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Vahdat-Lasemi F, Farhoudi L, Hosseinikhah SM, Santos RD, Sahebkar A. Angiopoietin-like protein inhibitors: Promising agents for the treatment of familial hypercholesterolemia and atherogenic dyslipidemia. Atherosclerosis 2025; 405:119235. [PMID: 40344904 DOI: 10.1016/j.atherosclerosis.2025.119235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/23/2025] [Accepted: 05/01/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND AND AIMS This review examines the physiological functions of Angiopoietin-like proteins (ANGPTLs) in lipid metabolism and the epidemiology of atherosclerotic cardiovascular disease (ASCVD), while discussing their potential as therapies for dyslipidemias. METHODS A review of contemporary literature on ANGPTLs was conducted. RESULTS ANGPTLs comprise eight secreted proteins that share structural similarities with the angiopoietin family and serve as key regulators of various physiological and biochemical functions. Notably, ANGPTL3, ANGPTL4, and ANGPTL8 act as physiological inhibitors of lipoprotein lipase (LPL), playing a crucial role in lipoprotein and triglyceride metabolism in response to the body's nutritional status. A deficiency in these proteins is linked to hypolipidemia, characterized by a decrease in all lipid fractions, and genetic studies indicate a reduced risk of ASCVD in individuals with loss-of-function variants in ANGPTL3 and ANGPTL4. Conversely, elevated levels of ANGPTL3, ANGPTL4, and ANGPTL8 seem to increase the risk of cardiovascular disease. The role of ANGPTLs in regulating lipid metabolism underscores their potential in targeted therapies for managing dyslipidemias and lowering ASCVD risk, particularly in patients with difficult-to-control dyslipidemia phenotypes, such as homozygous Familial Hypercholesterolemia and mixed dyslipidemia. CONCLUSIONS The development of ANGPTL inhibitors could provide an effective strategy for preventing ASCVD.
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Affiliation(s)
- Fatemeh Vahdat-Lasemi
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Leila Farhoudi
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyedeh Maryam Hosseinikhah
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Raul D Santos
- Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Lipid Clinic Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Abdelhameed F, Lagojda L, Kite C, Dallaway A, Mustafa A, Than NN, Kassi E, Randeva HS, Kyrou I. Circulating angiopoietin-like protein 8 (ANGPTL8) and steatotic liver disease related to metabolic dysfunction: an updated systematic review and meta-analysis. Front Endocrinol (Lausanne) 2025; 16:1574842. [PMID: 40276549 PMCID: PMC12018230 DOI: 10.3389/fendo.2025.1574842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 03/21/2025] [Indexed: 04/26/2025] Open
Abstract
Background Steatotic liver disease related to metabolic dysfunction is the most common cause of chronic liver disease globally. The spectrum of this condition includes steatosis and steatohepatitis and was previously referred to as non-alcoholic fatty liver disease (NAFLD) but has been renamed as metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently as metabolic dysfunction-associated steatotic liver disease (MASLD). Angiopoietin-like protein 8 (ANGPTL8), also known as betatrophin or lipasin, regulates triglycerides and has emerged as a potential novel biomarker for steatosis/steatohepatitis. Therefore, this systematic review aimed to identify and synthesize the evidence on the possible association of circulating ANGPTL8 concentrations with NAFLD, MAFLD or MASLD. Methods PubMed/MEDLINE, Cochrane Library, EMBASE, and Web of Science were searched for studies published in English reporting circulating ANGPTL8 concentrations in adults with NAFLD or MAFLD or MASLD and controls. A meta-analysis was performed, reporting the standardized mean difference (SMD) of circulating ANGPTL8 concentrations between these two groups. Study quality and risk of bias were assessed using the NIH quality assessment tool and RoBANS 2, respectively. Results Of the 104 identified publications, eight studies were eligible for this systematic review, whilst seven were also eligible for meta-analysis (543 NAFLD or MAFLD cases vs. 352 controls). Circulating ANGPTL8 concentrations were significantly higher in patients with NAFLD or MAFLD compared with controls (SMD: 0.62, 95%CI: 0.28-0.97; p<0.001). Considerable heterogeneity was noted among these studies, with six studies having high risk of bias in at least one RoBANS 2 domain. Conclusion These findings present up-to-date comprehensive evidence indicating that adults with steatotic liver disease related to metabolic dysfunction exhibit higher circulating ANGPTL8 concentrations compared with controls. Given the need for novel screening/diagnostic biomarkers for steatosis/steatohepatitis, as well for additional drug targets, large and prospective studies are required to confirm this association and explore its temporal direction, particularly under the new MASLD diagnosis/term.
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Affiliation(s)
- Farah Abdelhameed
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Lukasz Lagojda
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Sheffield Centre for Health and Related Research (SCHARR), School of Medicine and Population Health, University of Sheffield, Sheffield, United Kingdom
| | - Chris Kite
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, United Kingdom
- Faculty of Health, Medicine and Society, Division of Public Health, Sport and Wellbeing, University of Chester, Chester, United Kingdom
| | - Alexander Dallaway
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, United Kingdom
| | - Attia Mustafa
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Internal Medicine Department, Faculty of Medicine, Omar Almukhtar University, Al-Bayda, Libya
- Buckingham Medical School, University of Buckingham, Buckingham, United Kingdom
| | - Nwe Ni Than
- Gastroenterology and Hepatology Department, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, United Kingdom
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, United Kingdom
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, United Kingdom
- College of Health, Psychology and Social Care, University of Derby, Derby, United Kingdom
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, Athens, Greece
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Mohammedsaeed W, Binjawhar D. Dyslipidemia and ANGPTL8 evaluation in young females with Type 1 diabetes mellitus. Endocrine 2024; 86:564-573. [PMID: 38836992 DOI: 10.1007/s12020-024-03909-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/30/2024] [Indexed: 06/06/2024]
Abstract
PURPOSE ANGPTL8, commonly referred to as betatrophin, has demonstrated promise as a dependable marker for the onset of complications associated with diabetes mellitus, such as dyslipidemia. The objective of this study is to evaluate the lipid profile and ANGPTL8 levels in people diagnosed with Type 1 Diabetes Mellitus (T1DM). METHODS A retrospective case-control study was performed on a group of 100 adolescent females, aged 13-17 years. This group consisted of individuals diagnosed with T1DM from the Diabetes and Endocrine Department at Medina's King Fahad Hospital in Saudi Arabia. Additionally, 100 healthy adolescent females of the same age range were included as controls. The hospital conducted laboratory studies to evaluate glucose, HbA1c, insulin, and lipid profiles. The ANGPTL8 levels were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS Patients with T1DM had ANGPTL8 levels that were twice as high as those observed in individuals without any health conditions. The two groups had contrasting levels of fasting blood glucose (FBG), glycated hemoglobin (HbA1c), C-peptides, triacylglycerol (TG), and cholesterol, along with elevated Atherogenic Index of Plasma readings. Diabetes mellitus patients had considerably elevated values compared to the control group. There was a significant correlation between ANGPTL8 concentrations and lipid abnormalities, with P-values less than 0.05. 56% of the 100 patients exhibited dyslipidemia. The research found a correlation between dyslipidemia and elevated levels of ANGPTL8 in diabetic patients. The concentration of ANGPTL8 had a positive correlation with glucose, HbA1c, TG, and C-peptides while displaying a negative correlation with high-density lipoprotein cholesterol (HDL-C). CONCLUSION ANGPTL8 levels were found to be elevated in Saudi young women who were diagnosed with TIDM. ANGPTL8 may potentially contribute to dyslipidemia in individuals with T1DM, hence increasing the susceptibility to cardiovascular disease (CVD). Therefore, ANGPTL8 has the potential to impact lipid metabolism, namely Triglycerides, as a biological route. The results highlight the need to analyze lipid profiles and do ANGPTL8 testing in young females diagnosed with T1DM at an early stage to prevent complications.
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Affiliation(s)
- Walaa Mohammedsaeed
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Science at Taibah University, Madinah, Saudi Arabia.
| | - Dalal Binjawhar
- Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
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Yadav M, Verma S, Tiwari P, Mugale MN. Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives. Life Sci 2024; 353:122934. [PMID: 39089644 DOI: 10.1016/j.lfs.2024.122934] [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: 05/09/2024] [Revised: 06/26/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.
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Affiliation(s)
- Manisha Yadav
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Chen SM, Huang TY, Lee WJ, Chuang LM, Chang TJ. Positive correlation of ANGPTL8 expression in human visceral adipose tissue with body mass index. J Formos Med Assoc 2024; 123:860-865. [PMID: 38191275 DOI: 10.1016/j.jfma.2023.12.018] [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: 05/13/2023] [Revised: 12/21/2023] [Accepted: 12/27/2023] [Indexed: 01/10/2024] Open
Abstract
BACKGROUND Angiopoietin-like protein 8 (ANGPTL8) is an important regulator of lipid metabolism. We aimed to investigate the difference of ANGPTL8 expression in different depots of adipose tissues between individuals with and without obesity, and its correlation with various metabolic parameters. METHODS Subcutaneous (SAT) and visceral adipose tissue (VAT) samples were collected from patients who underwent bariatric or intra-abdominal surgery. Expression levels of ANGPTL8, monoglyceride lipase (MGL), monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin (APM1) were determined using real-time quantitative polymerase chain reaction. The correlation of ANGPTL8 expression with various metabolic parameters and other gene expression levels was analyzed using Person's correlation analysis. Logistic regression was used to establish a prediction model of obesity. RESULTS Totally 330 subjects (obese: 281, non-obese: 49) were recruited. ANGPTL8 expression in VAT was significantly higher in the obesity group than in the non-obesity group (P = 0.0096). ANGPTL8 expression in VAT was positively correlated with body mass index (BMI) (r = 0.1169, P < 0.05) and was independently associated with obesity (O.R., 1.246; 95 % C.I. 1.013-21.533, P = 0.038). We also found the gene expression of ANGPTL8 in SAT and VAT was negatively correlated with APM1 expression in respective SAT and VAT. CONCLUSION ANGPTL8 expression levels in VAT were higher in subjects with obesity, and positively correlated with BMI. This suggests a role of ANGPTL8 in the pathophysiology of obesity and may pave the way for novel treatment target of obesity.
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Affiliation(s)
- Shiau-Mei Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tse-Ying Huang
- Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan
| | - Wei-Jei Lee
- Department of Surgery, Taoyuan Min-Sheng General Hospital, Taoyuan, Taiwan
| | - Lee-Ming Chuang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; School of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tien-Jyun Chang
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; School of Medicine, National Taiwan University, Taipei, Taiwan.
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Bilgin AG, Ekici B, Ozuynuk-Ertugrul AS, Erkan AF, Coban N. The minor allele of ANGPTL8 rs2278426 has a protective effect against CAD in T2DM patients. Gene 2024; 914:148418. [PMID: 38552749 DOI: 10.1016/j.gene.2024.148418] [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: 01/04/2024] [Revised: 03/13/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Coronary artery disease (CAD) is the leading cause of death worldwide despite advanced treatment and diagnosis strategies. Angiopoietin-like protein 8 (ANGPTL8) mainly functions in the lipid mechanism, which is a dysregulated mechanism during CAD pathogenesis. In this study, we aimed to determine the associations between an ANGPTL8 polymorphism rs2278426 and the severity, presence, and risk factors of CAD. METHODS A total of 1367 unrelated Turkish individuals who underwent coronary angiography were recruited for the study and grouped as CAD (n = 736, ≥50 stenosis) and non-CAD (n = 549, ≤30 stenosis). Also, subjects were further divided into groups regarding type 2 diabetes mellitus (T2DM) status. Subjects were genotyped for rs2278426 (C/T) by quantitative real-time PCR. Secondary structure analyses of protein interactions were revealed using I-TASSER and PyMOL. RESULTS Among CAD patients, T allele carriage frequency was lower in the T2DM group (p = 0.046). Moreover, in male non-CAD group, T allele carriage was more prevalent among T2DM patients than non-T2DM (p = 0.033). In logistic regression analysis adjusted for obesity, T allele carrier males had an increased risk for T2DM in non-CAD group (OR = 2.244, 95 % CI: 1.057-4.761, p = 0.035). Also, in T2DM group, stenosis (p = 0.002) and SYNTAX score (p = 0.040) were lower in T allele carrier males than in non-carriers. Analyzes of secondary structure showed that ANGPTL8 could not directly form complexes with ANGPTL3 or ANGPTL4. CONCLUSION In conclusion, T allele carriage of ANGPTL8 rs2278426 has a protective effect on CAD in T2DM patients. Further research should be conducted to explore the association between ANGPTL8 polymorphism (rs2778426) and CAD.
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Affiliation(s)
- Aslihan Gizem Bilgin
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey; Istanbul University Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Berkay Ekici
- Department of Cardiology, Ufuk University Faculty of Medicine, Ankara, Turkey
| | - Aybike Sena Ozuynuk-Ertugrul
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey; Istanbul University Institute of Graduate Studies in Health Sciences, Istanbul, Turkey
| | - Aycan Fahri Erkan
- Department of Cardiology, Ufuk University Faculty of Medicine, Ankara, Turkey
| | - Neslihan Coban
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey; Istanbul University Institute of Graduate Studies in Health Sciences, Istanbul, Turkey.
