1
|
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] [MESH Headings] [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.
Collapse
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.
| |
Collapse
|
2
|
Gumuskaya PO, Yildirim E, Altun O, Uzun H. Clinical Value of Circulating Angiopoietin-like Protein 8/Betatrophin Levels in Patients with Acute Pancreatitis. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:708. [PMID: 40282999 PMCID: PMC12028795 DOI: 10.3390/medicina61040708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 04/06/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: Acute pancreatitis (AP) is an inflammatory disorder of the pancreas, with severe cases linked to a higher mortality rate. The prognosis of AP is influenced by factors such as necrosis, secondary infections, and organ failure. Tissue damage in AP is driven by the activation of leukocytes and the release of inflammatory mediators. Angiopoietin-like protein 8 (ANGPTL8), also known as betatrophin, is a recently discovered protein that regulates lipid metabolism. This study aimed to investigate the relationship between ANGPTL8 levels and disease severity in AP patients, and to explore the potential of ANGPTL8 as a biomarker. Materials and Methods: This prospective study included 50 patients diagnosed with AP who were admitted to the Department of Internal Medicine at Dr. Cemil Taşcıoğlu City Hospital between September 2021 and February 2022. Additionally, 39 healthy volunteers who underwent a check-up at the same hospital served as the control group. The Glasgow-Imrie (GI) score was used to assess the severity of pancreatitis. Results: ANGPTL8 levels were found to be significantly lower in the AP group compared to the control group, with a statistically significant correlation between ANGPTL8 levels and the severity of AP (p < 0.05). The cut-off level of ANGPTL8 based on the GI score was determined to be 70.9 ng/L. The GI score for ANGPTL8 was 0.749 (95% CI: 0.606-0.861) (p < 0.001). The overall cut-off value for ANGPTL8 was 179.2 ng/L, with an overall classification rate of 0.936 (95% CI: 0.864-0.977) (p < 0.001). Conclusions: This study demonstrates that ANGPTL8 levels vary between patients with and without AP, with lower levels observed in AP patients. Our research is the first to identify decreased ANGPTL8 levels as an independent predictor of AP severity. ANGPTL8 may play a crucial role in regulating inflammation or metabolic dysfunction in AP. However, further studies are needed to confirm these findings in larger populations and investigate ANGPTL8's mechanistic role in AP. Longitudinal studies could help determine whether ANGPTL8 levels act as a biomarker for disease progression or treatment response, potentially paving the way for targeted therapies to improve outcomes for AP patients.
Collapse
Affiliation(s)
- Perihan Ozkan Gumuskaya
- Department of Internal Medicine, Prof. Dr. Cemil Taşcıoğlu City Hospital, University of Health Sciences, 340110 Istanbul, Turkey;
| | - Emine Yildirim
- Department of General Surgery, Faculty of Medicine, Istanbul Atlas University, 34403 Istanbul, Turkey;
| | - Ozgur Altun
- Department of Internal Medicine, Prof. Dr. Cemil Taşcıoğlu City Hospital, University of Health Sciences, 340110 Istanbul, Turkey;
| | - Hafize Uzun
- Department of Medical Biochemistry, Faculty of Medicine, Istanbul Atlas University, 34403 Istanbul, Turkey;
| |
Collapse
|
3
|
Tramontano D, D'Erasmo L, Larouche M, Brisson D, Lauzière A, Di Costanzo A, Bini S, Minicocci I, Covino S, Baratta F, Pasquali M, Cerbelli B, Gaudet D, Arca M. The vicious circle of chronic kidney disease and hypertriglyceridemia: What is first, the hen or the egg? Atherosclerosis 2025; 403:119146. [PMID: 40056689 DOI: 10.1016/j.atherosclerosis.2025.119146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/10/2025]
Abstract
Chronic kidney disease (CKD) is documented to cause alterations in lipid metabolism, and this was considered a potent driver of increased cardiovascular risk. Among the diverse alteration of lipid traits in CKD, research endeavours have predominantly concentrated on low-density lipoproteins (LDL) in view of the potent pro-atherogenic role of these lipoprotein particles and the demonstration of protective cardiovascular effect of reducing LDL. However, few studies have focused on the metabolism of triglyceride-rich lipoproteins and even fewer on their role in causing kidney damage. Therefore, the comprehensive description of the impact of hypertriglyceridemia (HTG) in CKD pathophysiology remains largely undetermined. This reflects the difficulty of disentangling the independent role of triglycerides (TG) in the complex, bidirectional relationship between TG and kidney disease. Abnormal neutral lipid accumulation in the intrarenal vasculature and renal cells eventually due to HTG may also promote glomerular injury, throughout mechanisms including oxidative stress, mitochondrial dysfunction and proinflammatory responses. While epidemiological and experimental evidence suggests a potential role of TG in kidney damage, the causal mechanisms and their clinical relevance remain unclear, representing a significant area for future investigation. This review aims to highlight the intricate interplay between TG metabolism and kidney disease, shedding light on the mechanisms through which HTG may influence kidney functionality.
Collapse
Affiliation(s)
- Daniele Tramontano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy.
| | - Miriam Larouche
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Diane Brisson
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Alex Lauzière
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Ilenia Minicocci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Stella Covino
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Francesco Baratta
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Marzia Pasquali
- Department of Internal Medicine and Medical Specialities, Nephrology Unit, University Policlinico Umberto I Hospital, Rome, Italy
| | - Bruna Cerbelli
- Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome, Rome, Italy
| | - Daniel Gaudet
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| |
Collapse
|
4
|
Lee S, Ko K, Kim G, Park J, Ryu Y. Comparison of Meat Quality, Including Fatty Acid Content and Amino Acid Profile, and Transcriptome Profile among Hanwoo, Korea Black Cattle, and Jeju Black Cattle. Food Sci Anim Resour 2025; 45:553-572. [PMID: 40093631 PMCID: PMC11907422 DOI: 10.5851/kosfa.2024.e107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/21/2024] [Accepted: 10/21/2024] [Indexed: 03/19/2025] Open
Abstract
This study aimed to compare the meat quality, including fatty acid content, amino acid profile, and transcriptome profile, among three Korean cattle breeds: Hanwoo, Korean black cattle (KBC), and Jeju black cattle (JBC). We analyzed fatty acid compositions, revealing that Hanwoo had higher levels of saturated fatty acids such as pentadecanoic acid, palmitic acid, and margaric acid than other cattle breeds. In contrast, KBC showed higher levels of linolenic acid, which is one of the omega-3 polyunsaturated fatty acids. Free amino acid profiles showed that Hanwoo and JBC had significantly higher levels of glutamic acid, glycine, and phenylalanine compared to KBC. KBC had a significantly higher arginine content, while Hanwoo had a significantly higher serine content compared to the other two breeds. Regarding constituent amino acid content, JBC had a higher glutamic acid content, which is associated with umami, and exhibited a lower level of valine, arginine, isoleucine, and phenylalanine compared to the other breeds. RNA transcriptome analysis identified key differentially expressed genes involved in lipid metabolism and energy homeostasis, including MOGAT1, ANGPTL8, and SLC38A4. Network analysis highlighted substantial differences in muscle system processes, fat cell differentiation, and other pathways between the breeds. These findings provide foundational data for genetic selection programs aimed at enhancing meat quality and offer valuable insights into preserving the unique characteristics of Korean indigenous cattle.
Collapse
Affiliation(s)
- SangHoon Lee
- Division of Biotechnology, Sustainable Agriculture Research Institute, Jeju National University, Jeju 63243, Korea
| | - KyoungBo Ko
- Division of Biotechnology, Sustainable Agriculture Research Institute, Jeju National University, Jeju 63243, Korea
| | - GwangHeun Kim
- Division of Biotechnology, Sustainable Agriculture Research Institute, Jeju National University, Jeju 63243, Korea
| | - JongEun Park
- Division of Biotechnology, Sustainable Agriculture Research Institute, Jeju National University, Jeju 63243, Korea
| | - YounChul Ryu
- Division of Biotechnology, Sustainable Agriculture Research Institute, Jeju National University, Jeju 63243, Korea
| |
Collapse
|
5
|
Zhang Y, Zhou S, Zhao R, Xiong C, Huang Y, Zhang M, Wang Y. Multilayer regulation of postprandial triglyceride metabolism in response to acute cold exposure. J Lipid Res 2025; 66:100751. [PMID: 39892721 PMCID: PMC11903801 DOI: 10.1016/j.jlr.2025.100751] [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: 11/19/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/04/2025] Open
Abstract
Triglyceride-rich lipoproteins carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multilayered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.
