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You M, Zhou L, Wu F, Zhang L, Zhu SX, Zhang HX. Probiotics for the treatment of hyperlipidemia: Focus on gut-liver axis and lipid metabolism. Pharmacol Res 2025; 214:107694. [PMID: 40068270 DOI: 10.1016/j.phrs.2025.107694] [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: 12/05/2024] [Revised: 02/19/2025] [Accepted: 03/07/2025] [Indexed: 03/23/2025]
Abstract
Hyperlipidemia, a metabolic disorder marked by dysregulated lipid metabolism, is a key contributor to the onset and progression of various chronic diseases. Maintaining normal lipid metabolism is critical for health, as disruptions lead to dyslipidemia. The gut and liver play central roles in lipid homeostasis, with their bidirectional communication, known as the gut-liver axis, modulated by bile acids (BAs), gut microbiota, and their metabolites. BAs are essential for regulating their own synthesis, lipid metabolism, and anti-inflammatory responses, primarily through the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Available evidence suggests that high-fat diet-induced the gut microbiota dysbiosis can induce "leaky gut," allowing toxic microbial metabolites to enter the liver via portal circulation, triggering liver inflammation and lipid metabolism disturbances, ultimately leading to hyperlipidemia. Extensive studies have highlighted the roles of probiotics and Traditional Chinese Medicine (TCM) in restoring gut-liver axis balance and modulating lipid metabolism through regulating the levels of lipopolysaccharides, short-chain fatty acids, and BAs. However, the therapeutic potential of probiotics and TCM for hyperlipidemia remains unclear. Here, firstly, we explore the intricate interplay among gut microbiota and metabolites, lipid metabolism, gut-liver axis, and hyperlipidemia. Secondly, we summarize the mechanisms by which probiotics and TCM can alleviate hyperlipidemia by altering the composition of gut microbiota and regulating lipid metabolism via the gut-liver axis. Finally, we emphasize that more clinical trials of probiotics and TCM are necessary to examine their effects on lipid metabolism and hyperlipidemia.
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Affiliation(s)
- Min You
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Li Zhou
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Fan Wu
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Lei Zhang
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China
| | - Shu-Xiu Zhu
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China.
| | - Hong-Xing Zhang
- School of Medicine, Jianghan University, Wuhan, Hubei, China; Institute of Acupuncture and Moxibustion, Jianghan University, Wuhan, Hubei, China.
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2
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Sirtori CR, Cincotto G, Castiglione S, Pavanello C. HDL-replacement therapy: From traditional to emerging clinical applications. ATHEROSCLEROSIS PLUS 2025; 59:68-79. [PMID: 40103705 PMCID: PMC11914826 DOI: 10.1016/j.athplu.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/27/2025] [Accepted: 02/23/2025] [Indexed: 03/20/2025]
Abstract
The unique and multifaceted properties of high-density lipoproteins (HDL)-ranging from cholesterol efflux to anti-inflammatory, anti-oxidant, and immunomodulatory effects-have prompted their direct use, particularly in cardiovascular ischemic conditions. Recent advances have extended the interest in HDL-based treatments to novel applications, from improving stent biocompatibility, to treatment of heart failure to central nervous system (CNS) disorders. Strategies to harness HDL's therapeutic potential have evolved from the direct use of isolated HDL in animal models to reconstituted HDL (rHDL) in humans. For these latter, the use of isolated apoA-I associated with different phospholipids has been the most frequent approach, also involving apparently beneficial mutants, such as the apo A-I Milano (AIM). From the initial very promising results, particularly with this mutant in coronary patients, later studies have mostly been non-confirmatory, although issues such as possible inadequate dose/response and unexpected immunological properties have come to light. Most recently a study on isolated plasma HDL in coronary patients (AEGIS-II) provided overall negative findings, but a clear fall of major cardiovascular events was recorded when restricting analysis to hypercholesterolemic patients. Emerging approaches, including gene therapy and plant-derived recombinant HDL formulations, hold promise for enhancing the accessibility and efficacy of HDL-based interventions. At this time, an improved approach to heart failure treatment also appears feasible, and a better understanding of the role played by HDL in the CNS may lead to significant improvements in the handling of some dramatic diseases at this level. While challenges persist, the evolving landscape of HDL replacement therapies offers hope for significant progress in addressing both cardiovascular and non-cardiovascular conditions.