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Zhang R, Zhang K. A unified model for regulating lipoprotein lipase activity. Trends Endocrinol Metab 2024; 35:490-504. [PMID: 38521668 PMCID: PMC11663433 DOI: 10.1016/j.tem.2024.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/25/2024]
Abstract
The regulation of triglyceride (TG) tissue distribution, storage, and utilization, a fundamental process of energy homeostasis, critically depends on lipoprotein lipase (LPL). We review the intricate mechanisms by which LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, 4, 8), apolipoproteins (APOA5, APOC3, APOC2), and the cAMP-responsive element-binding protein H (CREBH). ANGPTL8 functions as a molecular switch, through complex formation, activating ANGPTL3 while deactivating ANGPTL4 in their LPL inhibition. The ANGPTL3-4-8 model integrates the roles of the aforementioned proteins in TG partitioning between white adipose tissue (WAT) and oxidative tissues (heart and skeletal muscles) during the feed/fast cycle. This model offers a unified perspective on LPL regulation, providing insights into TG metabolism, metabolic diseases, and therapeutics.
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Affiliation(s)
- Ren Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Hehl L, Creasy KT, Vitali C, Scorletti E, Seeling KS, Vell MS, Rendel MD, Conlon D, Vujkovic M, Zandvakili I, Trautwein C, Schneider KM, Rader DJ, Schneider CV. A genome-first approach to variants in MLXIPL and their association with hepatic steatosis and plasma lipids. Hepatol Commun 2024; 8:e0427. [PMID: 38668731 DOI: 10.1097/hc9.0000000000000427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/01/2024] [Indexed: 05/01/2024] Open
Abstract
BACKGROUND Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear. METHODS We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank. RESULTS Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol. CONCLUSIONS Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.
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Affiliation(s)
- Leonida Hehl
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Kate T Creasy
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Cecilia Vitali
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eleonora Scorletti
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Katharina S Seeling
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Mara S Vell
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Miriam D Rendel
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Donna Conlon
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Marijana Vujkovic
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Inuk Zandvakili
- Department of Medicine, Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Internal Medicine, Division of Digestive Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Christian Trautwein
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
| | - Kai M Schneider
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Daniel J Rader
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Carolin V Schneider
- Department of Medicine III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- The Institute for Translational Medicine and Therapeutics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Mohammedsaeed W, Binjawhar D. The correlations between angiopoietin like 8 and cardiometabolic risk factors in Saudi women with type 2 diabetes mellitus: A pilot study. Diab Vasc Dis Res 2024; 21:14791641241259792. [PMID: 38843864 PMCID: PMC11159548 DOI: 10.1177/14791641241259792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/09/2024] Open
Abstract
PURPOSE This study examines whether Angiopoietin Like 8 (ANGPTL8) is linked to cardiometabolic risk factors (CMRFs) in Saudi women with type 2 diabetes (T2DM). METHODS Case-control investigation compared 150 women aged 30-60 with T2DM to 140 healthy women of the same age and gender. RESULTS ANGPTL8 levels differed significantly between T2DM and non-diabetics. Fasting blood glucose (FBG), insulin resistance (IR), triglycerides (TG), high-sensitivity C-reactive protein (hs-CRP), body mass index (BMI), and atherogenic index (AIP) of plasma all correlated positively with ANGPTL8 concentrations. Insulin levels correlated negatively with ANGPTL8. Multiple linear regression models showed that elevated ANGPTL8 independently predicted higher FBG, hs-CRP, IR, TG, and AIP in T2DM patients. CONCLUSION The study found a significant association between ANGPTL8 levels and IR, hs-CRP, TG, AIP, and BMI in women with T2DM. These components are classified as CMRFs and have the potential to contribute to the development of cardiovascular disease (CVD).
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Affiliation(s)
- Walaa Mohammedsaeed
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Science, Taibah University, Madinah, Saudi Arabia
| | - Dalal Binjawhar
- Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
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Alshawaf E, Abu-Farha M, Mohammad A, Devarajan S, Al-Khairi I, Cherian P, Ali H, Al-Matrouk H, Al-Mulla F, Al Attar A, Abubaker J. Angiopoietin-2 and Angiopoietin-like Proteins with a Prospective Role in Predicting Diabetic Nephropathy. Biomedicines 2024; 12:949. [PMID: 38790911 PMCID: PMC11118931 DOI: 10.3390/biomedicines12050949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/14/2024] [Accepted: 04/20/2024] [Indexed: 05/26/2024] Open
Abstract
Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, p = 0.047), eGFR (r = -0.282, p = 0.021), and SBP (r = -0.28, p = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, p < 0.001) and ANGPTL8 (r = 0.41, p = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2's increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors.
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Affiliation(s)
- Eman Alshawaf
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
- Diabetology Unit, Amiri Hospital, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Anwar Mohammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Sriraman Devarajan
- National Dasman Diabetes Biobank, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Irina Al-Khairi
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Preethi Cherian
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (E.A.); (M.A.-F.); (A.M.); (I.A.-K.); (P.C.)
| | - Hamad Ali
- Functional Genomic Unit, Dasman Diabetes Institute, Dasman 15462, Kuwait; (H.A.); (F.A.-M.)
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Kuwait 15462, Kuwait
| | - Hawra Al-Matrouk
- Medical Department, Amiri Hospital, Ministry of Health, Kuwait 15462, Kuwait;
| | - Fahd Al-Mulla
- Functional Genomic Unit, Dasman Diabetes Institute, Dasman 15462, Kuwait; (H.A.); (F.A.-M.)
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Abdulnabi Al Attar
- Diabetology Unit, Amiri Hospital, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Jehad Abubaker
- National Dasman Diabetes Biobank, Dasman Diabetes Institute, Dasman 15462, Kuwait;
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Xu Q, Zhang J, Lu Y, Wu L. Association of metabolic-dysfunction associated steatotic liver disease with polycystic ovary syndrome. iScience 2024; 27:108783. [PMID: 38292434 PMCID: PMC10825666 DOI: 10.1016/j.isci.2024.108783] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), which has a prevalence of over 25% in adults, encompasses a wide spectrum of liver diseases. Metabolic-dysfunction associated steatotic liver disease (MASLD), the new term for NAFLD, is characterized by steatotic liver disease accompanied by cardiometabolic criteria, showing a strong correlation with metabolic diseases. Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease affecting 4-21% of women of reproductive age. Numerous studies have indicated that NAFLD and PCOS often occur together. However, as MASLD is a new term, there is still a lack of reports describing the effects of MASLD on the development of PCOS. In this review article, we have summarized the complex and multifaceted connections between MASLD and PCOS. Understanding the pathogenesis and treatment methods could not only guide the clinical prevention, diagnosis, and treatment of PCOS in patients with MASLD, but also increase the clinical attention of reproductive doctors to MASLD.
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Affiliation(s)
- Qiuyu Xu
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Zhang
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Lu
- Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Wu
- Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Hammad MM, Channanath AM, Abu-Farha M, Rahman A, Al Khairi I, Cherian P, Alramah T, Alam-Eldin N, Al-Mulla F, Thanaraj TA, Abubaker J. Adolescent obesity and ANGPTL8: correlations with high sensitivity C-reactive protein, leptin, and chemerin. Front Endocrinol (Lausanne) 2023; 14:1314211. [PMID: 38189043 PMCID: PMC10766807 DOI: 10.3389/fendo.2023.1314211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/06/2023] [Indexed: 01/09/2024] Open
Abstract
Angiopoietin-like proteins (ANGPTLs) mediate many metabolic functions. We had recently reported increased plasma levels of ANGPTL8 in obese adults of Arab ethnicity. However, data on ANGPTL8 levels in adolescent obesity is lacking. Arab population is characterized by a rapid transition, due to sudden wealth seen in the post-oil era, in lifestyle, food habits and extent of physical activity. We adopted a cross-sectional study on Arab adolescents from Kuwait to examine the role of ANGPTL8 in adolescent obesity. The study cohort included 452 adolescents, aged 11-14 years, recruited from Middle Schools across Kuwait. BMI-for-age growth charts were used to categorize adolescents as normal-weight, overweight, and obese. ELISA and bead-based multiplexing assays were used to measure plasma levels of ANGPTL8 and other inflammation and obesity-related biomarkers. Data analysis showed significant differences in the plasma levels of ANGPTL8 among the three subgroups, with a significant increase in overweight and obese children compared to normal-weight children. This observation persisted even when the analysis was stratified by sex. Multinomial logistic regression analysis illustrated that adolescents with higher levels of ANGPTL8 were 7 times more likely to become obese and twice as likely to be overweight. ANGPTL8 levels were correlated with those of hsCRP, leptin and chemerin. ANGPTL8 level had a reasonable prognostic power for obesity with an AUC of 0.703 (95%-CI=0.648-0.759). These observations relating to increased ANGPTL8 levels corresponding to increased BMI-for-age z-scores indicate that ANGPTL8, along with hsCRP, leptin and chemerin, could play a role in the early stages of obesity development in children. ANGPTL8 is a potential early marker for adolescent obesity and is associated with well-known obesity and inflammatory markers.
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Affiliation(s)
- Maha M. Hammad
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Arshad M. Channanath
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Abdur Rahman
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Kuwait City, Kuwait
| | - Irina Al Khairi
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Preethi Cherian
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Tahani Alramah
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Nada Alam-Eldin
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
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Eroğlu İ, Iremli BG, Idilman IS, Yuce D, Lay I, Akata D, Erbas T. Nonalcoholic Fatty Liver Disease, Liver Fibrosis, and Utility of Noninvasive Scores in Patients With Acromegaly. J Clin Endocrinol Metab 2023; 109:e119-e129. [PMID: 37590020 PMCID: PMC10735300 DOI: 10.1210/clinem/dgad490] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/19/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023]
Abstract
CONTEXT Nonalcoholic fatty liver disease (NAFLD) is a metabolical disorder and can lead to liver fibrosis. Because it is commonly seen, several noninvasive scores (NS) have been validated to identify high-risk patients. Patients with NAFLD have been shown to have higher serum angiopoietin-like protein-8 (ANGPTL-8) levels. OBJECTIVE The risk of NAFLD is known insufficiently in acromegaly. Moreover, the utility of the NS and the link between NAFLD and ANGPTL-8 in acromegaly is unknown. METHODS Thirty-two patients with acromegaly (n = 15, active [AA] and n = 17, controlled acromegaly [CA]) and 19 healthy controls were included. Magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) was used to evaluate hepatic steatosis, and magnetic resonance elastography to evaluate liver stiffness measurement. ANGPTL-8 levels were measured with ELISA. RESULTS Median liver MRI-PDFF and NAFLD prevalence in AA were lower than in CA (P = .026 and P < .001, respectively). Median magnetic resonance elastography-liver stiffness measurement were similar across groups. Of the NS, visceral adiposity index, fatty liver index, hepatic steatosis index, and triglyceride-glucose index (TyG) all showed positive correlation with the liver MRI-PDFF in the control group. However, only TyG significantly correlated with liver fat in the AA and CA groups. There was no correlation between traditional NAFLD risk factors (body mass index, waist circumference, C-reactive protein, homeostasis model assessment for insulin resistance, visceral adipose tissue) and liver MRI-PDFF in the AA and CA. Patients with acromegaly with NAFLD had lower GH, IGF-1, and ANGPTL-8 levels than in those without NAFLD (P = .025, P = .011, and P = .036, respectively). CONCLUSION Active acromegaly may protect from NAFLD because of high GH. In patients with acromegaly, NAFLD risk cannot be explained with classical risk factors; hence, additional risk factors must be identified. TyG is the best score to evaluate NAFLD risk. Lower ANGPTL-8 in patients with acromegaly and NAFLD implies this hormone may be raised because of insulin resistance rather than being a cause for NAFLD.
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Affiliation(s)
- İmdat Eroğlu
- Department of Internal Medicine, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
| | - Burcin Gonul Iremli
- Department of Internal Medicine, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
- Department of Endocrinology and Metabolism, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
| | - Ilkay S Idilman
- Department of Radiology, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
| | - Deniz Yuce
- Department of Preventive Oncology, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
| | - Incilay Lay
- Department of Biochemistry, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
| | - Deniz Akata
- Department of Radiology, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
| | - Tomris Erbas
- Department of Internal Medicine, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
- Department of Endocrinology and Metabolism, Hacettepe University, School of Medicine, 06230, Ankara, Turkey
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Abu-Farha M, Madhu D, Hebbar P, Mohammad A, Channanath A, Kavalakatt S, Alam-Eldin N, Alterki F, Taher I, Alsmadi O, Shehab M, Arefanian H, Ahmad R, Thanaraj TA, Al-Mulla F, Abubaker J. The Proinflammatory Role of ANGPTL8 R59W Variant in Modulating Inflammation through NF-κB Signaling Pathway under TNFα Stimulation. Cells 2023; 12:2563. [PMID: 37947641 PMCID: PMC10648545 DOI: 10.3390/cells12212563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/17/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Angiopoietin-like protein 8 (ANGPTL8) is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity and with IKK to modulate NF-κB activity. Further, a single nucleotide polymorphism (SNP) leading to the ANGPTL8 R59W variant associates with reduced low-density lipoprotein/high-density lipoprotein (LDL/HDL) and increased fasting blood glucose (FBG) in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of the R59W variant on the inflammatory activity of ANGPTL8. METHODS The ANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-κB activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. RESULTS The ANGPTL8 R59W variant was associated with increased circulatory levels of tumor necrosis factor alpha (TNFα) and interleukin 7 (IL7). Our in vitro studies using HepG2 cells revealed an increased phosphorylation of key inflammatory proteins of the NF-κB pathway in individuals with the R59W variant as compared to those with the wild type, and TNFα stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-κB p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-κB activity. CONCLUSION ANGPTL8 R59W is associated with increased circulatory TNFα, IL7, and NF-κB p65 activity. Weak transient binding of the ANGPTL8 R59W variant explains its regulatory role on the NF-κB pathway and inflammation.
