine whether common and rare coding variants contribute to variation in echocardiographic traits in AAs. We then used a data-driven procedure to prioritize and select genes for functional validation using a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model. Three genes [myosin VIIA and Rab interacting protein (MYRIP), trafficking protein particle complex 11 (TRAPPC11), and solute carrier family 27 member 6 (SLC27A6)] were prioritized based on statistical significance, variant functional annotations, gene expression in the hiPSC-CM model, and prior biological evidence and were subsequently knocked down in the hiPSC-CM model. Expression profiling of hypertrophic gene markers in the knockdowns suggested a decrease in hypertrophic expression profiles. MYRIP knockdowns showed a significant decrease in atrial natriuretic factor (NPPA) and brain natriuretic peptide (NPPB) expression. Knockdowns of the heart long chain fatty acid (FA) transporter SLC27A6 resulted in downregulated caveolin 3 (CAV3) expression, which has been linked to hypertrophic phenotypes in animal models. Finally, TRAPPC11 knockdown was linked to deficient calcium handling. Conclusions: The three genes are biologically plausible candidates that provide new insight to hypertrophic pathways.
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Affiliation(s)
- Marguerite R. Irvin
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Praful Aggarwal
- Department of Pediatrics, Children’s Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Steven A. Claas
- College of Public Health, University of Kentucky, Lexington, KY, United States
| | - Lisa de las Fuentes
- Cardiovascular Division, Department of Medicine and Division of Biostatistics, Washington University, St. Louis, MO, United States
| | - Anh N. Do
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - C. Charles Gu
- Division of Biostatistics, Washington University, St. Louis, MO, United States
| | - Andrea Matter
- Department of Pediatrics, Children’s Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Benjamin S. Olson
- Department of Pediatrics, Children’s Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Amit Patki
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Karen Schwander
- Division of Biostatistics, Washington University, St. Louis, MO, United States
| | - Joshua D. Smith
- Department of Genome Sciences, University of Washington, Seattle, WA, United States
| | | | - Hemant K. Tiwari
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Amy J. Turner
- Department of Pediatrics, Children’s Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Deborah A. Nickerson
- Department of Genome Sciences, University of Washington, Seattle, WA, United States
| | - Dabeeru C. Rao
- Division of Biostatistics, Washington University, St. Louis, MO, United States
| | - Ulrich Broeckel
- Department of Pediatrics, Children’s Research Institute, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Donna K. Arnett
- College of Public Health, University of Kentucky, Lexington, KY, United States
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Rinaldi L, Pafundi PC, Galiero R, Caturano A, Morone MV, Silvestri C, Giordano M, Salvatore T, Sasso FC. Mechanisms of Non-Alcoholic Fatty Liver Disease in the Metabolic Syndrome. A Narrative Review. Antioxidants (Basel) 2021; 10:270. [PMID: 33578702 PMCID: PMC7916383 DOI: 10.3390/antiox10020270] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) are two different entities sharing common clinical and physio-pathological features, with insulin resistance (IR) as the most relevant. Large evidence leads to consider it as a risk factor for cardiovascular disease, regardless of age, sex, smoking habit, cholesterolemia, and other elements of MS. Therapeutic strategies remain still unclear, but lifestyle modifications (diet, physical exercise, and weight loss) determine an improvement in IR, MS, and both clinical and histologic liver picture. NAFLD and IR are bidirectionally correlated and, consequently, the development of pre-diabetes and diabetes is the most direct consequence at the extrahepatic level. In turn, type 2 diabetes is a well-known risk factor for multiorgan damage, including an involvement of cardiovascular system, kidney and peripheral nervous system. The increased MS incidence worldwide, above all due to changes in diet and lifestyle, is associated with an equally significant increase in NAFLD, with a subsequent rise in both morbidity and mortality due to both metabolic, hepatic and cardiovascular diseases. Therefore, the slowdown in the increase of the "bad company" constituted by MS and NAFLD, with all the consequent direct and indirect costs, represents one of the main challenges for the National Health Systems.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
| | - Pia Clara Pafundi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
| | - Maria Vittoria Morone
- Department of Experimental Medicine, Section of Microbiology, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy;
| | - Chiara Silvestri
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
| | - Teresa Salvatore
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via De Crecchio 7, 80138 Naples, Italy;
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (L.R.); (P.C.P.); (R.G.); (A.C.); (C.S.); (M.G.)
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The role of FATP1 in lipid accumulation: a review. Mol Cell Biochem 2021; 476:1897-1903. [PMID: 33486652 DOI: 10.1007/s11010-021-04057-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 01/11/2021] [Indexed: 12/13/2022]
Abstract
Lipid accumulation in mammals has been widely studied for decades due to its significant association with obesity in humans and meat quality in livestock animals. Fatty acid transport 1 (FATP1) is an evolutionarily conserved protein that localizes to the plasma membrane to enhance the transportation of fatty acids (FAs). In line with this function, FATP1 is involved in the metabolism of FAs, including their esterification and oxidation. In addition, the expression of FATP1 can be regulated by several energy-related factors, such as insulin and PPAR activators and transcription factors. These events connect FATP1 with cellular lipid accumulation. Recently, several studies have suggested that FATP1 acts as a facilitator in cellular lipid accumulation, whereas others hold a contrary view. Here, we will review these data and probe the possibility that FATP1 acts as a regulator in lipid accumulation, which will provide effective information for studies on the relationship between FATP1 and obesity in humans and meat quality in livestock animals.
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