Collapse
Affiliation(s)
- Yiliang Zhang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Shengyang Zhou
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Runming Zhao
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Chunyu Xiong
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Yingzhen Huang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Minzhu Zhang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
| | - Yan Wang
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
| |
Collapse
|
6
|
Leander K, Chen YQ, Vikström M, Silveira A, Fisher RM, Konrad RJ, van 't Hooft FM. Circulating ANGPTL3/8 Concentrations Are Associated With an Atherogenic Lipoprotein Profile and Increased CHD Risk in Swedish Population-Based Studies. Arterioscler Thromb Vasc Biol 2025; 45:443-451. [PMID: 39882603 DOI: 10.1161/atvbaha.124.321308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 12/06/2024] [Accepted: 12/26/2024] [Indexed: 01/31/2025]
Abstract
BACKGROUND Binding of ANGPTL (angiopoietin-like protein)-3 to ANGPTL8 generates a protein complex (ANGPTL3/8) that strongly inhibits LPL (lipoprotein lipase) activity, as compared with ANGPTL3 alone, suggesting that ANGPTL3/8 concentrations are critical for the regulation of circulation lipoprotein concentrations and subsequent increased coronary heart disease (CHD) risk. To test this hypothesis in humans, we evaluated the associations of circulating free ANGPTL3 and ANGPTL3/8 complex concentrations with lipoprotein concentrations and CHD risk in 2 prospective cohort studies. METHODS Fasting blood samples were obtained in conjunction with the baseline evaluation of 9479 subjects from 2 population-based Swedish cohorts of middle-aged men and women. Standard biochemical blood analyses, including all lipid/lipoprotein measurements, were performed in these samples at baseline. Additional serum samples were stored at -80 °C and used at a later stage for ANGPTL3 and ANGPTL3/8 concentration measurements. Information about incident CHD was obtained for both cohorts by matching to the Swedish National Patient Register and the Cause of Death Register. RESULTS ANGPTL3 concentrations showed modest, positive associations with all lipoprotein concentrations but were not associated with CHD risk. In contrast, ANGPTL3/8 concentrations were associated in both cohorts with an atherogenic lipoprotein profile (characterized by increased triglyceride and LDL [low-density lipoprotein] concentrations and reduced HDL [high-density lipoprotein] concentrations). In the combined cohort, ANGPTL3/8 was associated with increased CHD risk. Hazard ratio per 1 SD increase was 1.10 (95% CI, 1.03-1.17) after adjustment for age, sex, cohort, smoking, and hypertension. CONCLUSIONS Elevated concentrations of ANGPTL3/8, but not ANGPTL3, are associated with an atherogenic lipoprotein profile and increased CHD risk in humans.
Collapse
Affiliation(s)
- Karin Leander
- Institute of Environmental Medicine, Unit of Cardiovascular and Nutritional Epidemiology (K.L., M.V.), Karolinska Institutet, Stockholm, Sweden
| | - Yan Q Chen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (Y.Q.C., R.J.K.)
| | - Max Vikström
- Institute of Environmental Medicine, Unit of Cardiovascular and Nutritional Epidemiology (K.L., M.V.), Karolinska Institutet, Stockholm, Sweden
| | - Angela Silveira
- Cardiovascular Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine (A.S., R.M.F., F.M.v.H.), Karolinska Institutet, Stockholm, Sweden
| | - Rachel M Fisher
- Cardiovascular Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine (A.S., R.M.F., F.M.v.H.), Karolinska Institutet, Stockholm, Sweden
| | - Robert J Konrad
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (Y.Q.C., R.J.K.)
| | - Ferdinand M van 't Hooft
- Cardiovascular Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine (A.S., R.M.F., F.M.v.H.), Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
7
|
Frydrych A, Kulita K, Jurowski K, Piekoszewski W. Lipids in Clinical Nutrition and Health: Narrative Review and Dietary Recommendations. Foods 2025; 14:473. [PMID: 39942064 PMCID: PMC11816940 DOI: 10.3390/foods14030473] [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: 12/30/2024] [Revised: 01/28/2025] [Accepted: 01/29/2025] [Indexed: 02/16/2025] Open
Abstract
Lipids are essential components of human health, serving as critical structural elements of cell membranes, energy sources, and precursors for bioactive molecules. This narrative review aims to examine the multifaceted roles of lipids in clinical nutrition and health, focusing on their impact on chronic disease prevention, management, and the potential of lipid-based therapies. A narrative review was conducted utilizing Scopus, Google Scholar, and Web of Science databases. Key terms such as lipids, dietary fats, and cholesterol were used to identify and analyze relevant studies. A total of 145 articles meeting inclusion criteria were reviewed for their insights into lipid metabolism, dietary sources, and clinical implications. The analysis highlighted the metabolic significance of various lipid classes-saturated, monounsaturated, and polyunsaturated fatty acids-along with evidence-based recommendations for their dietary intake. Lipids were shown to play a pivotal role in managing chronic diseases such as cardiovascular disease, obesity, and metabolic syndrome. Emerging therapies, including omega-3 fatty acids and medium-chain triglycerides, demonstrated potential benefits in clinical practice. By synthesizing current knowledge, this narrative review provides healthcare professionals with an updated understanding of the roles of lipids in clinical nutrition. The findings emphasize the importance of tailored dietary interventions and lipid-based therapies in optimizing health and managing chronic diseases effectively. Additionally, this review successfully presents practical dietary recommendations to guide clinical practice.
Collapse
Affiliation(s)
- Adrian Frydrych
- Laboratory of Innovative Toxicological Research and Analyses, Faculty of Medicine, Medical College, University of Rzeszów, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland; (A.F.); (K.J.)
| | - Kamil Kulita
- Toxicological Science Club ‘Paracelsus’, Faculty of Medicine, Medical College, University of Rzeszów, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland;
| | - Kamil Jurowski
- Laboratory of Innovative Toxicological Research and Analyses, Faculty of Medicine, Medical College, University of Rzeszów, Al. mjr. W. Kopisto 2a, 35-959 Rzeszów, Poland; (A.F.); (K.J.)
- Department of Regulatory and Forensic Toxicology, Institute of Medical Expertise, Łódź, ul. Aleksandrowska 67/93, 91-205 Łódź, Poland
| | - Wojciech Piekoszewski
- Laboratory of High Resolution of Mass Spectrometry, Faculty of Chemistry, Jagiellonian University, R. Ingardena 3, 30-060 Krakow, Poland
| |
Collapse
|
8
|
Ghosh A, Chénier I, Leung YH, Oppong AK, Peyot ML, Madiraju SRM, Al-Khairi I, Abubaker J, Al-Mulla F, Prentki M, Abu-Farha M. Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice. iScience 2024; 27:111292. [PMID: 39640567 PMCID: PMC11617963 DOI: 10.1016/j.isci.2024.111292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/28/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
Angiopoietin-like protein 8 (Angptl8), expressed in the liver and adipocytes, forms a complex with Angptl3 or Angptl4, which regulates lipoprotein lipase and triglyceride metabolism. However, the precise functions of adipocyte Angptl8 remain elusive. Here we report that adipocyte-specific inducible Angptl8-knockout (AT-A8-KO) male mice on normal diet showed minor phenotypic changes, but after a high-fat high fructose (HFHF) diet, exhibited decreased body weight gain and glycemia, elevated rectal temperature and early dark phase energy expenditure compared to the Cre controls. AT-A8-KO mice also displayed improved glucose tolerance, a trend for better insulin sensitivity, improved insulin-stimulated glucose uptake in adipose tissues, and reduced visceral adipose tissue crown-like structures, plasma MCP-1 and leptin levels. The results indicate the importance of adipose Angptl8 in the context of nutri-stress and obesity, as its deletion in mice promotes a metabolically healthy obese phenotype by slightly ameliorating obesity, improving glucose and energy homeostasis, and mitigating inflammation.
Collapse
Affiliation(s)
- Anindya Ghosh
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Isabelle Chénier
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Yat Hei Leung
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Abel K. Oppong
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Marie-Line Peyot
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - S. R. Murthy Madiraju
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, 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 Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| | - Marc Prentki
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche Du Centre Hospitalier de L’Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
- Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait
| |
Collapse
|
9
|
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.
Collapse
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
| |
Collapse
|
10
|
Emara AM, El Bendary AS, Ahmed LM, Okda HI. Evaluation of serum levels of sestrin 2 and betatrophin in type 2 diabetic patients with diabetic nephropathy. BMC Nephrol 2024; 25:231. [PMID: 39030467 PMCID: PMC11264897 DOI: 10.1186/s12882-024-03663-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 07/01/2024] [Indexed: 07/21/2024] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus (DM) and the leading cause of chronic kidney disease (CKD) worldwide. Since obesity and type 2 DM (T2DM) are considered as inflammatory conditions, thus reducing their accompanied systemic inflammation may lessen their complications. Sestrin 2 belongs to a group of stress induced proteins which are produced in response to oxidative stress, inflammation and DNA damage. Betatrophin; a hormone that stimulates the growth, proliferation and mass expansion of pancreatic beta-cells and improves glucose tolerance. The objective of the study was to evaluate levels of serum Sestrin 2 and betatrophin in patients with different stages of diabetic nephropathy (DN)) and compare results with healthy control. METHODS This cross sectional study was carried out on 60 patients above 18 years old, recruited from Tanta University hospitals out patients clinics and 20 apparently healthy individuals of matched sex and age as a control group. Participants were divided into two groups: group I: 20 normal subjects as control group and group II: 60 patients with type 2 DM,. further subdivided in to three equal groups: group 1IIA(20 patients) with normo-albuminuria (ACR < 30 mg/g), group IIB (20 patients) with micro albuminuria (ACR = 30 to 300 mg/g) and group IIC (20 patients) with macro albuminuria (ACR > 300 mg/g). They were subjected to detailed history taking, careful clinical examination and laboratory investigations including blood urea, serum creatinine, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique. RESULTS Serum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in macroalbuminuric group compared to control and other 2 diabetic groups (P value < 0.05). The cut off value of serum sestrin 2 was 0.98 ng/ml with sensitivity 99%, specificity 66% while the cut off value of serum betatrophin was > 98.25 ng/ml with sensitivity 98%, specificity 82%. Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin. Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR and serum albumin. Serum betatrophin are found to be risk factors or predictors for diabetic nephropathy. CONCLUSIONS Patients with DN, particularly the macroalbuminuria group, had a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 level. The function of Sestrin 2 is compromised in DN, and restoring it can reverse a series of molecular alterations with subsequent improvement of the renal functions, albuminuria and structural damage.