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Affiliation(s)
- Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (D.M.); (A.M.); (S.K.); (N.A.-E.)
| | - Dhanya Madhu
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (D.M.); (A.M.); (S.K.); (N.A.-E.)
| | - Prashantha Hebbar
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.H.); (A.C.); (F.A.-M.)
| | - Anwar Mohammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (D.M.); (A.M.); (S.K.); (N.A.-E.)
| | - Arshad Channanath
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.H.); (A.C.); (F.A.-M.)
| | - Sina Kavalakatt
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (D.M.); (A.M.); (S.K.); (N.A.-E.)
| | - Nada Alam-Eldin
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (D.M.); (A.M.); (S.K.); (N.A.-E.)
| | - Fatima Alterki
- Department of internal Medicine, Amiri Hospital, Ministry of Health, Kuwait City 15462, Kuwait;
| | - Ibrahim Taher
- Microbiology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka P.O. Box 2014, Saudi Arabia;
| | - Osama Alsmadi
- Department of Cell Therapy and Applied Genomics, King Hussein Cancer Center, Amman 1269, Jordan;
| | - Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Kuwait City 47061, Kuwait;
| | - Hossein Arefanian
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (H.A.); (R.A.)
| | - Rasheed Ahmad
- Department of Immunology & Microbiology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (H.A.); (R.A.)
| | - Thangavel Alphonse Thanaraj
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.H.); (A.C.); (F.A.-M.)
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (P.H.); (A.C.); (F.A.-M.)
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (D.M.); (A.M.); (S.K.); (N.A.-E.)
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AlMajed HT, Abu-Farha M, Alshawaf E, Devarajan S, Alsairafi Z, Elhelaly A, Cherian P, Al-Khairi I, Ali H, Jose RM, Thanaraj TA, Al-Ozairi E, Al-Mulla F, Al Attar A, Abubaker J. Increased Levels of Circulating IGFBP4 and ANGPTL8 with a Prospective Role in Diabetic Nephropathy. Int J Mol Sci 2023; 24:14244. [PMID: 37762544 PMCID: PMC10531667 DOI: 10.3390/ijms241814244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/17/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Diabetic nephropathy (DN) is a complicated condition related to type 2 diabetes mellitus (T2D). ANGPTL8 is a hepatic protein highlighted as a risk factor for DN in patients with T2D; additionally, recent evidence from DN studies supports the involvement of growth hormone/IGF/IGF-binding protein axis constituents. The potential link between ANGPTL8 and IGFBPs in DN has not been explored before. Here, we assessed changes in the circulating ANGPTL8 levels in patients with DN and its association with IGFBP-1, -3, and -4. Our data revealed a significant rise in circulating ANGPTL8 in people with DN, 4443.35 ± 396 ng/mL compared to 2059.73 ± 216 ng/mL in people with T2D (p < 0.001). Similarly, levels of IGFBP-3 and -4 were significantly higher in people with DN compared to the T2D group. Interestingly, the rise in ANGPTL8 levels correlated positively with IGFBP-4 levels in T2DM patients with DN (p < 0.001) and this significant correlation disappeared in T2DM patients without DN. It also correlated positively with serum creatinine and negatively with the estimated glomerular filtration rate (eGFR, All < 0.05). The area under the curve (AUC) on receiver operating characteristic (ROC) analysis of the combination of ANGPTL8 and IGFBP4 was 0.76 (0.69-0.84), p < 0.001, and the specificity was 85.9%. In conclusion, our results showed a significant increase in ANGPTL8 in patients with DN that correlated exclusively with IGFBP-4, implicating a potential role of both proteins in the pathophysiology of DN. Our findings highlight the significance of these biomarkers, suggesting them as promising diagnostic molecules for the detection of diabetic nephropathy.
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Affiliation(s)
- Hana Th. AlMajed
- Applied Health Science Department, College of Health Sciences, Kuwait 15462, Kuwait;
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (E.A.); (P.C.); (I.A.-K.)
| | - Eman Alshawaf
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (E.A.); (P.C.); (I.A.-K.)
| | - Sriraman Devarajan
- National Dasman Diabetes Biobank, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (S.D.); (R.M.J.)
| | - Zahra Alsairafi
- Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait 15462, Kuwait;
| | - Ashraf Elhelaly
- Clinical Laboratory, Amiri Hospital Kuwait, Kuwait 15462, Kuwait;
| | - Preethi Cherian
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (E.A.); (P.C.); (I.A.-K.)
| | - Irina Al-Khairi
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (E.A.); (P.C.); (I.A.-K.)
| | - Hamad Ali
- Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (H.A.); (T.A.T.); (F.A.-M.)
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Kuwait 15462, Kuwait
| | - Rose Mol Jose
- National Dasman Diabetes Biobank, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (S.D.); (R.M.J.)
| | | | - Ebaa Al-Ozairi
- Medical Division, Dasman Diabetes Institute, Kuwait 15462, Kuwait;
| | - Fahd Al-Mulla
- Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (H.A.); (T.A.T.); (F.A.-M.)
| | - Abdulnabi Al Attar
- Diabetology Unit, Amiri Hospital, Dasman Diabetes Institute, Kuwait 15462, Kuwait;
| | - Jehad Abubaker
- Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait 15462, Kuwait; (E.A.); (P.C.); (I.A.-K.)
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Dong Y, Li W, Yin J. The intestinal-hepatic axis: a comprehensive review on fructose metabolism and its association with mortality and chronic metabolic diseases. Crit Rev Food Sci Nutr 2023; 64:12473-12486. [PMID: 37671898 DOI: 10.1080/10408398.2023.2253468] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Fructose is a common ingredient of food industry in the form of sucrose and high fructose corn sirup (HFCS). Due to its unique metabolic properties, excessive intake of fructose has been linked to various diseases, including obesity, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), chronic renal insufficiency, and even increase the risk of death. Interestingly, although high fructose intake may induce gout, it does not cause hyperuricemia, and the underlying molecular mechanisms remain debated. While previous studies focused on the liver as the primary site of fructose metabolism, recent evidence has suggested a crucial role for the intestine-hepatic axis in fructose metabolism. Low dose fructose is mainly metabolized in the small intestine. Only when the intake exceeds the intestine's metabolic capacity fructose spills over to be metabolized in the liver. High fructose diets also have a significant impact on the diversity of the gut microbiota, leading to alterations in the metabolic byproducts produced by these gut bacteria and thereby inducing endotoxemia. This paper provides a comprehensive review of the epidemiological and pathological studies conducted in recent years, describing the metabolic differences between fructose and glucose and the possible mechanisms underlying the link between excessive fructose intake and chronic metabolic diseases.
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Affiliation(s)
- Yiling Dong
- Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
| | - Wen Li
- Department of Endocrinology and Metabolism, Haikou Orthopedics and Diabetes Hospital of Shanghai Sixth People's Hospital, Haikou, China
| | - Jun Yin
- Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China
- Department of Endocrinology and Metabolism, Shanghai Eighth People's Hospital, Shanghai, China
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17
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Arikan FB, Ulas M, Ustundag Y, Boyunaga H, Badem ND. Investigation of the relationship between betatrophin and certain key enzymes involved in carbohydrate and lipid metabolism in insulin-resistant mice. Horm Mol Biol Clin Investig 2023; 44:311-320. [PMID: 36869875 DOI: 10.1515/hmbci-2022-0104] [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: 11/15/2022] [Accepted: 02/08/2023] [Indexed: 03/05/2023]
Abstract
OBJECTIVES The present study sought to examine the relationship of betatrophin with certain key enzymes, namely lactate dehydrogenase-5 (LDH5), citrate synthase (CS), and acetyl-CoA carboxylase-1 (ACC1), in insulin-resistant mice. METHODS Eight-week-old male C57BL6/J mice were used in this study (experimental group n=10 and control group n=10). S961 was administered using an osmotic pump to induce insulin resistance in the mice. The betatrophin, LDH5, CS, and ACC1 expression levels were determined from the livers of the mice using the real-time polymerase chain reaction (RT-PCR) method. Moreover, biochemical parameters such as the serum betatrophin, fasting glucose, insulin, triglyceride, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels were analyzed. RESULTS The betatrophin expression and serum betatrophin (p=0.000), fasting glucose, insulin, triglyceride (p≤0.001), and total cholesterol (p=0.013) levels were increased in the experimental group. In addition, the CS gene expression level was statistically significantly decreased in the experimental group (p=0.01). Although strong correlation was found between the expression and serum betatrophin and triglyceride levels, no correlation was found between the betatrophin gene expression and the LDH5, ACC1, and CS gene expression levels. CONCLUSIONS The betatrophin level appears to play an important role in the regulation of triglyceride metabolism, while insulin resistance increases both the betatrophin gene expression and serum levels and decreases the CS expression level. The findings suggest that betatrophin may not regulate carbohydrate metabolism through CS and LDH5 or lipid metabolism directly through the ACC1 enzyme.
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Affiliation(s)
- Funda Bulut Arikan
- Faculty of Medicine, Department of Physiology, Kırıkkale University, Kırıkkale, Türkiye
| | - Mustafa Ulas
- Faculty of Medicine, Department of Physiology, Fırat University, Elazığ, Türkiye
| | - Yasemin Ustundag
- Faculty of Veterinary, Department of Anatomy, Dokuz Eylul University, Izmir, Türkiye
| | - Hakan Boyunaga
- Faculty of Medicine, Medical Biochemistry Department, Medipol University, Ankara, Türkiye
| | - Nermin Dindar Badem
- Department of Medical Biochemistry, Health Sciences University, Gülhane Training and Research Hospital, Ankara, Türkiye
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Abu-Farha M, Joseph S, Mohammad A, Channanath A, Taher I, Al-Mulla F, Mujammami M, Thanaraj TA, Abubaker J, Abdel Rahman AM. Targeted Metabolomics Analysis of Individuals Carrying the ANGPTL8 R59W Variant. Metabolites 2023; 13:972. [PMID: 37755252 PMCID: PMC10536441 DOI: 10.3390/metabo13090972] [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: 07/23/2023] [Revised: 08/15/2023] [Accepted: 08/17/2023] [Indexed: 09/28/2023] Open
Abstract
ANGPTL8 is recognized as a regulator of lipid metabolism through its role in inhibiting lipoprotein lipase activity. ANGPTL8 gene variants, particularly rs2278426 leading to the R59W variant in the protein, have been associated with lipid traits in various ethnicities. We aimed to use metabolomics to understand the impact of the ANGPTL8 R59W variant on metabolites in humans. We used the Biocrates-p400 kit to quantify 408 plasma metabolites in 60 adult male Arab individuals from Kuwait and identify differences in metabolite levels between individuals carrying reference genotypes and those with carrier genotypes at ANGPTL8 rs2278426. Individuals with carrier genotypes (CT+TT) compared to those carrying the reference genotype (CC) showed statistically significant differences in the following metabolites: acylcarnitine (perturbs metabolic pathways), phosphatidylcholine (supports liver function and cholesterol levels), cholesteryl ester (brings chronic inflammatory response to lipoprotein depositions in arteries), α-aminoadipic acid (modulates glucose homeostasis), histamine (regulates glucose/lipid metabolism), sarcosine (links amino acid and lipid metabolism), diacylglycerol 42:1 (regulates homeostasis of cellular lipid stores), and lysophosphatidylcholine (regulates oxidative stress and inflammatory response). Functional aspects attributed to these metabolites indicate that the ANGPTL8 R59W variant influences the concentrations of lipid- and inflammation-related metabolites. This observation further highlights the role of ANGPTL8 in lipid metabolism.
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Affiliation(s)
- Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (S.J.); (A.M.)
| | - Shibu Joseph
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (S.J.); (A.M.)
| | - Anwar Mohammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (S.J.); (A.M.)
| | - Arshad Channanath
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (A.C.); (F.A.-M.)
| | - Ibrahim Taher
- Microbiology Unit, Department of Pathology, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia;
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (A.C.); (F.A.-M.)
| | - Muhammad Mujammami
- Endocrinology and Diabetes Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 11421, Saudi Arabia;
- University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh 11421, Saudi Arabia
| | - Thangavel Alphonse Thanaraj
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15462, Kuwait; (A.C.); (F.A.-M.)