Collapse
Affiliation(s)
- Asmaa Mounir Emara
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Amal Said El Bendary
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Laila Mahmoud Ahmed
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hanaa Ibrahim Okda
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| |
Collapse
|
11
|
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.
Collapse
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
| |
Collapse
|
12
|
Zhang J, Liu Z, Ni Y, Yu Y, Guo F, Lu Y, Wang X, Hao H, Li S, Wei P, Yu W, Hu W. Branched-chain amino acids promote occurrence and development of cardiovascular disease dependent on triglyceride metabolism via activation of the mTOR/SREBP-1/betatrophin pathway. Mol Cell Endocrinol 2024; 584:112164. [PMID: 38262527 DOI: 10.1016/j.mce.2024.112164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 01/25/2024]
Abstract
Branched-chain amino acid (BCAA) metabolism is associated with triglyceride (TG) metabolism and the development of cardiovascular disease (CVD). However, the underlying mechanism remains uncertain. This study included 1302 subjects and followed for 4-5 years. A hyperbranched-chain aminoacidemia rat model was induced by high fructose diet (HFTD). The relationship between BCAAs and TG level and its regulatory mechanism was investigated in vitro. As results, as baseline BCAA percentile increased, subjects had higher prevalence and incidence of T2DM, NAFLD, and CVD risk (P < 0.05). In animal model, the accumulation of BCAAs and TG and betatrophin expression were significantly elevated in the HFTD group when comparing with those in the SD group(P < 0.05). Immunofluorescence and Masson's trichrome staining revealed that the area of interstitial fibrosis was significantly increased in the HFTD group compared with control group. Met treatment significantly decreased TG levels and betatrophin expression and reversed myocardial fibrosis (P < 0.05). In vitro, LO2 cells, stimulated with 0.1-5 mM BCAAs, displayed a significant dose-dependent increase in betatrophin expression (P < 0.05). And 5 mM BCAAs stimulation significantly increased the p-mTOR and SREBP-1 expression (P < 0.05). However, this effect could be reversed by using the corresponding inhibitor or siRNAs. In conclusions, BCAAs promote occurrence and development of cardiovascular disease dependent on TG metabolism via activation of the mTOR/SREBP-1/betatrophin pathway. The study provides a new theory for the pathogenesis of CVD caused by amino acid metabolism disorders.
Collapse
Affiliation(s)
- Jie Zhang
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Ziyu Liu
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Yaojun Ni
- Department of Cardiothoracic Surgery, Hospital Affiliated to Nanjing Medical College and Huai'an First People's Hospital, No. 6, Beijing West Road, Huaiyin District, Huai'an, 223021, China
| | - Yang Yu
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Fei Guo
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Yanwen Lu
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Xiaoqing Wang
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Hairong Hao
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Shayan Li
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Pan Wei
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Weinan Yu
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China
| | - Wen Hu
- Department of Endocrinology and Metabolism, Huai'an Hospital Affiliated to Xuzhou Medical University, No. 62, Huaihai South Road, Qingjiangpu District, Huai'an, 223002, China.
| |
Collapse
|
13
|
Su X, Xu Q, Li Z, Ren Y, Jiao Q, Wang L, Wang Y. Role of the angiopoietin-like protein family in the progression of NAFLD. Heliyon 2024; 10:e27739. [PMID: 38560164 PMCID: PMC10980950 DOI: 10.1016/j.heliyon.2024.e27739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease, with a range of conditions including non-alcoholic fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Currently recognized as the liver component of the metabolic syndrome, NAFLD is intimately linked to metabolic diseases. Angiopoietin-like proteins (ANGPTLs) comprise a class of proteins that resemble angiopoietins structurally. It is closely related to obesity, insulin resistance and lipid metabolism, and may be the critical factor of metabolic syndrome. In recent years, many studies have found that there is a certain correlation between ANGPTLs and the occurrence and progression of NAFLD disease spectrum. This article reviews the possible mechanisms and roles of ANGPTL protein in the pathogenesis and progression of NAFLD.
Collapse
Affiliation(s)
- Xin Su
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Qinchen Xu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Zigan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Yidan Ren
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Qinlian Jiao
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| | - Lina Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Yunshan Wang
- Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong Province, China
| |
Collapse
|
14
|
Wen Y, Chen YQ, Konrad RJ. Angiopoietin-like protein 8: a multifaceted protein instrumental in regulating triglyceride metabolism. Curr Opin Lipidol 2024; 35:58-65. [PMID: 37962908 DOI: 10.1097/mol.0000000000000910] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
PURPOSE OF REVIEW The angiopoietin-like (ANGPTL) proteins ANGPTL3 and ANGPTL4 are critical lipoprotein lipase (LPL) inhibitors. This review discusses the unique ability of the insulin-responsive protein ANGPTL8 to regulate triglyceride (TG) metabolism by forming ANGPTL3/8 and ANGPTL4/8 complexes that control tissue-specific LPL activities. RECENT FINDINGS After feeding, ANGPTL4/8 acts locally in adipose tissue, has decreased LPL-inhibitory activity compared to ANGPTL4, and binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin, which cleaves ANGPTL4/8 and other LPL inhibitors. This enables LPL to be fully active postprandially to promote efficient fatty acid (FA) uptake and minimize ectopic fat deposition. In contrast, liver-derived ANGPTL3/8 acts in an endocrine manner, has markedly increased LPL-inhibitory activity compared to ANGPTL3, and potently inhibits LPL in oxidative tissues to direct TG toward adipose tissue for storage. Circulating ANGPTL3/8 levels are strongly correlated with serum TG, and the ANGPTL3/8 LPL-inhibitory epitope is blocked by the TG-lowering protein apolipoprotein A5 (ApoA5). SUMMARY ANGPTL8 plays a crucial role in TG metabolism by forming ANGPTL3/8 and ANGPTL4/8 complexes that differentially modulate LPL activities in oxidative and adipose tissues respectively. Selective ANGPTL8 inhibition in the context of the ANGPTL3/8 complex has the potential to be a promising strategy for treating dyslipidemia.
Collapse
Affiliation(s)
- Yi Wen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA
| | | | | |
Collapse
|
15
|
Ghosh A, Leung YH, Yu J, Sladek R, Chénier I, Oppong AK, Peyot ML, Madiraju SRM, Al-Khairi I, Thanaraj TA, Abubaker J, Al-Mulla F, Prentki M, Abu-Farha M. Silencing ANGPTL8 reduces mouse preadipocyte differentiation and insulin signaling. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159461. [PMID: 38272177 DOI: 10.1016/j.bbalip.2024.159461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/12/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024]
Abstract
ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation. To better understand the role of intracellular ANGPTL8 in adipocytes and assess whether it may play a role in adipocyte differentiation, we knocked down its expression in normal mouse subcutaneous preadipocytes. ANGPTL8 knockdown reduced adipocyte differentiation, cellular TG accumulation and also isoproterenol-stimulated lipolysis at day 7 of differentiation. RNA-Seq analysis of ANGPTL8 siRNA or control siRNA transfected SC preadipocytes on days 0, 2, 4 and 7 of differentiation showed that ANGPTL8 knockdown impeded the early (day 2) expression of adipogenic and insulin signaling genes, PPARγ, as well as genes related to extracellular matrix and NF-κB signaling. Insulin mediated Akt phosphorylation was reduced at an early stage during adipocyte differentiation. This study based on normal primary cells shows that ANGPTL8 has intracellular actions in addition to effects in the extracellular space, like modulating LPL activity. Preadipocyte ANGPTL8 expression modulates their differentiation possibly via changes in insulin signaling gene expression.