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Dasman 15462, Kuwait; (M.A.-F.); (S.J.); (A.M.)
| | - Anas M. Abdel Rahman
- Metabolomics Section, Department of Clinical Genomics, Centre for Genome Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia;
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Chemistry, College of Science, Memorial University of Newfoundland, St. John’s, NL A1C 5S7, Canada
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Xu F, Shen L, Yang Y, Kong L, Zu W, Tian D, Cao X, Huang G. Association Between Plasma Levels of ANGPTL3, 4, 8 and the Most Common Additional Cardiovascular Risk Factors in Patients with Hypertension. Diabetes Metab Syndr Obes 2023; 16:1647-1655. [PMID: 37309506 PMCID: PMC10257919 DOI: 10.2147/dmso.s411483] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 06/01/2023] [Indexed: 06/14/2023] Open
Abstract
Background ANGPTL3, 4 and 8 have been reported to be involved in the regulation of lipid and glucose metabolism. The aim of this study was to investigate the expression of ANGPTL3, 4, 8 in hypertensive patients with or without overweight/obesity, T2D, and hyperlipidemia, and the possible association between their expression and the status of the aforementioned comorbidities. Methods Plasma levels of ANGPTL3, 4, and 8 in 87 hospitalized patients with hypertension were measured using ELISA kits. Associations between circulating ANGPTLs levels and the most common additional cardiovascular risk factors were assessed using multivariate linear regression analyses. Pearson's correlation analysis was used to examine the association between ANGPTLs and clinical parameters. Results In the context of hypertension, (1) although not statistically significant, circulating ANGPTL3 levels were higher in the overweight/obese group than in the normal weight group; (2) circulating levels of ANGPTL3 and ANGPTL8 were significantly lower in patients with T2D than in non-diabetic patients; (3) circulating ANGPTL3 levels were significantly higher in the hyperlipidemic group than in the non-hyperlipidemic group. ANGPTL3 was associated with T2D and hyperlipidemia status, whereas ANGPTL8 was independently associated with T2D status. In addition, circulating ANGPTL3 levels were positively correlated with TC, TG, LDL-C, HCY, and ANGPTL8, and circulating ANGPTL4 levels were positively correlated with UACR and BNP. Conclusion Changes in circulating ANGPTL3 and ANGPTL8 levels have been observed in hypertensive patients with the most common additional cardiovascular risk factors, suggesting a role in the common comorbidities of hypertension and cardiovascular disease. Hypertensive patients with overweight/obesity or hyperlipidemia may benefit from therapies targeting ANGPTL3.
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Affiliation(s)
- Fangfang Xu
- Key Laboratory of Geriatrics, Institute of Geriatrics, Department of Geriatric Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Lijun Shen
- Department of Clinical Medical Research Center, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Yongguang Yang
- Department of Clinical Medical Research Center, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Limin Kong
- Department of General Medicine, Xinxiang Medical University, the Sixth People’s Hospital of Zhengzhou, Zhengzhou, People’s Republic of China
| | - Wufan Zu
- Department of Immunology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, People’s Republic of China
| | - Dandan Tian
- Department of Hypertension, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Xuanchao Cao
- Key Laboratory of Geriatrics, Institute of Geriatrics, Department of Geriatric Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
| | - Gairong Huang
- Key Laboratory of Geriatrics, Institute of Geriatrics, Department of Geriatric Medicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China
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Susanto H, Sugiharto, Taufiq A, Pranoto A, Dwi Trijoyo Purnomo J. Dynamic alteration of plasma levels of betatrophin in younger female onset obesity post acute moderate-intensity exercise training. Saudi J Biol Sci 2023; 30:103546. [PMID: 36624736 PMCID: PMC9823226 DOI: 10.1016/j.sjbs.2022.103546] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 11/19/2022] [Accepted: 12/17/2022] [Indexed: 12/25/2022] Open
Abstract
Obesity is a global metabolic disease anchored by a lack of physical activity lipid disturbances. Hitherto, betatrophin is a potential liver-derived hormone that regulates lipid metabolism. A total of 26 selected onset obese individuals (BMI range ± 28-31) were enrolled in this study and given moderate-intensity exercise. Importantly, our data show that acute moderate-intensity interval exercise (MIIE) and acute moderate-intensity continue to exercise (MICE) for 40 min significantly decrease the plasma level of full-length betatrophin respectively (174.18 ± 48.19 ng/mL; 182.31 ± 52.69 ng/mL), compared to the placebo (283.97 ± 32.23 ng/mL) post 10 min and 6 h exercise treatment (p ≤ 0.05). The plasma level of betatrophin was significantly and negatively correlated with BMI (r = - 0.412, p = 0.037), fasting blood glucose (r = - 0.390, p = 0.049), and positively correlated with VO2max (r = 0.456, p = 0.019). In addition, the linear and ordinal logistic regression analysis shows that betatrophin, is a potential predictor for BMI [estimate value = 0.995, p = 0.037 and OR (95 % CI) = 0.992 (0.0984-1.00), p = 0,048]. In summary, our data demonstrate that the circulating levels of betatrophin were decreased after acute moderate-intensity exercise training.
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Affiliation(s)
- Hendra Susanto
- Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Negeri Malang, Malang, East Java 65145, Indonesia,Corresponding author at: Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Negeri Malang, Semarang No. 5 Street, Malang, East Java 65145, Indonesia.
| | - Sugiharto
- Department of Sports Science, Faculty of Sports Science, Universitas Negeri Malang, Malang, East Java 65145, Indonesia
| | - Ahmad Taufiq
- Department of Physics, Faculty of Mathematics and Natural Sciences, Universitas Negeri Malang, Malang, East Java 65145, Indonesia
| | - Adi Pranoto
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, East Java 60132, Indonesia
| | - Jerry Dwi Trijoyo Purnomo
- Department of Statistics, Faculty of Science and Data Analytics, Institut Teknologi Sepuluh Nopember, Surabaya, East Java 60117, Indonesia
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Pérez-López FR, Yuan J, Sánchez-Prieto M, López-Baena MT, Pérez-Roncero GR, Varikasuvu SR. Maternal and cord blood betatrophin (angiopoietin-like protein 8) in pregnant women with gestational diabetes and normoglycemic controls: A systematic review, meta-analysis, and meta-regression. Diabetes Metab Res Rev 2023; 39:e3612. [PMID: 36656279 DOI: 10.1002/dmrr.3612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/15/2022] [Accepted: 01/13/2023] [Indexed: 01/20/2023]
Abstract
AIMS This systematic review and meta-analysis examined maternal and cord blood betatrophin levels in pregnant women with gestational diabetes mellitus (GDM) and normoglycemic controls. MATERIAL AND METHODS PubMed, Cochrane Library, Embase, LILACS, WangFang, and China National Knowledge Infrastructure were searched for literature from inception until May 2022. The primary outcomes were maternal and cord blood betatrophin levels. A random-effect meta-analysis was used to estimate the pooled results. The mean differences (MDs) or standardised MDs (SMD) and their 95% confidence intervals (CIs) were calculated. I2 tests were used to evaluate the heterogeneity. The quality of studies was evaluated using the Newcastle-Ottawa Scale. RESULTS Betatrophin levels were reported in 22 studies with a total of 3034 pregnant women, and in seven studies including cord blood from 456 infants. Women with GDM display higher betatrophin levels than the normoglycemic controls (SMD = 0.85, 95% CI: 0.38-1.31) during the second half of the pregnancy. The sensitivity analysis indicated that no single study had significantly influenced the betatrophin overall outcomes. There was heterogeneity between the studies as evidenced by high I2 values. Meta-regression analysis indicated a significant regression coefficient for maternal betatrophin and glycosilated haemoglobin. There was no significant difference in cord blood betatrophin in infants from women with and without GDM (SMD = 0.34, 95% CI: -0.15-0.83). Women with GDM also had significantly higher insulin, glucose, glycosylated haemoglobin, HOMA-IR, LDL-cholesterol, HDL-cholesterol, triglycerides, and body mass index compared with the normoglycemic controls. CONCLUSIONS Maternal betatrophin levels were higher in women with GDM than in the normoglycemic controls. There was no difference in cord blood betatrophin. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42022311372.
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Affiliation(s)
- Faustino R Pérez-López
- Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
- Aragón Health Research Institute, Zaragoza, Spain
| | - Junhua Yuan
- Special Medicine Department, School of Basic Medicine, Qingdao University, Qingado, China
| | - Manuel Sánchez-Prieto
- Department of Obstetrics and Gynecology, Dexeus University Hospital, Barcelona, Spain
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Carbinatti T, Régnier M, Parlati L, Benhamed F, Postic C. New insights into the inter-organ crosstalk mediated by ChREBP. Front Endocrinol (Lausanne) 2023; 14:1095440. [PMID: 36923222 PMCID: PMC10008936 DOI: 10.3389/fendo.2023.1095440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/11/2023] [Indexed: 03/01/2023] Open
Abstract
Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases.
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23
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Horn P, Radtke S, Metzing UB, Steidl R, Sponholz C, Sommerfeld O, Roth J, Claus RA, Birkenfeld AL, Settmacher U, Rauchfuß F, von Loeffelholz C. Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis. Biomedicines 2022; 10:3151. [PMID: 36551906 PMCID: PMC9775570 DOI: 10.3390/biomedicines10123151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/17/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Sepsis is defined by life-threatening organ dysfunction mediated by the host’s response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete. The cytokine betatrophin/Angiopoietin-like protein 8 (ANGPTL8) plays a role in the regulation of triacylglyceride metabolism, though its function in septic dyslipidemia remains unknown. Sixty-six patients were enrolled in a cross-sectional study. Circulating concentrations and adipose tissue (AT) mRNA expression of betatrophin/ANGPTL8 were studied in patients suffering from peritoneal sepsis. Insulin-resistant individuals and subjects without metabolic derangement/systemic inflammation were enrolled as controls. All underwent open abdominal surgery. Circulating betatrophin/ANGPTL8 was analyzed by an enzyme-linked immunosorbent assay and AT mRNA expression levels were assessed by real-time PCR. Standard laboratory analyses including lipid electrophoresis were evaluated. Sepsis patients showed pronounced septic dyslipidemia (p < 0.05 for all major lipid classes). Despite comparable betatrophin/ANGPTL8 mRNA expression in AT (p = 0.24), we found significantly increased circulating betatrophin/ANGPTL8 with septic dyslipidemia (p = 0.009). Expression levels of betatrophin/ANGPTL8 in AT correlated with circulating concentrations in both control groups (r = 0.61; p = 0.008 and r = 0.43; p = 0.034), while this association was undetectable in sepsis. After stratification, betatrophin/ANGPTL8 remained associated with hypertriacylglyceridemia (p < 0.05).
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Affiliation(s)
- Paul Horn
- Department of Internal Medicine IV, Gastroenterology, Hepatology and Infectious Diseases, Jena University Hospital, 07747 Jena, Germany
| | - Sascha Radtke
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Uta Barbara Metzing
- Department of Trauma, Hand and Reconstructive Surgery, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Ricardo Steidl
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Christoph Sponholz
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Oliver Sommerfeld
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Johannes Roth
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Ralf A. Claus
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
| | - Andreas L. Birkenfeld
- Department of Diabetology Endocrinology and Nephrology, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
- Department of Therapy of Diabetes, Institute of Diabetes Research and Metabolic Diseases in the Helmholtz Center Munich, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
- Division of Diabetes and Nutritional Sciences, Rayne Institute, King’s College London, London SE5 9RJ, UK
| | - Utz Settmacher
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
| | - Falk Rauchfuß
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
| | - Christian von Loeffelholz
- Department of Anaesthesiology and Intensive Care, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
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Rashvand F, Irandoust K, Taheri M, Gholamzadeh Khoei S, Gheibi N. The Effect of Four Weeks of Long-Term Endurance Training with and Without Propolis Supplementation on Serum Levels of Betatrophin/ANGPTL8 in Male Athletes. Asian J Sports Med 2022; 13. [DOI: 10.5812/asjsm-120515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 08/14/2022] [Accepted: 09/06/2022] [Indexed: 11/09/2023] Open
Abstract
Background: Betatrophin/angiopoietin-like protein (ANGPTL8) is defined as an adipokine that regulates blood glucose and triglyceride levels. Objectives: This study aimed to evaluate the effect of propolis supplementation for the first time on serum levels of the hormone betatrophin, as a drug target in the treatment of dyslipidemia, in male endurance athletes for four weeks. Methods: 44 male athletes with an average age of 22 ± 3 years, a height of 177.5 ± 6.5 cm, and a weight of 76 ± 6 kg were selected in Qazvin. They were randomly divided into four groups: Supplementation, placebo, physical activity, and control. The supplementation and placebo groups received two 500 mg tablets of propolis and cellulose (in terms of shape and color, are similar to the original supplement and have no properties, flavor, and aroma) once after lunch and once after dinner, respectively. The drug treatment lasted for four weeks. The athletes' weight and serum levels of betatrophin were measured at the beginning and the end of 4 weeks of treatment. The ELISA method was used to assess the serum concentration of betatrophin. Analyzes were performed by the ANCOVA method. Results: The results showed that the long-term endurance training plus propolis supplementation would result in significant changes in the betatrophin serum levels and weight in participants (P = 0.001), but in the athletes without supplementation, these changes were not significant (P > 0.05). Conclusions: The results indicated that betatrophin serum levels in endurance athletes are increased by propolis supplementation, and their weight is decreased.
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Betatrophin and Insulin Resistance. Metabolites 2022; 12:metabo12100925. [PMID: 36295827 PMCID: PMC9610572 DOI: 10.3390/metabo12100925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/09/2022] [Accepted: 09/24/2022] [Indexed: 11/18/2022] Open
Abstract
Betatrophin (angiopoietin-like protein 8 (ANGPTL8)) is a hormone that was recently discovered in the human liver. Multiple homologous sequences have been detected in mammalian liver, white adipose, and brown adipose tissues. Betatrophin is crucial for the development of type 2 diabetes (T2D), insulin resistance, and lipid metabolism. Similar to the intake of insulin, thyroid hormones, irisin, and calories, betatrophin expression in the organism is usually attributed to energy consumption or heat generation. It can mediate the activity of lipoprotein lipase (LPL), which is the key enzyme of lipoprotein lipolysis. Due to its association with metabolic markers and the roles of glucose and lipid, the physiological function of betatrophin in glucose homeostasis and lipid metabolism can be more comprehensively understood. Betatrophin was also shown to facilitate pancreatic β-cell proliferation in a mouse model of insulin resistance. There are also reports that demonstrate that betatrophin regulates triglycerides (TGs) in the liver. Therefore, the process of regulating the physiological function by betatrophin is complicated, and its exact biological significance remains elusive. This study provides a comprehensive review of the current research, and it discusses the possible physiological functions of betatrophin, and specifically the mechanism of betatrophin in regulating blood glucose and blood lipids.
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Adiponectin Intervention to Regulate Betatrophin Expression, Attenuate Insulin Resistance and Enhance Glucose Metabolism in Mice and Its Response to Exercise. Int J Mol Sci 2022; 23:ijms231810630. [PMID: 36142528 PMCID: PMC9505482 DOI: 10.3390/ijms231810630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/03/2022] [Accepted: 09/08/2022] [Indexed: 11/17/2022] Open
Abstract
Aims: Adiponectin stimulates mitochondrial biogenesis through peroxisome proliferator-activated receptor-coactivator1α (PGC-1α), a major regulator of mitochondrial biogenesis, and its effect on the genesis of insulin resistance is organ-specific. Expressed predominantly in fat and liver tissues, betatrophin is primarily involved in lipid metabolism, and could be a putative therapeutic target in metabolic syndrome and T2D. We hypothesized that the adiponectin pathway may regulate the production and/or secretion of betatrophin in liver. We aimed to determine whether exercise and adiponectin affect betatrophin to improve insulin resistance in mice. Methods: To investigate this hypothesis, we used wild-type C57BL/6 mice subjected to a high-fat diet, an exercise regimen, and i.p. injection of recombinant mouse adiponectin (Acrp30), and adiponectin knockout (Adipoq−/−) mice (C57BL/6 background) subjected to i.p. injection of Acrp30. Results: In Adipoq–/– mice, betatrophin levels in the plasma and liver were upregulated. In mice, plasma and liver betatrophin levels were significantly upregulated following a high-fat diet. Exercise and i.p. Acrp30 downregulated betatrophin levels and increased adiponectin mRNA and protein expression in the plasma and liver. The trend of change in PGC-1α and betatrophin levels in the liver was consistent. Conclusions/interpretation: Exercise reverses pathogenic changes in adiponectin and betatrophin levels in insulin-resistant mice. Exercise increased adiponectin levels and reduced betatrophin levels. Furthermore, exercise reduced betatrophin levels via adiponectin, which modulated the LKB1/AMPK/PGC-1α signaling axis but was not solely dependent on it for exerting its effects.
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Zhang Z, Yuan Y, Hu L, Tang J, Meng Z, Dai L, Gao Y, Ma S, Wang X, Yuan Y, Zhang Q, Cai W, Ruan X, Guo X. ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways. J Adv Res 2022; 47:41-56. [PMID: 36031141 PMCID: PMC10173191 DOI: 10.1016/j.jare.2022.08.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/24/2022] [Accepted: 08/08/2022] [Indexed: 10/15/2022] Open
Abstract
INTRODUCTION High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood. OBJECTIVES This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation. METHODS The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression. RESULTS ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo. CONCLUSIONS Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.
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Affiliation(s)
- Zongli Zhang
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Yue Yuan
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Lin Hu
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Jian Tang
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Zhongji Meng
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Shiyan, Hubei 442000, China
| | - Longjun Dai
- Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Yujiu Gao
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Shinan Ma
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Xiaoli Wang
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Yahong Yuan
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Qiufang Zhang
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China
| | - Weibin Cai
- Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
| | - Xuzhi Ruan
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
| | - Xingrong Guo
- Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.
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Fu CP, Oczypok EE, Ali H, DeLany JP, Reeves VL, Chang RF, Kershaw EE. Effect of physical activity in a weight loss program on circulating total ANGPTL8 concentrations in northern Americans with obesity: A prospective randomized controlled trial. Nutr Metab Cardiovasc Dis 2022; 32:1725-1733. [PMID: 35527126 PMCID: PMC9233128 DOI: 10.1016/j.numecd.2022.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/22/2022] [Accepted: 04/07/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND AND AIMS The primary goals of this study were to clarify 1) the effect of weight loss by lifestyle intervention on circulating total angiopoietin-like protein 8 (ANGPTL8), and 2) the role of physical activity on serum total ANGPTL8 in northern Americans with obesity but without diabetes. METHODS AND RESULTS A total of 130 subjects with body mass index (BMI) ≧ 35 kg/m2 but without diabetes were recruited, and 121 subjects completed a weight loss program for data analysis. Abdominal adipose tissue was determined by non-contrast computed tomography (CT). Serum total ANGPTL8 was higher in the group with obesity than in the lean control group. Serum total ANGPTL8 was positively correlated with waist circumference (WC), BMI, fasting insulin, HOMA-IR, HOMA-B, QUICKI, hs-CRP, IL-6, and leptin. Serum total ANGPTL8 did not significantly differ between the two intervention groups at baseline, and it was significantly lower after weight loss, with comparable changes with diet only and diet plus physical activity. CONCLUSION Among northern Americans with obesity but without diabetes, a lifestyle modification resulted in significant reduction of circulating total ANGPTL8 concentrations in a 6-month weight-loss period. Although addition of physical activity resulted in greater total and liver fat loss, it did not promote further significant decline of serum total ANGPTL8 beyond diet alone.
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Affiliation(s)
- Chia-Po Fu
- Graduate Institute of Biomedical Electronics and Bioinformatics, College of Electrical Engineering and Computer Science, National Taiwan University, Taipei, Taiwan; Division of Endocrinology and Metabolism, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Elizabeth E Oczypok
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Hira Ali
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - James P DeLany
- Translational Research Institute Adventhealth, Florida, USA
| | - Valerie L Reeves
- Customer Delivery, Data Science Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02412, USA
| | - Ruey-Feng Chang
- Graduate Institute of Biomedical Electronics and Bioinformatics, College of Electrical Engineering and Computer Science, National Taiwan University, Taipei, Taiwan
| | - Erin E Kershaw
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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TİMURKAAN M, AYYILDIZ H. Tip 2 diyabetli hastalarda angiopoietin benzeri protein 8 (ANGPTL8) ve Alarin düzeylerinin karşılaştırmalı bir değerlendirmesi. CUKUROVA MEDICAL JOURNAL 2022. [DOI: 10.17826/cumj.1038569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Purpose: Type 2 Diabetes Mellitus (T2DM) is one of the most serious public health problems that affect millions of people worldwide. There are 537 million adults diagnosed with diabetes worldwide and approximately 90% of these adults have type 2 diabetes. The study examined angiopoietin-like protein 8 (ANGPTL8) and Alarin levels of the patients diagnosed with T2DM in comparison with each other and with the healthy control group.
Materials and Methods: The study was conducted with a diabetes group consisting of 67 patients who were newly diagnosed with T2DM and who did not use any medication, and the control group consisting of 55 healthy people. ANGPTL8 and Alarin levels were measured using the ELISA (enzyme-linked immunosorbent assay) method.
Results: We found a significant increase in alarin and ANGPTL8 levels in the diabetic group compared to the control group. Furthermore, a positive correlation between Alarin levels and ANGPTL8, triglyceride, and insulin levels was found in the patient group. In addition, while both adipokines were higher in males in the patient group, both adipokines levels were lower in males than females in the control group, and there was a significant difference in ANGPTL8 levels.
Conclusion: High levels of ANGPTL8 and Alarin may facilitate the development of diabetes through the insulin resistance pathway. If this mechanism is more clearly elucidated, there may be a significant improvement in diabetic treatment projection.
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Affiliation(s)
| | - Hakan AYYILDIZ
- SAĞLIK BİLİMLERİ ÜNİVERSİTESİ, ELAZIĞ FETHİ SEKİN ŞEHİR SAĞLIK UYGULAMA VE ARAŞTIRMA MERKEZİ
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Inoue Y, Ienaga M, Kamiya T, Adachi T, Ohta M, Hara H. Royal jelly fatty acids downregulate ANGPTL8 expression through the decrease in HNF4α protein in human hepatoma HepG2 cells. Biosci Biotechnol Biochem 2022; 86:747-754. [PMID: 35325025 DOI: 10.1093/bbb/zbac043] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022]
Abstract
Royal jelly (RJ) intake has been reported to be effective for reducing serum lipids; however, the mechanism is not fully understood. Angiopoietin-like protein 8 (ANGPTL8), a secreted protein, plays a key role in lipid metabolism. In this study, we investigated the effects of specific fatty acids included in RJ (RJ fatty acids), such as 10-hydroxy-2-decenoic acid, 10-hydroxydecanoic acid, and sebacic acid (SA), on expression of ANGPTL8 in human hepatoma HepG2 cells. SA markedly reduced the expression of ANGPTL8. Reporter assay revealed that SA suppressed ANGPTL8 promoter activity. In addition, we identified a functional binding site of hepatocyte nuclear factor-4α (HNF4α), a liver-enriched transcription factor, in the ANGPTL8 promoter. SA reduced the levels of HNF4α protein and the binding of HNF4α to the ANGPTL8 promoter. Moreover, siRNA knockdown of HNF4α suppressed the expression of ANGTPL8 mRNA. Taken together, we conclude that SA downregulates ANGPTL8 expression via the decrease in HNF4α protein.
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Affiliation(s)
- Yuki Inoue
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Marina Ienaga
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Tetsuro Kamiya
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Tetsuo Adachi
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
| | - Mitsuhiro Ohta
- Biomarker Laboratory, Research Institute for Production Development, Kyoto, Japan
| | - Hirokazu Hara
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Japan
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Rejeki PS, Baskara PG, Herawati L, Pranoto A, Setiawan HK, Lesmana R, Halim S. Moderate-intensity exercise decreases the circulating level of betatrophin and its correlation among markers of obesity in women. J Basic Clin Physiol Pharmacol 2022; 33:769-777. [PMID: 35286051 DOI: 10.1515/jbcpp-2021-0393] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/15/2022] [Indexed: 12/21/2022]
Abstract
OBJECTIVES Positive energy homeostasis due to overnutrition and a sedentary lifestyle triggers obesity. Obesity has a close relationship with elevated levels of betatrophin and may increase the risk of developing metabolic syndrome. Therefore, lifestyle modification through a nonpharmacological approach based on physical exercise is the right strategy in lowering betatrophin levels. This study aimed to analyze the effect of moderate-intensity interval and continuous exercises on decreased betatrophin levels and the association between betatrophin levels and obesity markers in women. METHODS A total of 30 women aged 20-24 years old were randomly divided into three groups. Measurement of betatrophin levels using Enzyme-Linked Immunosorbent Assay (ELISA). Data analysis techniques used were one-way ANOVA and parametric linear correlation. RESULTS The results showed that the average levels of betatrophin pre-exercise were 200.40 ± 11.03 pg/mL at CON, 203.07 ± 42.48 pg/mL at MIE, 196.62 ± 21.29 pg/mL at MCE, and p=0.978. Average levels of betatrophin post-exercise were 226.65 ± 18.96 pg/mL at CON, 109.31 ± 11.23 pg/mL at MIE, 52.38 ± 8.18 pg/mL at MCE, and p=0.000. Pre-exercise betatrophin levels were positively correlated with age, BMI, FM, WHR, FBG, and PBF (p≤0.001). CONCLUSIONS Our study showed that betatrophin levels are decreased by 10 min post-MIE and post-MCE. However, moderate-intensity continuous exercise is more effective in lowering betatrophin levels than moderate-intensity interval exercise. In addition, pre-exercise betatrophin levels also have a positive correlation with obesity markers.