Collapse
Affiliation(s)
- Anindya Ghosh
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Yat Hei Leung
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Jeffrey Yu
- Department of Medicine, McGill University, Montréal, QC, Canada
| | - Robert Sladek
- Department of Medicine, McGill University, Montréal, QC, Canada
| | - Isabelle Chénier
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Abel K Oppong
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - Marie-Line Peyot
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | - S R Murthy Madiraju
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada
| | | | | | | | | | - Marc Prentki
- Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, and Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
| | | |
Collapse
|
16
|
Prater MC, Scheurell AR, Paton CM, Cooper JA. Eight weeks of daily cottonseed oil intake attenuates postprandial angiopoietin-like proteins 3 and 4 responses compared to olive oil in adults with hypercholesterolemia: A secondary analysis of a randomized clinical trial. Nutr Res 2024; 123:88-100. [PMID: 38295507 DOI: 10.1016/j.nutres.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 02/02/2024]
Abstract
Angiopoietin-like proteins (ANGPTLs) -3, -4, and -8 are regulators of lipid metabolism and have been shown to respond to changes in dietary fats. It is unknown how ANGPTLs respond to cottonseed oil (CSO) and olive oil (OO) consumption in a population with hypercholesterolemia. The purpose of this study was to determine the impact of CSO vs. OO consumption on fasting and postprandial ANGPTL responses in adults with hypercholesterolemia. We hypothesized that CSO would have lower fasting and postprandial ANGPTL responses compared with OO. Forty-two adults with high cholesterol completed a single-blind, randomized trial comparing CSO (n = 21) vs. OO (n = 21) diet enrichment. An 8-week partial outpatient feeding intervention provided ∼60% of the volunteers' total energy expenditure (∼30% of total energy expenditure as CSO or OO). The remaining 40% was not controlled. Fasting blood draws were taken at pre-, mid-, and postintervention visits. Volunteers consumed a high saturated fat meal followed by 5 hours of blood draws pre- and postvisits. Fasting ANGPTL3 had a marginally significant treatment by visit interaction (P = .06) showing an increase from pre- to postintervention in CSO vs. OO (CSO: 385.1 ± 27.7 to 440.3 ± 33.9 ng/mL; OO: 468.2 ± 38.3 to 449.2 ± 49.5 ng/mL). Both postprandial ANGPTL3 (P = .02) and ANGPTL4 (P < .01) had treatment by visit interactions suggesting increases from pre- to postintervention in OO vs. CSO with no differences between groups in ANGPTL8. These data show a worsening (increase) of postprandial ANGPTLs after the OO, but not CSO, intervention. This aligns with previously reported data in which postprandial triglycerides were protected from increases compared with OO. ANGPTLs may mediate protective effects of CSO consumption on lipid control. This trial was registered at clinicaltrials.gov (NCT04397055).
Collapse
Affiliation(s)
- M Catherine Prater
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA
| | - Alex R Scheurell
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA
| | - Chad M Paton
- Department of Nutritional Sciences, University of Georgia, Athens, GA, USA; Department of Food Science and Technology, University of Georgia, Athens, GA, USA
| | - Jamie A Cooper
- Department of Kinesiology, University of Georgia, Athens, GA, USA.
| |
Collapse
|
17
|
Hoffmann WG, Chen YQ, Schwartz CS, Barber JL, Dev PK, Reasons RJ, Miranda Maravi JS, Armstrong B, Gerszten RE, Silbernagel G, Konrad RJ, Bouchard C, Sarzynski MA. Effects of exercise training on ANGPTL3/8 and ANGPTL4/8 and their associations with cardiometabolic traits. J Lipid Res 2024; 65:100495. [PMID: 38160757 PMCID: PMC10832466 DOI: 10.1016/j.jlr.2023.100495] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024] Open
Abstract
Angiopoietin-like protein (ANGPTL) complexes 3/8 and 4/8 are established inhibitors of LPL and novel therapeutic targets for dyslipidemia. However, the effects of regular exercise on ANGPTL3/8 and ANGPTL4/8 are unknown. We characterized ANGPTL3/8 and ANGPTL4/8 and their relationship with in vivo measurements of lipase activities and cardiometabolic traits before and after a 5-month endurance exercise training intervention in 642 adults from the HERITAGE (HEalth, RIsk factors, exercise Training And GEnetics) Family Study. At baseline, higher levels of both ANGPTL3/8 and ANGPTL4/8 were associated with a worse lipid, lipoprotein, and cardiometabolic profile, with only ANGPTL3/8 associated with postheparin LPL and HL activities. ANGPTL3/8 significantly decreased with exercise training, which corresponded with increases in LPL activity and decreases in HL activity, plasma triglycerides, apoB, visceral fat, and fasting insulin (all P < 5.1 × 10-4). Exercise-induced changes in ANGPTL4/8 were directly correlated to concomitant changes in total cholesterol, LDL-C, apoB, and HDL-triglycerides and inversely related to change in insulin sensitivity index (all P < 7.0 × 10-4). In conclusion, exercise-induced decreases in ANGPTL3/8 and ANGPTL4/8 were related to concomitant improvements in lipase activity, lipid profile, and cardiometabolic risk factors. These findings reveal the ANGPTL3-4-8 model as a potential molecular mechanism contributing to adaptations in lipid metabolism in response to exercise training.
Collapse
Affiliation(s)
| | - Yan Q Chen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Charles S Schwartz
- Department of Exercise Science, University of South Carolina, Columbia, SC, USA
| | - Jacob L Barber
- Department of Exercise Science, University of South Carolina, Columbia, SC, USA; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Prasun K Dev
- Department of Exercise Science, University of South Carolina, Columbia, SC, USA
| | - Riley J Reasons
- Department of Exercise Science, University of South Carolina, Columbia, SC, USA
| | | | - Bridget Armstrong
- Department of Exercise Science, University of South Carolina, Columbia, SC, USA
| | - Robert E Gerszten
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Günther Silbernagel
- Division of Vascular Medicine, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Robert J Konrad
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - Claude Bouchard
- Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Mark A Sarzynski
- Department of Exercise Science, University of South Carolina, Columbia, SC, USA.
| |
Collapse
|
18
|
Wheless A, Gunn KH, Neher SB. Macromolecular Interactions of Lipoprotein Lipase (LPL). Subcell Biochem 2024; 104:139-179. [PMID: 38963487 DOI: 10.1007/978-3-031-58843-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024]
Abstract
Lipoprotein lipase (LPL) is a critical enzyme in humans that provides fuel to peripheral tissues. LPL hydrolyzes triglycerides from the cores of lipoproteins that are circulating in plasma and interacts with receptors to mediate lipoprotein uptake, thus directing lipid distribution via catalytic and non-catalytic functions. Functional losses in LPL or any of its myriad of regulators alter lipid homeostasis and potentially affect the risk of developing cardiovascular disease-either increasing or decreasing the risk depending on the mutated protein. The extensive LPL regulatory network tunes LPL activity to allocate fatty acids according to the energetic needs of the organism and thus is nutritionally responsive and tissue dependent. Multiple pharmaceuticals in development manipulate or mimic these regulators, demonstrating their translational importance. Another facet of LPL biology is that the oligomeric state of the enzyme is also central to its regulation. Recent structural studies have solidified the idea that LPL is regulated not only by interactions with other binding partners but also by self-associations. Here, we review the complexities of the protein-protein and protein-lipid interactions that govern LPL structure and function.
Collapse
Affiliation(s)
- Anna Wheless
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kathryn H Gunn
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Stony Brook University, Stony Brook, USA
| | - Saskia B Neher
- University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| |
Collapse
|
19
|
Ziqubu K, Dludla PV, Mabhida SE, Jack BU, Keipert S, Jastroch M, Mazibuko-Mbeje SE. Brown adipose tissue-derived metabolites and their role in regulating metabolism. Metabolism 2024; 150:155709. [PMID: 37866810 DOI: 10.1016/j.metabol.2023.155709] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 09/28/2023] [Accepted: 10/14/2023] [Indexed: 10/24/2023]
Abstract
The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as "batokines", which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.
Collapse
Affiliation(s)
- Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Phiwayinkosi V Dludla
- Cochrane South Africa, South African Medical Research Council, Tygerberg 7505, South Africa; Department of Biochemistry and Microbiology, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa 3886, South Africa
| | - Sihle E Mabhida
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Babalwa U Jack
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Susanne Keipert
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
| | - Martin Jastroch
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
| | | |
Collapse
|
20
|
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.
Collapse
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
| |
Collapse
|
21
|
Stefanaki K, Ilias I, Paschou SA, Karagiannakis DS. Hepatokines: the missing link in the development of insulin resistance and hyperandrogenism in PCOS? Hormones (Athens) 2023; 22:715-724. [PMID: 37704921 DOI: 10.1007/s42000-023-00487-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 09/06/2023] [Indexed: 09/15/2023]
Abstract
The liver plays a critical role in several metabolic pathways, including the regulation of glucose and lipid metabolism. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, is closely associated with insulin resistance (IR) and metabolic syndrome (MetS). Hepatokines, newly discovered proteins secreted by hepatocytes, have been linked to the induction of these metabolic dysregulations. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, has been associated with NAFLD and IR, while hyperandrogenism additionally appears to be implicated in the pathogenesis of the latter. However, the potential role of hepatokines in the development of metabolic disorders in PCOS has not been fully investigated. Therefore, the aim of this review is to critically appraise the current evidence regarding the interplay of hepatokines with NAFLD, hyperandrogenism, and IR in PCOS.
Collapse
Affiliation(s)
- Katerina Stefanaki
- Department of Clinical Therapeutics, Medical School of the National and Kapodistrian University of Athens, "Alexandra" Hospital, Athens, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Diabetes and Metabolism, "Elena Venizelou" Hospital, Athens, Greece
| | - Stavroula A Paschou
- Department of Clinical Therapeutics, Medical School of the National and Kapodistrian University of Athens, "Alexandra" Hospital, Athens, Greece
| | - Dimitrios S Karagiannakis
- Academic Department of Gastroenterology, Medical School of the National and Kapodistrian University of Athens, "Laiko" General Hospital, Athens, Greece.
| |
Collapse
|
22
|
Ye H, Zong Q, Zou H, Zhang R. Emerging insights into the roles of ANGPTL8 beyond glucose and lipid metabolism. Front Physiol 2023; 14:1275485. [PMID: 38107478 PMCID: PMC10722441 DOI: 10.3389/fphys.2023.1275485] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Angiopoietin-like protein 8 (ANGPTL8) is a secreted protein predominantly expressed in liver and adipose tissue. ANGPTL8 modulates the clearance of triglycerides (TGs) by suppressing the activity of lipoprotein lipase (LPL) within the plasma. Previous studies found that circulating ANGPTL8 levels were significantly increased in metabolic disorder-related diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Whether ANGPTL8 has a direct pathogenic role in these diseases remains to be determined. In this review, we summarize the emerging roles of ANGPTL8 in the regulation of inflammation, tumours, circulatory system-related diseases, and ectopic lipid deposition, which may provide new insights into the diverse functions of ANGPTL8 in various diseases beyond its well-established functions in glucose and lipid metabolism.
Collapse
Affiliation(s)
- Huimin Ye
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qinghai University, Xining, China
| | - Qunchuan Zong
- Department of Traumatology and Orthopaedics, The Affiliated Hospital of Qinghai University, Xining, China
| | - Huajie Zou
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qinghai University, Xining, China
| | - Ruixia Zhang
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qinghai University, Xining, China
| |
Collapse
|
23
|
Thorin E, Labbé P, Lambert M, Mury P, Dagher O, Miquel G, Thorin-Trescases N. Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases. Can J Cardiol 2023; 39:1736-1756. [PMID: 37295611 DOI: 10.1016/j.cjca.2023.06.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/27/2023] [Accepted: 06/02/2023] [Indexed: 06/12/2023] Open
Abstract
Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation. ANGPTLs display a multitude of physiological and pathologic functions; they contribute to inflammation, angiogenesis, cell death, senescence, hematopoiesis, and play a role in repair, maintenance, and tissue homeostasis. ANGPTLs-particularly the triad ANGPTL3, 4, and 8-have an established role in lipid metabolism through the regulation of triacylglycerol trafficking according to the nutritional status. Some ANGPTLs also contribute to glucose metabolism. Therefore, dysregulation in ANGPTL expression associated with abnormal circulating levels are linked to a plethora of CVD and metabolic disorders including atherosclerosis, heart diseases, diabetes, but also obesity and cancers. Because ANGPTLs bind to different receptors according to the cell type, antagonists are therapeutically inadequate. Recently, direct inhibitors of ANGPTLs, mainly ANGPTL3, have been developed, and specific monoclonal antibodies and antisense oligonucleotides are currently being tested in clinical trials. The aim of the current review is to provide an up-to-date preclinical and clinical overview on the function of the 8 members of the ANGPTL family in the cardiovascular system, their contribution to CVD, and the therapeutic potential of manipulating some of them.
Collapse
Affiliation(s)
- Eric Thorin
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.
| | - Pauline Labbé
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
| | - Mélanie Lambert
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Pauline Mury
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Pharmacology, Université de Montréal, Montréal, Québec, Canada
| | - Olina Dagher
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada; Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada; Department of Cardiac Sciences, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | - Géraldine Miquel
- Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
| | | |
Collapse
|
24
|
Larouche M, Khoury E, Brisson D, Gaudet D. Inhibition of Angiopoietin-Like Protein 3 or 3/8 Complex and ApoC-III in Severe Hypertriglyceridemia. Curr Atheroscler Rep 2023; 25:1101-1111. [PMID: 38095804 DOI: 10.1007/s11883-023-01179-y] [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] [Accepted: 11/21/2023] [Indexed: 01/06/2024]
Abstract
PURPOSE OF REVIEW The role of the inhibition of ANGPTL3 in severe or refractory hypercholesterolemia is well documented, less in severe hyperTG. This review focuses on the preclinical and clinical development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory forms of hypertriglyceridemia to prevent cardiovascular disease or other morbidities. RECENT FINDINGS APOC3 and ANGPTL3 became targets for drug development following the identification of naturally occurring loss of function variants in families with a favorable lipid profile and low cardiovascular risk. The inhibition of ANGPTL3 covers a broad spectrum of lipid disorders from severe hypercholesterolemia to severe hypertriglyceridemia, while the inhibition of ApoC-III can treat hypertriglyceridemia regardless of the severity. Preclinical and clinical data suggest that ApoC-III inhibitors, ANGPTL3 inhibitors, and inhibitors of the ANGPTL3/8 complex that is formed postprandially are highly effective for the treatment of severe or refractory hypertriglyceridemia. Inhibition of ANGPTL3 or the ANGPTL3/8 complex upregulates LPL and facilitates the hydrolysis and clearance of triglyceride-rich lipoproteins (TRL) (LPL-dependent mechanisms), whereas ApoC-III inhibitors contribute to the management and clearance of TRL through both LPL-dependent and LPL-independent mechanisms making it possible to successfully lower TG in subjects completely lacking LPL (familial chylomicronemia syndrome). Most of these agents are biologicals including monoclonal antibodies (mAb), antisense nucleotides (ASO), small interfering RNA (siRNA), or CRISPR-cas gene editing strategies.
Collapse
Affiliation(s)
- Miriam Larouche
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Etienne Khoury
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Diane Brisson
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Daniel Gaudet
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada.
| |
Collapse
|
25
|
Lőrincz H, Csiha S, Ratku B, Somodi S, Sztanek F, Seres I, Paragh G, Harangi M. Gender-Dependent Associations between Serum Betatrophin Levels and Lipoprotein Subfractions in Diabetic and Nondiabetic Obese Patients. Int J Mol Sci 2023; 24:16504. [PMID: 38003693 PMCID: PMC10671489 DOI: 10.3390/ijms242216504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
Betatrophin, also known as angiopoietin-like protein 8 (ANGPTL8), mainly plays a role in lipid metabolism. To date, associations between betatrophin and lipoprotein subfractions are poorly investigated. For this study, 50 obese patients with type 2 diabetes (T2D) and 70 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index (BMI) as well as 49 gender- and age-matched healthy, normal-weight controls were enrolled. Serum betatrophin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint gel electrophoresis. Betatrophin concentrations were found to be significantly higher in the T2D and NDO groups compared to the controls in all subjects and in females, but not in males. We found significant positive correlations between triglyceride, very low density lipoprotein (VLDL), large LDL (low density lipoprotein), small LDL, high density lipoprotein (HDL) -6-10 subfractions, and betatrophin, while negative correlations were detected between betatrophin and IDL, mean LDL size, and HDL-1-5. Proportion of small HDL was the best predictor of betatrophin in all subjects. Small LDL and large HDL subfractions were found to be the best predictors in females, while in males, VLDL was found to be the best predictor of betatrophin. Our results underline the significance of serum betatrophin measurement in the cardiovascular risk assessment of obese patients with and without T2D, but gender differences might be taken into consideration.
Collapse
Affiliation(s)
- Hajnalka Lőrincz
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Sára Csiha
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
| | - Balázs Ratku
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
- Department of Emergency Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- Institute of Health Studies, Faculty of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
| | - Sándor Somodi
- Department of Emergency Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Ferenc Sztanek
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Ildikó Seres
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - György Paragh
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Mariann Harangi
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- Institute of Health Studies, Faculty of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary
| |
Collapse
|
26
|
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.