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Affiliation(s)
- Purwo Sri Rejeki
- Department of Medical Physiology and Biochemistry, Physiology Division, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Pradika Gita Baskara
- Sport Health Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Lilik Herawati
- Department of Medical Physiology and Biochemistry, Physiology Division, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Adi Pranoto
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Hayuris Kinandita Setiawan
- Department of Medical Physiology and Biochemistry, Physiology Division, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ronny Lesmana
- Department of Biomedical Science, Physiology Division, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Shariff Halim
- Clinical Research Centre, Management and Science University, Shah Alam, Malaysia
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Zhang R, Zhang K. An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues. Prog Lipid Res 2022; 85:101140. [PMID: 34793860 PMCID: PMC8760165 DOI: 10.1016/j.plipres.2021.101140] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 01/03/2023]
Abstract
In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissues (heart and skeletal muscle) for energy production, a process referred to as TG partitioning. Lipoprotein lipase (LPL), a rate-limiting enzyme in this fundamental physiological process, hydrolyzes circulating TG to generate free fatty acids that are taken up by peripheral tissues. The postprandial activity of LPL declines in oxidative tissues but rises in WAT, directing TG to WAT; the reverse is true during fasting. However, the molecular mechanism in regulating tissue-specific LPL activity during the fed-fast cycle has not been completely understood. Research on angiopoietin-like (ANGPTL) proteins (A3, A4, and A8) has resulted in an ANGPTL3-4-8 model to explain the TG partitioning between WAT and oxidative tissues. Food intake induces A8 expression in the liver and WAT. Liver A8 activates A3 by forming the A3-8 complex, which is then secreted into the circulation. The A3-8 complex acts in an endocrine manner to inhibit LPL in oxidative tissues. WAT A8 forms the A4-8 complex, which acts locally to block A4's LPL-inhibiting activity. Therefore, the postprandial activity of LPL is low in oxidative tissues but high in WAT, directing circulating TG to WAT. Conversely, during fasting, reduced A8 expression in the liver and WAT disables A3 from inhibiting oxidative-tissue LPL and restores WAT A4's LPL-inhibiting activity, respectively. Thus, the fasting LPL activity is high in oxidative tissues but low in WAT, directing TG to the former. According to the model, we hypothesize that A8 antagonism has the potential to simultaneously reduce TG and increase HDL-cholesterol plasma levels. Future research on A3, A4, and A8 can hopefully provide more insights into human health, disease, and therapeutics.
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Affiliation(s)
- Ren Zhang
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 East Canfield Street, Detroit, MI 48201, USA.
| | - Kezhong Zhang
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 East Canfield Street, Detroit, MI 48201, USA
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López-Bermudo L, Luque-Sierra A, Maya-Miles D, Gallego-Durán R, Ampuero J, Romero-Gómez M, Berná G, Martín F. Contribution of Liver and Pancreatic Islet Crosstalk to β-Cell Function/Dysfunction in the Presence of Fatty Liver. Front Endocrinol (Lausanne) 2022; 13:892672. [PMID: 35651973 PMCID: PMC9148952 DOI: 10.3389/fendo.2022.892672] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/12/2022] [Indexed: 11/13/2022] Open
Abstract
Tissue-to-tissue crosstalk regulates organ function, according to growing data. This phenomenon is relevant for pancreatic β-cells and the liver, as both tissues are involved in glucose homeostasis and lipid metabolism. The ability to fine-tune regulation and adaptive responses is enabled through communication between pancreatic β-cells and the liver. However, the crosstalk between both tissues changes when metabolic dysregulation is present. Factors and cargo from extracellular vesicles (EVs) released by liver and pancreatic β-cells that reach the circulation form the words of this interaction. The molecules released by the liver are called hepatokines and are usually secreted in response to the metabolic state. When hepatokines reach the pancreatic islets several mechanisms are initiated for their protection or damage. In the case of the crosstalk between pancreatic β-cells and the liver, only one factor has been found to date. This protein, pancreatic derived factor (PANDER) has been proposed as a novel linker between insulin resistance (IR) and type 2 diabetes mellitus (T2D) and could be considered a biomarker for non-alcoholic fatty liver disease (NAFLD) and T2D. Furthermore, the cargo released by EVs, mainly miRNAs, plays a significant role in this crosstalk. A better knowledge of the crosstalk between liver and pancreatic β-cells is essential to understand both diseases and it could lead to better prevention and new therapeutic options.
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Affiliation(s)
- Lucía López-Bermudo
- Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER), University Pablo Olavide, University of Seville, CSIC, Seville, Spain
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Amparo Luque-Sierra
- Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER), University Pablo Olavide, University of Seville, CSIC, Seville, Spain
| | - Douglas Maya-Miles
- Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Sevilla, Spain
- Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Gallego-Durán
- Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Sevilla, Spain
- Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Ampuero
- Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Sevilla, Spain
- Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Manuel Romero-Gómez
- Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Sevilla, Spain
- Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Genoveva Berná
- Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER), University Pablo Olavide, University of Seville, CSIC, Seville, Spain
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Franz Martín, ; Genoveva Berná,
| | - Franz Martín
- Andalusian Center of Molecular Biology and Regenerative Medicine (CABIMER), University Pablo Olavide, University of Seville, CSIC, Seville, Spain
- Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Franz Martín, ; Genoveva Berná,
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Herman MA, Birnbaum MJ. Molecular aspects of fructose metabolism and metabolic disease. Cell Metab 2021; 33:2329-2354. [PMID: 34619074 PMCID: PMC8665132 DOI: 10.1016/j.cmet.2021.09.010] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/02/2021] [Accepted: 09/13/2021] [Indexed: 02/06/2023]
Abstract
Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.
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Affiliation(s)
- Mark A Herman
- Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, NC, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
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Alduraywish AA. Cardiorespiratory and metabolic fitness indicators in novice volleyball trainees: effect of 1-week antioxidant supplementation with N-acetyl-cysteine/zinc/vitamin C. J Int Med Res 2021; 49:3000605211067125. [PMID: 34939440 PMCID: PMC8725015 DOI: 10.1177/03000605211067125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 11/29/2021] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES This study aimed to determine the effect of 7-day dietary supplementation of N-acetylcysteine (NAC)/zinc/vitamin C on the time-to-exhaustion (TTE), the cardiorespiratory fitness (CRF) index, and metabolic indicators. METHODS This study enrolled volleyball student trainees (n = 18 men) who took NAC/zinc/vitamin C (750 mg/5 mg/100 mg) for 7 days at Jouf University, Saudi Arabia. The CRF index and TTE were determined. Serum concentrations of metabolic regulators (insulin, betatrophin, and hepatocyte growth factor), biomarkers of cellular damage/hypoxia, and indicators of lipid and glycemic control were measured. RESULTS Supplementation improved the TTE and CRF index, and lowered cytochrome c, C-reactive protein, hypoxia-inducible factor-1α (HIF-1α), total cholesterol, insulin, and glycated hemoglobin values. Before and after supplementation, the CRF index was negatively correlated with body mass index and positively correlated with the TTE. Before supplementation, the CRF index was positively correlated with betatrophin concentrations, and hepatocyte growth factor concentrations were positively correlated with betatrophin concentrations and negatively correlated with the homeostasis model assessment of insulin resistance index. After supplementation, the CRF index was negatively correlated with HIF-1α concentrations and metabolites. Additionally, the TTE was negatively correlated with HIF-1α, cytochrome c, and triacylglycerol concentrations. CONCLUSION Supplementation of NAC/zinc/vitamin C improves metabolic and CRF performance.
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Abstract
ANGPTL8 is an important cytokine, which is significantly increased in type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome. Many studies have shown that ANGPTL8 can be used as a bio-marker of these metabolic disorders related diseases, and the baseline ANGPTL8 level has also been found to be positively correlated with retinopathy and all-cause mortality in patients with T2DM. This may be related to the inhibition of lipoprotein lipase activity and the reduction of circulating triglyceride (TG) clearance by ANGPTL8. Consistently, inhibition of ANGPTL8 seems to prevent or improve atherosclerosis. However, it is puzzling that ANGPTL8 seems to have a directing function for TG uptake in peripheral tissues; that is, ANGPTL8 specifically enhances the reserve and buffering function of white adipose tissue, which may alleviate the ectopic lipid accumulation to a certain extent. Furthermore, ANGPTL8 can improve insulin sensitivity and inhibit hepatic glucose production. These contradictory results lead to different opinions on the role of ANGPTL8 in metabolic disorders. In this paper, the correlation between ANGPTL8 and metabolic diseases, the regulation of ANGPTL8 and the physiological role of ANGPTL8 in the process of glucose and lipid metabolism were summarized, and the physiological/pathological significance of ANGPTL8 in the process of metabolic disorder was discussed.
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Affiliation(s)
- Chang Guo
- Department of Nephrology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Chenxi Wang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Xia Deng
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Jianqiang He
- Department of Nephrology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Ling Yang
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
| | - Guoyue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang 212001, Jiangsu, People's Republic of China
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Kaewkrasaesin C, Chatchomchuan W, Muanpetch S, Khovidhunkit W. ANGPTL3 and ANGPTL8 in Thai subjects with hyperalphalipoproteinemia and severe hypertriglyceridemia. J Clin Lipidol 2021; 15:752-759. [PMID: 34535418 DOI: 10.1016/j.jacl.2021.08.059] [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: 05/09/2021] [Revised: 08/21/2021] [Accepted: 08/25/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND The role of ANGPTL3 and ANGPTL8 in lipid regulation in patients with very high levels of HDL-cholesterol and triglyceride is unknown. OBJECTIVE We examined plasma levels of ANGPTL3 and ANGPTL8 in subjects with hyperalphalipoproteinemia (HALP) and in those with severe hypertriglyceridemia (HTG). METHODS Plasma ANGPTL3 and ANGPTL8 levels were measured by ELISA in 320 subjects, consisting of HALP subjects with HDL-cholesterol ≥100 mg/dl (n=90) and healthy controls (n=90) and subjects with triglyceride ≥886 mg/dl (n=89) and control subjects (n=51). RESULTS The mean plasma ANGPTL3 level was significantly higher in the HALP group compared to that of the controls (297 ± 112 ng/mL vs. 230 ± 100 ng/mL, p<0.001). Similarly, the mean plasma ANGPTL8 level was also higher in the HALP group (30 ± 11 ng/mL vs. 20 ± 8 ng/mL, p<0.001). Both ANGPTL3 and ANGPTL8 levels positively correlated with HDL-cholesterol levels. In the severe HTG group, plasma ANGPTL3 level was significantly higher than those in the control group (223 ± 105 ng/mL vs. 151 ± 60 ng/mL, p<0.001), but not ANGPTL8 (23 ± 20 ng/mL vs. 31 ± 23 ng/mL in controls, p=0.028). Only ANGPTL3, but not ANGPTL8, levels positively correlated with triglyceride levels. CONCLUSION Plasma level of ANGPTL3 was increased in both HALP and severe HTG whereas an increase in plasma level of ANGPTL8 was found only in HALP, and not in severe HTG, suggesting that both ANGPTL3 and ANGPTL8 might play distinct roles in lipid regulation on these two extremes of dyslipidemia.
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Affiliation(s)
- Chatchon Kaewkrasaesin
- Division of Endocrinology and Metabolism, Department of Medicine, and Hormonal and Metabolic Disorders Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Medicine, and Excellence Center for Diabetes, Hormone, and Metabolism, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Waralee Chatchomchuan
- Division of Endocrinology and Metabolism, Department of Medicine, and Hormonal and Metabolic Disorders Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Medicine, and Excellence Center for Diabetes, Hormone, and Metabolism, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Suwanna Muanpetch
- Department of Medicine, and Excellence Center for Diabetes, Hormone, and Metabolism, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Weerapan Khovidhunkit
- Division of Endocrinology and Metabolism, Department of Medicine, and Hormonal and Metabolic Disorders Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Department of Medicine, and Excellence Center for Diabetes, Hormone, and Metabolism, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
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Hao Q, Zheng A, Zhang H, Cao H. Down-regulation of betatrophin enhances insulin sensitivity in type 2 diabetes mellitus through activation of the GSK-3β/PGC-1α signaling pathway. J Endocrinol Invest 2021; 44:1857-1868. [PMID: 33464548 DOI: 10.1007/s40618-020-01493-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 12/23/2020] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The incidence of type 2 diabetes mellitus (T2DM) among children and adolescents has been rising. Accumulating evidences have noted the significant role of betatrophin in the regulation of lipid metabolism and glucose homeostasis. In our study, we tried to figure out the underlying mechanism of betatrophin in insulin resistance (IR) in type 2 diabetes mellitus (T2DM). METHODS First, fasting serum betatrophin, fasting blood glucose (FBG), insulin, total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were detected in T2DM children. The homeostasis model assessment of insulin resistance (HOMA-IR), Gutt insulin sensitivity index (ISIG) and Matsuda insulin sensitivity index (ISIM) were calculated. A T2DM-IR mouse model was induced by high-fat diet, with the expression of GSK-3β and PGC-1α detected. Besides, HepG2 cells were induced by a high concentration of insulin to establish an IR cell model (HepG2-IR). The cell viability, glucose consumption, liver glycogen content, inflammation, and fluorescence level of GSK-3β and PGC-1α were analyzed. RESULTS Betatrophin was highly expressed in serum of T2DM children and was positively correlated with FBG, insulin, TC, TG, LDL-C and HOMA-IR, while negatively correlated with ISIG and ISIM. Betatrophin and GSK-3β in the liver tissues of T2DM-IR mice were increased, while the PGC-1α expression was decreased. Betatrophin expression was negatively correlated with PGC-1α and positively correlated with GSK-3β. Silencing of betatrophin enhanced insulin sensitivity through the activation of GSK-3β/PGC-1α signaling pathway. In vitro experiments also found that silencing of betatrophin promoted glucose consumption and glycogen synthesis while inhibited inflammation. CONCLUSION Our findings concluded that silencing of betatrophin could enhance insulin sensitivity and improve histopathological morphology through the activation of GSK-3β/PGC-1α signaling pathway.