Collapse
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.)
| |
Collapse
|
27
|
Zheng Z, Lyu W, Hong Q, Yang H, Li Y, Zhao S, Ren Y, Xiao Y. Phylogenetic and expression analysis of the angiopoietin-like gene family and their role in lipid metabolism in pigs. Anim Biosci 2023; 36:1517-1529. [PMID: 37170504 PMCID: PMC10475376 DOI: 10.5713/ab.23.0057] [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: 02/20/2023] [Revised: 03/12/2023] [Accepted: 04/19/2023] [Indexed: 05/13/2023] Open
Abstract
OBJECTIVE The objective of this study was to investigate the phylogenetic and expression analysis of the angiopoietin-like (ANGPTL) gene family and their role in lipid metabolism in pigs. METHODS In this study, the amino acid sequence analysis, phylogenetic analysis, and chromosome adjacent gene analysis were performed to identify the ANGPTL gene family in pigs. According to the body weight data from 60 Jinhua pigs, different tissues of 6 pigs with average body weight were used to determine the expression profile of ANGPTL1-8. The ileum, subcutaneous fat, and liver of 8 pigs with distinct fatness were selected to analyze the gene expression of ANGPTL3, ANGPTL4, and ANGPTL8. RESULTS The sequence length of ANGPTLs in pigs was between 1,186 and 1,991 bp, and the pig ANGPTL family members shared common features with human homologous genes, including the high similarity of the amino acid sequence and chromosome flanking genes. Amino acid sequence analysis showed that ANGPTL1-7 had a highly conserved domain except for ANGPTL8. Phylogenetic analysis showed that each ANGPTL homologous gene shared a common origin. Quantitative reverse-transcription polymerase chain reaction analysis showed that ANGPTL family members had different expression patterns in different tissues. ANGPTL3 and ANGPTL8 were mainly expressed in the liver, while ANGPTL4 was expressed in many other tissues, such as the intestine and subcutaneous fat. The expression levels of ANGPTL3 in the liver and ANGPTL4 in the liver, intestine and subcutaneous fat of Jinhua pigs with low propensity for adipogenesis were significantly higher than those of high propensity for adipogenesis. CONCLUSION These results increase our knowledge about the biological role of the ANGPTL family in this important economic species, it will also help to better understand the role of ANGPTL3, ANGPTL4, and ANGPTL8 in lipid metabolism of pigs, and provide innovative ideas for developing strategies to improve meat quality of pigs.
Collapse
Affiliation(s)
- Zibin Zheng
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021,
China
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193,
China
| | - Wentao Lyu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021,
China
| | - Qihua Hong
- College of Animal Sciences, Zhejiang University, Hangzhou 310058,
China
| | - Hua Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021,
China
| | - Ying Li
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, College of Life Science and Engineering, Foshan University, Foshan 528000,
China
| | - Shengjun Zhao
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023,
China
| | - Ying Ren
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023,
China
| | - Yingping Xiao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021,
China
| |
Collapse
|
28
|
Chen YQ, Zhen EY, Russell AM, Ehsani M, Siegel RW, Qian Y, Konrad RJ. Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity. J Lipid Res 2023; 64:100441. [PMID: 37666362 PMCID: PMC10550811 DOI: 10.1016/j.jlr.2023.100441] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/17/2023] [Accepted: 08/28/2023] [Indexed: 09/06/2023] Open
Abstract
After feeding, adipose tissue lipoprotein lipase (LPL) activity should be maximized, therefore the potent LPL-inhibitory activity of angiopoietin-like protein 4 (ANGPTL4) must be blocked by ANGPTL8 through formation of ANGPTL4/8 complexes. ANGPTL4/8 tightly binds and protects LPL but also partially inhibits its activity. Recently, we demonstrated ANGPTL4/8 also binds tissue plasminogen activator (tPA) and plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity. Although fully active LPL in the fat postprandially is desirable, ANGPTL4/8 removal could subject LPL to profound inhibition by ANGPTL3/8 (the most potent circulating LPL inhibitor), inhibition by other LPL inhibitors like ANGPTL4, ANGPTL3, and ApoC3 or interfere with ApoC2-mediated LPL activation. To understand better these potential paradoxes, we examined LPL inhibition by ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 and LPL stimulation by ApoC2 in the presence of ANGPTL4/8 + tPA + plasminogen. Remarkably, ANGPTL3/8-mediated LPL inhibition was almost completely blocked, with the mechanism being cleavage of fibrinogen-like domain-containing ANGPTL3 present in the ANGPTL3/8 complex. The LPL-inhibitory effects of ANGPTL4, ANGPTL3, and ApoC3 were also largely reduced in the presence of ANGPTL4/8 + tPA + plasminogen. In contrast, the ability of ApoC2 to stimulate LPL activity was unaffected by ANGPTL4/8-mediated plasmin generation. Together, these results explain how plasmin generated by increased postprandial ANGPTL4/8 levels in adipose tissue enables maximal LPL activity by preventing ANGPTL3/8, ANGPTL4, ANGPTL3, and ApoC3 from inhibiting LPL, while permitting ApoC2-mediated LPL activation to occur.
Collapse
Affiliation(s)
- Yan Q Chen
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA
| | - Eugene Y Zhen
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA
| | - Anna M Russell
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA
| | - Mariam Ehsani
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA
| | - Robert W Siegel
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA
| | - Yuewei Qian
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA
| | - Robert J Konrad
- Lilly Research Laboratories, Eli Lilly, and Company, Indianapolis, IN, USA.
| |
Collapse
|
29
|
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.
Collapse
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.)
| |
Collapse
|
30
|
Saghafi S, Chamani E, Salmani F, Fadaei R, Shafiei E, Moradi N, Tavakoli T. Genetic predisposition to nonalcoholic fatty liver disease: insights from ANGPTL8 gene variants in Iranian adults. Lipids Health Dis 2023; 22:147. [PMID: 37679750 PMCID: PMC10483745 DOI: 10.1186/s12944-023-01905-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 08/15/2023] [Indexed: 09/09/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease with a global prevalence, and modulation of ANGPTL8 expression has emerged as a promising predictor of NAFLD susceptibility. This research was conducted to scrutinize ANGPTL8 protein expression in NAFLD patients and elucidate the interplay between ANGPTL8 gene polymorphisms and their lipid profiles, thus shedding new light on the pathophysiology of this complex disease. The study comprised 423 unrelated participants, including 222 healthy controls and 201 individuals with NAFLD, screened using FibroScan/ultrasonography and laboratory tests. The main goal focused on the genotype and allele frequency distribution in the ANGPTL8 gene, specifically analyzing two genetic variations: rs737337 (T/C) and rs2278426 (C/T). The participants diagnosed with NAFLD were slightly younger (P ≥ 0.05) and had a higher body mass index (BMI) than the individuals in the control group. Notably, there was a significant difference in the occurrence of the rs737337 polymorphism between the NAFLD and control groups, with a lower frequency observed in the NAFLD group. Our results indicated that individuals with the TC + CC genotype and C allele of rs737337 (T/C) had a decreased risk of higher levels of ALT and AST. Conversely, those with the CT, CT + TT genotype, and T allele of rs2278426 (C/T) exhibited an increased risk of higher levels of ALT and AST. The results imply that the rs2278426 (C/T) variant of the ANGPTL8 gene is more strongly linked to an increased risk of NAFLD compared to the rs737337 polymorphism. However, additional research is needed to understand the specific molecular mechanisms responsible for the upregulation of ANGPTL8 in individuals with NAFLD.
Collapse
Affiliation(s)
- Samira Saghafi
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Elham Chamani
- Department of Clinical Biochemistry, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Salmani
- Department of Epidemiology and Biostatistics, Social Determinants of Health Research Center, Faculty of Health, Birjand University of Medical Sciences, Birjand, Iran
| | - Reza Fadaei
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Efat Shafiei
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Nariman Moradi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Tahmine Tavakoli
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran.
- Cardiovascular Research Center, Birjand University of Medical Sciences, Birjand, Iran.
| |
Collapse
|
31
|
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.
Collapse
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
| |
Collapse
|
32
|
Li DP, Huang L, Kan RR, Meng XY, Wang SY, Zou HJ, Guo YM, Luo PQ, Pan LM, Xiang YX, Mao BB, Xie YY, Wang ZH, Yang M, He R, Yang Y, Liu ZL, Xie JH, Ma DL, Zhang BP, Shao SY, Chen X, Xu SM, He WT, Li WJ, Chen Y, Yu XF. LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis. Nat Commun 2023; 14:4436. [PMID: 37481670 PMCID: PMC10363120 DOI: 10.1038/s41467-023-40183-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 07/18/2023] [Indexed: 07/24/2023] Open
Abstract
Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.
Collapse
Affiliation(s)
- Dan-Pei Li
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Li Huang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Ran-Ran Kan
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xiao-Yu Meng
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Shu-Yun Wang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Hua-Jie Zou
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Ya-Ming Guo
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Pei-Qiong Luo
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Li-Meng Pan
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yu-Xi Xiang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Bei-Bei Mao
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yu-Yu Xie
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Zhi-Han Wang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Min Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Rui He
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yan Yang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Zhe-Long Liu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Jun-Hui Xie
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - De-Lin Ma
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Ben-Ping Zhang
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Shi-Ying Shao
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Xi Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Si-Miao Xu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Wen-Tao He
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Wen-Jun Li
- Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Chen
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China.
| | - Xue-Feng Yu
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China.
| |
Collapse
|
33
|
Yu H, Jiao X, Yang Y, Lv Q, Du Z, Li L, Hu C, Du Y, Zhang J, Li F, Sun Q, Wang Y, Chen D, Zhang X, Qin Y. ANGPTL8 deletion attenuates abdominal aortic aneurysm formation in ApoE-/- mice. Clin Sci (Lond) 2023; 137:979-993. [PMID: 37294581 PMCID: PMC10311111 DOI: 10.1042/cs20230031] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/01/2023] [Accepted: 06/09/2023] [Indexed: 06/10/2023]
Abstract
Angiopoietin-like protein 8 (ANGPTL8) plays important roles in lipid metabolism, glucose metabolism, inflammation, and cell proliferation and migration. Clinical studies have indicated that circulating ANGPTL8 levels are increased in patients with thoracic aortic dissection (TAD). TAD shares several risk factors with abdominal aortic aneurysm (AAA). However, the role of ANGPTL8 in AAA pathogenesis has never been investigated. Here, we investigated the effect of ANGPTL8 knockout on AAA in ApoE-/- mice. ApoE-/-ANGPTL8-/- mice were generated by crossing ANGPTL8-/- and ApoE-/- mice. AAA was induced in ApoE-/- using perfusion of angiotensin II (AngII). ANGPTL8 was significantly up-regulated in AAA tissues of human and experimental mice. Knockout of ANGPTL8 significantly reduced AngII-induced AAA formation, elastin breaks, aortic inflammatory cytokines, matrix metalloproteinase expression, and smooth muscle cell apoptosis in ApoE-/- mice. Similarly, ANGPTL8 sh-RNA significantly reduced AngII-induced AAA formation in ApoE-/- mice. ANGPTL8 deficiency inhibited AAA formation, and ANGPTL8 may therefore be a potential therapeutic target for AAA.