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Affiliation(s)
- Q Hao
- Department of Endocrinology, The First People's Hospital of Shangqiu, No.292 Kaixuan South Road, Shangqiu, 476100, Henan, People's Republic of China
| | - A Zheng
- College of Biology and Food, Shangqiu Normal University, Shangqiu, 476000, Henan, People's Republic of China
| | - H Zhang
- Department of Endocrinology, The First People's Hospital of Shangqiu, No.292 Kaixuan South Road, Shangqiu, 476100, Henan, People's Republic of China
| | - H Cao
- Department of Endocrinology, The First People's Hospital of Shangqiu, No.292 Kaixuan South Road, Shangqiu, 476100, Henan, People's Republic of China.
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Yeoh SG, Sum JS, Lai JY, W Isa WYH, Lim TS. Potential of Phage Display Antibody Technology for Cardiovascular Disease Immunotherapy. J Cardiovasc Transl Res 2021; 15:360-380. [PMID: 34467463 DOI: 10.1007/s12265-021-10169-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 08/22/2021] [Indexed: 11/26/2022]
Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. CVD includes coronary artery diseases such as angina, myocardial infarction, and stroke. "Lipid hypothesis" which is also known as the cholesterol hypothesis proposes the linkage of plasma cholesterol level with the risk of developing CVD. Conventional management involves the use of statins to reduce the serum cholesterol levels as means for CVD prevention or treatment. The regulation of serum cholesterol levels can potentially be regulated with biological interventions like monoclonal antibodies. Phage display is a powerful tool for the development of therapeutic antibodies with successes over the recent decade. Although mainly for oncology, the application of monoclonal antibodies as immunotherapeutic agents could potentially be expanded to CVD. This review focuses on the concept of phage display for antibody development and discusses the potential target antigens that could potentially be beneficial for serum cholesterol management.
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Affiliation(s)
- Soo Ghee Yeoh
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800, Penang, Malaysia
| | - Jia Siang Sum
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800, Penang, Malaysia
| | - Jing Yi Lai
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800, Penang, Malaysia
| | - W Y Haniff W Isa
- School of Medical Sciences, Department of Medicine, Universiti Sains Malaysia, Kubang Kerian, 16150, Kelantan, Malaysia
| | - Theam Soon Lim
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 11800, Penang, Malaysia.
- Analytical Biochemistry Research Centre, Universiti Sains Malaysia, 11800, Penang, Malaysia.
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Harada M, Yamakawa T, Kashiwagi R, Ohira A, Sugiyama M, Sugiura Y, Kondo Y, Terauchi Y. Association between ANGPTL3, 4, and 8 and lipid and glucose metabolism markers in patients with diabetes. PLoS One 2021; 16:e0255147. [PMID: 34293055 PMCID: PMC8297858 DOI: 10.1371/journal.pone.0255147] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 07/09/2021] [Indexed: 11/18/2022] Open
Abstract
Lipid management, especially with respect to triglyceride (TG) metabolism, in patients with diabetes is not sufficient with current therapeutic agents, and new approaches for improvement are needed. Members of the angiopoietin-like protein (ANGPTL) family, specifically ANGPTL3, 4, and 8, have been reported as factors that inhibit lipoprotein lipase (LPL) activity and affect TGs. The present study investigated the association between lipid and glucose metabolism markers and the mechanism by which these proteins affect lipid metabolism. A total of 84 patients hospitalized for diabetes treatment were evaluated. Lipid and glucose metabolism markers in blood samples collected before breakfast, on the day after hospitalization, were analyzed. ANGPTL8 showed a significant positive correlation with TG values. HDL-C values displayed a significant positive correlation with ANGPTL3 but a negative correlation with ANGPTL4 and ANGPTL8. The results did not indicate a significant correlation among ANGPTL3, 4, and 8 levels. Thus, it is possible that the distribution of these proteins differs among patients. When patients were divided into groups according to the levels of ANGPTL3 and ANGPTL8, those with high levels of both ANGPTL3 and ANGPTL8 also had high levels of TG and small dense LDL-C/LDL-C (%). Multiple regression analysis indicated that low LPL, high ApoC2, high ApoC3, high ApoE, and high ANGPTL8 levels were the determinants of fasting hypertriglyceridemia. By contrast, no clear association was observed between any of the ANGPTLs and glucose metabolism markers, but ANGPTL8 levels were positively correlated with the levels of HOMA2-IR and BMI. Patients with high levels of both ANGPTL3 and ANGPTL8 had the worst lipid profiles. Among ANGPTL3, 4, and 8, ANGPTL8 is more important as a factor determining plasma TG levels. We anticipate that the results of this research will facilitate potential treatments targeting ANGPTL8 in patients with diabetes.
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Affiliation(s)
- Marina Harada
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Tadashi Yamakawa
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
- * E-mail:
| | - Rie Kashiwagi
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Akeo Ohira
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Mai Sugiyama
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Yasuyuki Sugiura
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoshinobu Kondo
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University School of Medicine, Yokohama, Japan
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Sonmez A, Dogru T, Ercin CN, Genc H, Celebi G, Gurel H, Tapan S, Cicek AF, Barcin C, Haymana C, Kirik A, Rizzo M. Betatrophin Levels Are Related to the Early Histological Findings in Nonalcoholic Fatty Liver Disease. Metabolites 2021; 11:425. [PMID: 34203342 PMCID: PMC8306475 DOI: 10.3390/metabo11070425] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/17/2021] [Accepted: 06/24/2021] [Indexed: 02/06/2023] Open
Abstract
Betatrophin, a liver hormone, regulates glucose and lipid metabolism. We investigated the betatrophin levels in nonalcoholic fatty liver disease (NAFLD) and searched for any relationship with histological severity and metabolic parameters. Fifty males with NAFLD [Nonalcoholic Steatohepatitis (NASH) (n = 32); non-NASH (n = 18)] and 30 healthy controls were included. Plasma betatrophin was measured by ELISA method. Insulin sensitivity was assessed by HOMA-IR index. Histological features were scored by the semi quantitative classification and combined as the NAFLD activity score (NAS). Betatrophin levels in the non-NASH group were significantly higher than the controls. Betatrophin was positively correlated to the age, waist circumference, total cholesterol, triglycerides, LDL cholesterol, glucose, insulin, HOMA-IR index and gamma glutamyl transpeptidase levels, and negatively correlated to the steatosis and NAS. In the stepwise linear regression analysis, the triglyceride (β = 0.457, p < 0.001), glucose (β = 0.281, p = 0.02) and NAS (β = -0.260, p = 0.03) were the independent determinants of betatrophin. Betatrophin levels are higher in the early stages of NAFLD and tend to decrease when the disease progresses. This could be an important preliminary mechanistic finding to explain the increased frequency of glucose intolerance during the course of NAFLD.
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Affiliation(s)
- Alper Sonmez
- Department of Endocrinology and Metabolism, Gulhane School of Medicine, University of Health Sciences, Ankara 06010, Turkey
| | - Teoman Dogru
- Department of Gastroenterology, School of Medicine, Balikesir University, Cagis, Balikesir 10145, Turkey;
| | - Cemal Nuri Ercin
- Department of Gastroenterology, Gulhane School of Medicine, University of Health Sciences, Ankara 06010, Turkey; (C.N.E.); (G.C.)
| | - Halil Genc
- Department of Gastroenterology, Batigoz Hospital, Balcova, Izmir 35330, Turkey;
| | - Gurkan Celebi
- Department of Gastroenterology, Gulhane School of Medicine, University of Health Sciences, Ankara 06010, Turkey; (C.N.E.); (G.C.)
| | - Hasan Gurel
- Department of Gastroenterology, University of Health Sciences, Samsun Training and Research Hospital, Samsun 55090, Turkey;
| | - Serkan Tapan
- Section of Biochemistry, ENA Laboratory, Ankara 06680, Turkey;
| | - Ali Fuat Cicek
- Department of Pathology, Gulhane School of Medicine, University of Health Sciences, Etlik, Ankara 06010, Turkey;
| | - Cem Barcin
- Department of Cardiology, Gulhane School of Medicine, University of Health Sciences, Ankara 06010, Turkey;
| | - Cem Haymana
- Department of Endocrinology and Metabolism, Gulhane Training and Research Hospital, University of Health Sciences, Ankara 06010, Turkey;
| | - Ali Kirik
- Department of Internal Medicine, School of Medicine, Balikesir University, Cagis, Balikesir 10145, Turkey;
| | - Manfredi Rizzo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of South Carolina, Columbia, SC 29208, USA;
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90133 Palermo, Italy
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ANGPTL8 in cardio-metabolic diseases. Clin Chim Acta 2021; 519:260-266. [PMID: 34023284 DOI: 10.1016/j.cca.2021.05.017] [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: 01/22/2021] [Revised: 05/08/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022]
Abstract
Dyslipidemia has been identified as an important factor in obesity, diabetes mellitus, and cardiovascular diseases (CVD), grouped as cardio-metabolic disorder diseases. Accordingly, dyslipidemia has become a major determinant in health worldwide. Both genome-wide association studies (GWAS) and research studies have focused on the elucidation of potential genetic mechanisms of dyslipidemia and the identification of new gene loci which contribute to the development of cardio-metabolic disorder diseases. Recent results indicate that both the ANGPTL8 gene and ANGPTL8 protein perform vital roles in modulating serum glucose and lipid metabolism. In this review, we examine the modulatory effects of ANGPTL8 and explore the potential mechanisms whereby ANGPTL8 affects serum glucose and lipid metabolism in cardio-metabolic disorder diseases.
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Oldoni F, Bass K, Kozlitina J, Hudson H, Shihanian LM, Gusarova V, Cohen JC, Hobbs HH. Genetic and Metabolic Determinants of Plasma Levels of ANGPTL8. J Clin Endocrinol Metab 2021; 106:1649-1667. [PMID: 33619548 PMCID: PMC8118582 DOI: 10.1210/clinem/dgab120] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Indexed: 12/16/2022]
Abstract
CONTEXT ANGPTL8 (A8) plays a key role in determining the tissue fate of circulating triglycerides (TGs). Plasma A8 levels are associated with several parameters of glucose and TG metabolism, but the causality of these relationships and the contribution of genetic variants to differences in A8 levels have not been explored. OBJECTIVE To characterize the frequency distribution of plasma A8 levels in a diverse population using a newly-developed enzyme-linked immunosorbent assay (ELISA) and to identify genetic factors contributing to differences in plasma A8 levels. METHODS We studied a population-based sample of Dallas County, comprising individuals in the Dallas Heart Study (DHS-1, n = 3538; DHS-2, n = 3283), including 2131 individuals with repeated measurements 7 to 9 years apart (age 18-85 years; >55% female; 52% Black; 29% White; 17% Hispanic; and 2% other). The main outcome measures were associations of A8 levels with body mass index (BMI), plasma levels of glucose, insulin, lipids, and hepatic TGs, as well as DNA variants identified by exome-wide sequencing. RESULTS A8 levels varied over a 150-fold range (2.1-318 ng/mL; median, 13.3 ng/mL) and differed between racial/ethnic groups (Blacks > Hispanics > Whites). A8 levels correlated with BMI, fasting glucose, insulin, and TG levels. A variant in A8, R59W, accounted for 17% of the interindividual variation in A8 levels but was not associated with the metabolic parameters correlated with plasma A8 concentrations. CONCLUSIONS A8 levels were strongly associated with indices of glucose and TG metabolism, but the lack of association of genetic variants at the A8 locus that impact A8 levels with these parameters indicates that differences in A8 levels are not causally related to the associated metabolic phenotypes.
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Affiliation(s)
- Federico Oldoni
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kevin Bass
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Julia Kozlitina
- The Eugene McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Hannah Hudson
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | | | - Jonathan C Cohen
- The Eugene McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- The Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Helen H Hobbs
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
- The Eugene McDermott Center of Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Su X, Zhang G, Cheng Y, Wang B. New insights into ANGPTL8 in modulating the development of cardio-metabolic disorder diseases. Mol Biol Rep 2021; 48:3761-3771. [PMID: 33864591 DOI: 10.1007/s11033-021-06335-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/02/2021] [Indexed: 12/14/2022]
Abstract
Dyslipidemia is being identified as the most important factors of several health problems, such as obesity, diabetes mellitus, and cardiovascular diseases (CVD), which are always grouped together as cardio-metabolic disorder diseases. Consistently, dyslipidemia has become one of the most rising crisis of general health. Recently, it is worth noting that both genome-wide association studies (GWAS) and experimental research are being taken advantage to elucidate the potential genetic mechanisms of dyslipidemia and to identify new gene loci which contribute to the development of cardio-metabolic disorder diseases. According to the results, both ANGPTL8 gene and ANGPTL8 protein has been shown to embrace vital functions in modulating serum glucose and lipid metabolism. In the current review, the modulatory effects of ANGPTL8 in cardio-metabolic disorder diseases were summarized. In addition, novel insights which elucidate the potential mechanisms whereby ANGPTL8 affects glucose and lipid metabolism were also provided.