Collapse
Affiliation(s)
- Huahui Yu
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Xiaolu Jiao
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yunyun Yang
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Qianwen Lv
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Zhiyong Du
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Linyi Li
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Chaowei Hu
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yunhui Du
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Jing Zhang
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Fan Li
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Qiuju Sun
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yu Wang
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Dong Chen
- Department of Pathology, Beijing AnZhen Hospital, Capital Medical University, Beijing 100029, China
| | - Xiaoping Zhang
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| | - Yanwen Qin
- The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
| |
Collapse
|
34
|
Zhang R, Zhang K. Mitochondrial NAD kinase in health and disease. Redox Biol 2023; 60:102613. [PMID: 36689815 PMCID: PMC9873681 DOI: 10.1016/j.redox.2023.102613] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome.
Collapse
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
| |
Collapse
|
35
|
Circulating ANGPTL8 as a Potential Protector of Metabolic Complications in Patients with Psoriasis. J Clin Med 2023; 12:jcm12062346. [PMID: 36983346 PMCID: PMC10058172 DOI: 10.3390/jcm12062346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/13/2023] [Accepted: 03/14/2023] [Indexed: 03/19/2023] Open
Abstract
Angiopoietin-like protein 8 (ANGPTL8) exerts pleiotropic effects, taking part in lipid and carbohydrate metabolism, inflammation, hematopoiesis and oncogenesis. So far, the exact molecular targets of ANGPTL8 remain poorly defined. We aimed to evaluate the serum concentration of ANGPTL8 in individuals with psoriasis and examine how systemic therapy affects the concentration of ANGPTL8. The study enrolled 35 patients with plaque-type psoriasis that were followed for 3 months of treatment with methotrexate or acitretin, and 18 healthy volunteers without psoriasis as controls. Serum ANGPTL8 concentrations were analyzed by ELISA and differences between groups were determined using Student’s t-test or the Mann–Whitney test, while correlations were assessed using Spearman’s rank test. The average concentration of ANGPTL8 differed significantly between the psoriasis group (before and after therapy) and the control group (p < 0.05). Significant negative correlations between ANGPTL8 and total cholesterol and LDL levels were noted (both p < 0.05). A significant increase in ANGPTL8 concentration was observed after acitretin (p < 0.05), whereas in patients treated with methotrexate the ANGPTL8 did not change significantly (p > 0.05). Additionally, a negative, statistically significant correlation with PASI was found after treatment (p < 0.05). Based on our study, it appears that elevated levels of ANGPTL8 may reduce the likelihood of atherogenic dyslipidemia in individuals with psoriasis, and treatment for psoriasis may impact the protective effects of ANGPTL8.
Collapse
|
36
|
Dong R, Wang Z, Zhao Q, Yan Y, Jiang Q. Molecular characterization and immune functions of lipasin in Nile tilapia (Oreochromis niloticus): Involvement in the regulation of tumor necrosis factor-α secretion. FISH & SHELLFISH IMMUNOLOGY 2023; 133:108549. [PMID: 36646336 DOI: 10.1016/j.fsi.2023.108549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 06/17/2023]
Abstract
Lipasin, the product of the angiopoietin-like 8 (angptl8) gene, is known as a critical regulator of plasma lipid metabolism. However, its immune function in vertebrates is currently poorly understood. By 5'/3'-rapid amplification of cDNA ends (RACE), we established the structural identity of Nile tilapia (Oreochromis niloticus) angptl8. The transcripts of tilapia angptl8 were widely expressed in various tissues, with the highest levels in the liver. Following lipopolysaccharide in vivo challenges, time-dependent angptl8 gene expression was observed in the head kidney and liver. On the basis of the sequence obtained, we produced recombinant lipasin that inhibited lipoprotein lipase activity. Treatment of head kidney leukocytes with lipasin stimulated tumor necrosis factor-α (TNF-α) secretion and gene expression. In addition, lipasin-induced TNF-α secretion could be prevented by inhibiting the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, lipasin enhanced the phosphorylation and degradation of IκBα and promoted translocation of the p65 subunit of NF-κB to the nucleus. Collectively, the current findings suggested that lipasin was involved in the immune response of Nile tilapia and stimulated TNF-α secretion by activating the NF-κB pathway in tilapia head kidney leukocytes.
Collapse
Affiliation(s)
- Rui Dong
- Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China
| | - Zixi Wang
- Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China
| | - Qianqian Zhao
- Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China
| | - Yisha Yan
- Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China
| | - Quan Jiang
- Key Laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, PR China.
| |
Collapse
|
37
|
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.
Collapse
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
| | | | | | | |
Collapse
|
38
|
Landfors F, Chorell E, Kersten S. Genetic Mimicry Analysis Reveals the Specific Lipases Targeted by the ANGPTL3-ANGPTL8 Complex and ANGPTL4. J Lipid Res 2023; 64:100313. [PMID: 36372100 PMCID: PMC9852701 DOI: 10.1016/j.jlr.2022.100313] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 10/14/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022] Open
Abstract
Angiopoietin-like proteins, ANGPTL3, ANGPTL4, and ANGPTL8, are involved in regulating plasma lipids. In vitro and animal-based studies point to LPL and endothelial lipase (EL, LIPG) as key targets of ANGPTLs. To examine the ANGPTL mechanisms for plasma lipid modulation in humans, we pursued a genetic mimicry analysis of enhancing or suppressing variants in the LPL, LIPG, lipase C hepatic type (LIPC), ANGPTL3, ANGPTL4, and ANGPTL8 genes using data on 248 metabolic parameters derived from over 110,000 nonfasted individuals in the UK Biobank and validated in over 13,000 overnight fasted individuals from 11 other European populations. ANGPTL4 suppression was highly concordant with LPL enhancement but not HL or EL, suggesting ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. The LPL-independent effects of ANGPTL3 suppression on plasma metabolic parameters showed a striking inverse resemblance with EL suppression, suggesting ANGPTL3 not only targets LPL but also targets EL. Investigation of the impact of the ANGPTL3-ANGPTL8 complex on plasma metabolite traits via the ANGPTL8 R59W substitution as an instrumental variable showed a much higher concordance between R59W and EL activity than between R59W and LPL activity, suggesting the R59W substitution more strongly affects EL inhibition than LPL inhibition. Meanwhile, when using a rare and deleterious protein-truncating ANGPTL8 variant as an instrumental variable, the ANGPTL3-ANGPTL8 complex was very LPL specific. In conclusion, our analysis provides strong human genetic evidence that the ANGPTL3-ANGPTL8 complex regulates plasma metabolic parameters, which is achieved by impacting LPL and EL. By contrast, ANGPTL4 influences plasma metabolic parameters exclusively via LPL.
Collapse
Affiliation(s)
- Fredrik Landfors
- Department of Public Health and Clinical Medicine, Section of Medicine, Umeå University, Umeå, Sweden.
| | - Elin Chorell
- Department of Public Health and Clinical Medicine, Section of Medicine, Umeå University, Umeå, Sweden
| | - Sander Kersten
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands
| |
Collapse
|
39
|
Heintz MM, Eccles JA, Olack EM, Maner-Smith KM, Ortlund EA, Baldwin WS. Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity. PLoS One 2022; 17:e0277053. [PMID: 36520866 PMCID: PMC9754190 DOI: 10.1371/journal.pone.0277053] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/18/2022] [Indexed: 12/23/2022] Open
Abstract
Multiple factors in addition to over consumption lead to obesity and non-alcoholic fatty liver disease (NAFLD) in the United States and worldwide. CYP2B6 is the only human detoxification CYP whose loss is associated with obesity, and Cyp2b-null mice show greater diet-induced obesity with increased steatosis than wildtype mice. However, a putative mechanism has not been determined. LC-MS/MS revealed that CYP2B6 metabolizes PUFAs, with a preference for metabolism of ALA to 9-HOTrE and to a lesser extent 13-HOTrE with a preference for metabolism of PUFAs at the 9- and 13-positions. To further study the role of CYP2B6 in vivo, humanized-CYP2B6-transgenic (hCYP2B6-Tg) and Cyp2b-null mice were fed a 60% high-fat diet for 16 weeks. Compared to Cyp2b-null mice, hCYP2B6-Tg mice showed reduced weight gain and metabolic disease as measured by glucose tolerance tests, however hCYP2B6-Tg male mice showed increased liver triglycerides. Serum and liver oxylipin metabolite concentrations increased in male hCYP2B6-Tg mice, while only serum oxylipins increased in female hCYP2B6-Tg mice with the greatest increases in LA oxylipins metabolized at the 9 and 13-positions. Several of these oxylipins, specifically 9-HODE, 9-HOTrE, and 13-oxoODE, are PPAR agonists. RNA-seq data also demonstrated sexually dimorphic changes in gene expression related to nuclear receptor signaling, especially CAR > PPAR with qPCR suggesting PPARγ signaling is more likely than PPARα signaling in male mice. Overall, our data indicates that CYP2B6 is an anti-obesity enzyme, but probably to a lesser extent than murine Cyp2b's. Therefore, the inhibition of CYP2B6 by xenobiotics or dietary fats can exacerbate obesity and metabolic disease potentially through disrupted PUFA metabolism and the production of key lipid metabolites.
Collapse
Affiliation(s)
- Melissa M. Heintz
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Jazmine A. Eccles
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Emily M. Olack
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Kristal M. Maner-Smith
- Emory Integrated Metabolomics and Lipodomics Core, Emory University, Atlanta, Georgia, United States of America
| | - Eric A. Ortlund
- Department of Biochemistry, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America
| | - William S. Baldwin
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
- * E-mail:
| |
Collapse
|
40
|
Wen Y, Chen YQ, Konrad RJ. The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity. Adv Biol (Weinh) 2022; 6:e2200093. [PMID: 35676229 DOI: 10.1002/adbi.202200093] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/03/2022] [Indexed: 01/28/2023]
Abstract
Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue-specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue-specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin-like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed.
Collapse
Affiliation(s)
- Yi Wen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
| | - Yan Q Chen
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
| | - Robert J Konrad
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA
| |
Collapse
|
41
|
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.
Collapse
|
42
|
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.
Collapse
|
43
|
Jia W, Wu X, Zhang R, Wang X, Shi L. Novel insight into the resilient drivers of bioaccumulation perchlorate on lipid nutrients alterations in goat milk by spatial multi-omics. Lebensm Wiss Technol 2022. [DOI: 10.1016/j.lwt.2022.113717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
44
|
ANGPTL8 is a negative regulator in pathological cardiac hypertrophy. Cell Death Dis 2022; 13:621. [PMID: 35851270 PMCID: PMC9293964 DOI: 10.1038/s41419-022-05029-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 06/09/2022] [Accepted: 06/16/2022] [Indexed: 01/21/2023]
Abstract
Pathological cardiac hypertrophy is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the role of angiopoietin-like protein 8 (ANGPTL8) in pathological cardiac hypertrophy. We found that serum ANGPTL8 levels were significantly increased in hypertensive patients with cardiac hypertrophy and in mice with cardiac hypertrophy induced by Ang II or TAC. Furthermore, the secretion of ANGPTL8 from the liver was increased during hypertrophic processes, which were triggered by Ang II. In the Ang II- and transverse aortic constriction (TAC)-induced mouse cardiac hypertrophy model, ANGPTL8 deficiency remarkably accelerated cardiac hypertrophy and fibrosis with deteriorating cardiac dysfunction. Accordingly, both recombinant human full-length ANGPTL8 (rANGPTL8) protein and ANGPTL8 overexpression significantly mitigated Ang II-induced cell enlargement in primary neonatal rat cardiomyocytes (NRCMs) and H9c2 cells. Mechanistically, the antihypertrophic effects of ANGPTL8 depended on inhibiting Akt and GSK-3β activation, and the Akt activator SC-79 abolished the antihypertrophic effects of rANGPTL8 in vitro. Moreover, we demonstrated that ANGPTL8 directly bound to the paired Ig-like receptor PIRB (LILRB3) by RNA-seq and immunoprecipitation-mass screening. Remarkably, the antihypertrophic effects of ANGPTL8 were largely blocked by anti-LILRB3 and siRNA-LILRB3. Our study indicated that ANGPTL8 served as a novel negative regulator of pathological cardiac hypertrophy by binding to LILRB3 (PIRB) and inhibiting Akt/GSK3β activation, suggesting that ANGPTL8 may provide synergistic effects in combination with AT1 blockers and become a therapeutic target for cardiac hypertrophy and heart failure.
Collapse
|
45
|
Vachher M, Bansal S, Kumar B, Yadav S, Arora T, Wali NM, Burman A. Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma. J Cell Biochem 2022; 123:1553-1584. [PMID: 35818831 DOI: 10.1002/jcb.30252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/16/2022]
Abstract
Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.
Collapse
Affiliation(s)
- Meenakshi Vachher
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Savita Bansal
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Bhupender Kumar
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Sandeep Yadav
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Taruna Arora
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Nalini Moza Wali
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| | - Archana Burman
- Department of Biochemistry, Institute of Home Economics, University of Delhi, Delhi, India
| |
Collapse
|
46
|
Kim K, Ginsberg HN, Choi SH. New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins. Diabetes Metab J 2022; 46:517-532. [PMID: 35929170 PMCID: PMC9353557 DOI: 10.4093/dmj.2022.0198] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/20/2022] [Indexed: 11/24/2022] Open
Abstract
Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.
Collapse
Affiliation(s)
- Kyuho Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam,
Korea
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Henry N. Ginsberg
- Department of Preventive Medicine and Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY,
USA
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam,
Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul,
Korea
| |
Collapse
|
47
|
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.
Collapse
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.
| |
Collapse
|
48
|
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.
Collapse
Affiliation(s)
| | - Hakan AYYILDIZ
- SAĞLIK BİLİMLERİ ÜNİVERSİTESİ, ELAZIĞ FETHİ SEKİN ŞEHİR SAĞLIK UYGULAMA VE ARAŞTIRMA MERKEZİ
| |
Collapse
|
49
|
Deng M, Kutrolli E, Sadewasser A, Michel S, Joibari MM, Jaschinski F, Olivecrona G, Nilsson SK, Kersten S. ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy. J Lipid Res 2022; 63:100237. [PMID: 35667416 PMCID: PMC9270256 DOI: 10.1016/j.jlr.2022.100237] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/30/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022] Open
Abstract
Angiopoietin-like 4 (ANGPTL4) is an important regulator of plasma triglyceride (TG) levels and an attractive pharmacological target for lowering plasma lipids and reducing cardiovascular risk. Here, we aimed to study the efficacy and safety of silencing ANGPTL4 in the livers of mice using hepatocyte-targeting GalNAc-conjugated antisense oligonucleotides (ASOs). Compared with injections with negative control ASO, four injections of two different doses of ANGPTL4 ASO over 2 weeks markedly downregulated ANGPTL4 levels in liver and adipose tissue, which was associated with significantly higher adipose LPL activity and lower plasma TGs in fed and fasted mice, as well as lower plasma glucose levels in fed mice. In separate experiments, injection of two different doses of ANGPTL4 ASO over 20 weeks of high-fat feeding reduced hepatic and adipose ANGPTL4 levels but did not trigger mesenteric lymphadenopathy, an acute phase response, chylous ascites, or any other pathological phenotypes. Compared with mice injected with negative control ASO, mice injected with ANGPTL4 ASO showed reduced food intake, reduced weight gain, and improved glucose tolerance. In addition, they exhibited lower plasma TGs, total cholesterol, LDL-C, glucose, serum amyloid A, and liver TG levels. By contrast, no significant difference in plasma alanine aminotransferase activity was observed. Overall, these data suggest that ASOs targeting ANGPTL4 effectively reduce plasma TG levels in mice without raising major safety concerns.
Collapse
Affiliation(s)
- Mingjuan Deng
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, the Netherlands
| | - Elda Kutrolli
- Lipigon Pharmaceuticals AB, Tvistevägen 48C, 907 36, Umeå, Sweden
| | - Anne Sadewasser
- Secarna Pharmaceuticals GmbH & Co. KG, Am Klopferspitz 19, 82152 Planegg, Germany
| | - Sven Michel
- Secarna Pharmaceuticals GmbH & Co. KG, Am Klopferspitz 19, 82152 Planegg, Germany
| | | | - Frank Jaschinski
- Secarna Pharmaceuticals GmbH & Co. KG, Am Klopferspitz 19, 82152 Planegg, Germany
| | - Gunilla Olivecrona
- Lipigon Pharmaceuticals AB, Tvistevägen 48C, 907 36, Umeå, Sweden; Department of Medical Biosciences, Umeå University, SE-901 87, Umeå, Sweden
| | - Stefan K Nilsson
- Lipigon Pharmaceuticals AB, Tvistevägen 48C, 907 36, Umeå, Sweden
| | - Sander Kersten
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, the Netherlands.
| |
Collapse
|
50
|
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.
Collapse
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
| |
Collapse
|