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Affiliation(s)
- Xin Su
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, Xiamen, 361000, Fujian, China
| | - Guoming Zhang
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, Xiamen, 361000, Fujian, China
| | - Ye Cheng
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, Xiamen, 361000, Fujian, China.
| | - Bin Wang
- Department of Cardiology, The Xiamen Cardiovascular Hospital of Xiamen University, No. 2999 Jinshan Road, Xiamen, 361000, Fujian, China.
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Navaeian M, Asadian S, Ahmadpour Yazdi H, Gheibi N. ANGPTL8 roles in proliferation, metabolic diseases, hypothyroidism, polycystic ovary syndrome, and signaling pathways. Mol Biol Rep 2021; 48:3719-3731. [PMID: 33864588 DOI: 10.1007/s11033-021-06270-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 03/05/2021] [Indexed: 12/18/2022]
Abstract
A new and atypical member of the ANGPTL family is angiopoietin-like protein 8 (ANGPTL8). This newly discovered hormone is a drug target that can be used to treat diabetes and dyslipidemia. The protein, as a hepatocyte-derived circulating factor, can control the triglyceride level of plasma. ANGPTL8 is significantly associated with inflammation and metabolic syndrome consequences such as obesity, diabetes, hypothyroidism, and PCOS. ANGPTL8 gene has four exons encoding a 22/5 kDa weight of 198 amino acid polypeptides. A highly preserved ANGPTL8 gene among mammals exhibits the essential hormone functions of ANGPTL8. Nevertheless, the physiological function of this hormone in the body is poorly understood. Studies published in PubMed (2008-2020), Google Scholar (2004-2020), and Scopus (2004-2020) databases of clinical trials were reviewed. This analysis is aimed at collecting information on ANGPTL8. The emphasis of this review was on gathering information about the role of ANGPTL8 in the metabolism of glucose and lipids and cell proliferation. It addition to the different roles of ANGPTL8 in diabetes and lipid metabolism, this review emphasized on the protein role in signaling pathways. The study also proposes the signaling pathways that may be considered as a new target for treatment.
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Affiliation(s)
- Maryam Navaeian
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Samieh Asadian
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hossein Ahmadpour Yazdi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Nematollah Gheibi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
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Gong W, Bilixzi A, Wang X, Lu Y, Wan L, Han L. The role of serum β-trophin and endostatin in patients with polycystic ovary syndrome: Are they correlated? BMC WOMENS HEALTH 2021; 21:104. [PMID: 33706732 PMCID: PMC7953644 DOI: 10.1186/s12905-021-01198-4] [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: 04/14/2020] [Accepted: 01/28/2021] [Indexed: 11/10/2022]
Abstract
Background It’s necessary to investigate the serum β-trophin and endostatin (ES) level and its influencing factors in patients with newly diagnosed polycystic ovary syndrome (PCOS). Methods Newly diagnosed PCOS patients treated in our hospital were selected, and healthy women who took physical examination during the same period as healthy controls. We detected and compared the related serum indicators between two groups, Pearson correlation were conducted to identify the factors associated with β-trophin and ES, and the influencing factors of β-trophin and ES were analyzed by logistic regression. Results A total of 62 PCOS patients and 65 healthy controls were included. The BMI, WHI, LH, FSH, TT, FAI, FBG, FINS, HOMA-IR, TC, TG, LDL, ES in PCOS patients were significantly higher than that of healthy controls, while the SHBG and HDL in PCOS patients were significantly lower than that of healthy controls (all p < 0.05). β-trophin was closely associated with BMI (r = 0.427), WHR (r = 0.504), FBG (r = 0.385), TG (r = 0.405) and LDL (r = 0.302, all p < 0.05), and ES was closely associated with BMI (r = 0.358), WHR (r = 0.421), FBG (r = 0.343), TC (r = 0.319), TG (r = 0.404, all p < 0.05). TG, BMI, WHR and FBG were the main factors affecting the serum β-trophin levels (all p < 0.05). FBG, TC and BMI were the main factors affecting the serum ES levels (all p < 0.05). The TG, β-trophin, ES level in PCOS patients with insulin resistance (IR) were significantly higher than that of those without IR (all p < 0.05). Conclusion Increased β-trophin is closely associated with increased ES in patients with PCOS, which may be the useful indicators for the management of PCOS.
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Affiliation(s)
- Wei Gong
- Department of Gynecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Urumqi, 214000, Xinjiang, China
| | - Aikmu Bilixzi
- Department of Gynecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Urumqi, 214000, Xinjiang, China
| | - Xinmei Wang
- Department of Gynecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Urumqi, 214000, Xinjiang, China
| | - Yanli Lu
- Department of Gynecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Urumqi, 214000, Xinjiang, China
| | - Li Wan
- Department of Gynecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Urumqi, 214000, Xinjiang, China
| | - Lu Han
- Department of Gynecology, The Fourth Affiliated Hospital of Xinjiang Medical University, No. 116 Huanghe Road, Urumqi, 214000, Xinjiang, China.
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Atkinson EG, Maihofer AX, Kanai M, Martin AR, Karczewski KJ, Santoro ML, Ulirsch JC, Kamatani Y, Okada Y, Finucane HK, Koenen KC, Nievergelt CM, Daly MJ, Neale BM. Tractor uses local ancestry to enable the inclusion of admixed individuals in GWAS and to boost power. Nat Genet 2021; 53:195-204. [PMID: 33462486 PMCID: PMC7867648 DOI: 10.1038/s41588-020-00766-y] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 12/15/2020] [Indexed: 12/26/2022]
Abstract
Admixed populations are routinely excluded from genomic studies due to concerns over population structure. Here, we present a statistical framework and software package, Tractor, to facilitate the inclusion of admixed individuals in association studies by leveraging local ancestry. We test Tractor with simulated and empirical two-way admixed African-European cohorts. Tractor generates accurate ancestry-specific effect-size estimates and P values, can boost genome-wide association study (GWAS) power and improves the resolution of association signals. Using a local ancestry-aware regression model, we replicate known hits for blood lipids, discover novel hits missed by standard GWAS and localize signals closer to putative causal variants.
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Affiliation(s)
- Elizabeth G Atkinson
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Adam X Maihofer
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Masahiro Kanai
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA
- Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Alicia R Martin
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Konrad J Karczewski
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Marcos L Santoro
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, Brazil
- Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Jacob C Ulirsch
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
| | - Yoichiro Kamatani
- Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Yukinori Okada
- Department of Statistical Genetics, Graduate School of Medicine, Osaka University, Suita, Japan
- Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
| | - Hilary K Finucane
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Karestan C Koenen
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | | | - Mark J Daly
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Benjamin M Neale
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Salama MM, Kabiel WA, Hana SS, Mohamed GA. Correlation of serum betatrophin levels with disease severity and the emergence of insulin resistance in cirrhotic patients. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00039-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Insulin resistance (IR) is frequently associated with chronic liver disease. There has been an increased interest in betatrophin protein and its involvement in the compensatory response to IR. We aimed to investigate the correlation of serum betatrophin levels with disease severity and the emergence of IR in cirrhotic patients. This study included 27 cirrhotic patients and 30 healthy participants who served as a control group. IR was assessed by the Homeostasis Model Assessment (HOMA-IR). Serum insulin and betatrophin levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA).
Results
IR was existing in 74% of cirrhotic patients (p < 0.001). Subjects with IR had higher serum betatrophin levels than those without IR (p = 0.04). Serum betatrophin levels were significantly higher in cirrhotic patients than controls (p < 0.001). In addition, Child-Pugh class C patients had higher serum betatrophin levels than those with Child-Pugh class B cirrhosis (p = 0.01). Moreover, the highest serum betatrophin levels were detected in patients with tense ascites followed by those with moderate and mild ascites (p = 0.01). In the cirrhosis group, serum betatrophin levels correlated positively with fasting blood glucose levels (p < 0.001), fasting insulin levels (p = 0.006), HOMA-IR (p = 0.006), Child-Pugh score (p = 0.023), MELD score (p < 0.001), and INR (p = 0.005), and correlated negatively with platelets count (p = 0.01).
Conclusion
Cirrhotic patients have higher serum betatrophin levels; moreover, these levels are positively correlated with disease severity as well as the emergence of insulin resistance.
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Abu-Farha M, Ghosh A, Al-Khairi I, Madiraju SRM, Abubaker J, Prentki M. The multi-faces of Angptl8 in health and disease: Novel functions beyond lipoprotein lipase modulation. Prog Lipid Res 2020; 80:101067. [PMID: 33011191 DOI: 10.1016/j.plipres.2020.101067] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 09/17/2020] [Accepted: 09/29/2020] [Indexed: 12/18/2022]
Abstract
Angiopoietin-like protein (ANGPTL) family members, mainly ANGPTL3, ANGPTL4 and ANGPTL8, are physiological inhibitors of lipoprotein lipase (LPL), and play a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 has been described by different names in various studies and has been ascribed various functions at the systemic and cellular levels. Circulating ANGPTL8 originates mainly from the liver and to a smaller extent from adipose tissues. In the blood, ANGPTL8 forms a complex with ANGPTL3 or ANGPTL4 to inhibit LPL in fed or fasted conditions, respectively. Evidence is emerging for additional intracellular and receptor-mediated functions of ANGPTL8, with implications in NFκB mediated inflammation, autophagy, adipogenesis, intra-cellular lipolysis and regulation of circadian clock. Elevated levels of plasma ANGPTL8 are associated with metabolic syndrome, type 2 diabetes, atherosclerosis, hypertension and NAFLD/NASH, even though the precise relationship is not known. Whether ANGPTL8 has direct pathogenic role in these diseases, remains to be explored. In this review, we develop a balanced view on the proposed association of this protein in the regulation of several pathophysiological processes. We also discuss the well-established functions of ANGPTL8 in lipoprotein metabolism in conjunction with the emerging novel extracellular and intracellular roles of ANGPTL8 and the implicated metabolic and signalling pathways. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states should unveil new opportunities of therapeutic intervention for cardiometabolic disorders.
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Affiliation(s)
- Mohamed Abu-Farha
- Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Anindya Ghosh
- Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Irina Al-Khairi
- Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - S R Murthy Madiraju
- Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute, Kuwait City, Kuwait..
| | - Marc Prentki
- Departments of Nutrition, Biochemistry and Molecular Medicine, Université de Montréal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
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Mohany KM, Al Rugaie O, Al-Wutayd O, Al-Nafeesah A, Saleem TH. Association between circulating microRNAs 486, 146b and 15b and serum betatrophin levels in obese; type 2 diabetic and non-diabetic children. BMC Endocr Disord 2020; 20:145. [PMID: 32988370 PMCID: PMC7523287 DOI: 10.1186/s12902-020-00628-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/17/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND This study tested the association between serum levels of microRNA-486, -146b and -15b and betatrophin in normal and obese children with/without type 2 diabetes mellitus (T2DM). METHODS the study included 120 children; divided into three groups: G1 (50 healthy), G2 (35 obese) and G3 (35 obese with T2DM). The levels of microRNA-486, 146b and 15b and serum betatrophin were measured by their corresponding methods. RESULTS serum microRNA-486, -146b, -15b and betatrophin levels were significantly high in G3 followed by G2 then G1 (p = 0.002, > 0.001, > 0.001, and > 0.001, respectively). Especially in G3, these levels correlated positively with the BMI percentile (r = 0.44, 0.58, 0.38, and 0.46, p = 0.007, > 0.001, 0.021, and 0.005, respectively), serum glucose (r = 0.56, 0.49, 0.82, 0.60, and 0.42, p > 0.001, 0.003, > 0.001, and > 0.001, respectively) and HbA1c% (r = 0.56, 0.39, 0.66, and 0.42, p > 0.001, 0.019, > 0.001, and 0.032, respectively) while, showed negative correlations with correlated with serum insulin levels (r = - 0.37, - 0.42, - 0.58, and - 0.41, p = 0.021, 0.012, > 0.001 and 0.013, respectively) and with serum C-peptide levels (r = - 0.76, - 0.50, - 0.35 and - 0.42, p > 0.001, 0.002, 0.036 and 0.011, respectively). Serum betatrophin levels correlated positively with microRNA-486, -146b and -15b levels in G2 (r = 0.35, 0.80, and 0.67, p = 0.036, > 0.001, and,> 0.001, respectively), and in G3 (r = 0.57, 0.36, and 0.38, p > 0.001, 0.029 and, 0.023, respectively). CONCLUSIONS Circulating microRNA-486, 146b and 15b increase significantly in obese children with T2DM and these levels correlate positively with serum betatrophin levels. Further studies are required to test the role of targeting of these microRNAs and betatrophin in the timely management of obesity and/or T2DM in children.
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Affiliation(s)
- Khalid M Mohany
- Department of medical biochemistry, College of Medicine, Assiut University, Assiut, Egypt.
- Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia.
| | - Osamah Al Rugaie
- Department of Basic Medical Sciences, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Osama Al-Wutayd
- Department of Family and Community Medicine, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Abdullah Al-Nafeesah
- Department of Pediatrics, Unaizah College of Medicine and Medical Sciences, Qassim University, Unaizah, Saudi Arabia
| | - Tahia H Saleem
- Department of medical biochemistry, College of Medicine, Assiut University, Assiut, Egypt
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