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Affiliation(s)
- Cesare Riccardo Sirtori
- Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy
- Dyslipidemia Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giulia Cincotto
- Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy
| | - Sofia Castiglione
- Dyslipidemia Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy
| | - Chiara Pavanello
- Dyslipidemia Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Centro E. Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari "Rodolfo Paoletti", Università Degli Studi di Milano, Milan, Italy
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3
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Wu B, Liu Y, Li H, Zhu L, Zeng L, Zhang Z, Peng W. Liver as a new target organ in Alzheimer's disease: insight from cholesterol metabolism and its role in amyloid-beta clearance. Neural Regen Res 2025; 20:695-714. [PMID: 38886936 PMCID: PMC11433892 DOI: 10.4103/1673-5374.391305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/14/2023] [Accepted: 11/07/2023] [Indexed: 06/20/2024] Open
Abstract
Alzheimer's disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer's disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer's disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease. In this review, we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
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Affiliation(s)
- Beibei Wu
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yuqing Liu
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Hongli Li
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Lemei Zhu
- Academician Workstation, Changsha Medical University, Changsha, Hunan Province, China
| | - Lingfeng Zeng
- Academician Workstation, Changsha Medical University, Changsha, Hunan Province, China
| | - Zhen Zhang
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- Yangsheng College of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou Province, China
- Qinhuangdao Shanhaiguan Pharmaceutical Co., Ltd, Qinhuangdao, Hebei Province, China
| | - Weijun Peng
- Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Mental Disorder, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
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Kang XZ, Jin DY, Cheng Y. C1orf115 interacts with clathrin adaptors to undergo endocytosis and induces ABCA1 to promote enteric cholesterol efflux. Cell Mol Life Sci 2025; 82:59. [PMID: 39847086 PMCID: PMC11757849 DOI: 10.1007/s00018-025-05590-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/31/2024] [Accepted: 01/12/2025] [Indexed: 01/24/2025]
Abstract
C1orf115 has been identified in high-throughput screens as a regulator of multidrug resistance possibly mediated through an interaction with ATP-dependent membrane transporter ABCB1. Here we show that C1orf115 not only shares structural similarities with FACI/C11orf86 to interact with clathrin adaptors to undergo endocytosis, but also induces ABCA1 transcription to promote cholesterol efflux. C1orf115 consists of an N-terminal intrinsically disordered region and a C-terminal α-helix. Its α-helix binds to phosphoinositides, and mediates C1orf115 localization to the plasma membrane, nucleolus and nuclear speckles. An acidic dileucine-like motif "ExxxIL" within C1orf115 binds with the AP2 complex and mediates its localization to clathrin-coating pits. The positively charged amphipathic α-helix undergoes acetylation, which redistributes C1orf115 from the plasma membrane and nucleolus to nuclear speckles. C1orf115 is widely expressed and most abundant in the small intestine. The ability of C1orf115 in clathrin-mediated endocytosis is required for its regulation of drug resistance, which is modulated by acetylation. RNA-seq analysis reveals that C1orf115 induces intestinal transcription of another ATP-dependent transporter ABCA1 and consequently promotes ABCA1-mediated cholesterol efflux in enterocytes. Our study provides mechanistic insight into how C1orf115 modulates drug resistance and cholesterol efflux through clathrin-mediated endocytosis and ABCA1 expression.
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Affiliation(s)
- Xiao-Zhuo Kang
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong
| | - Dong-Yan Jin
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
- State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
| | - Yun Cheng
- School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.
- State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
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Le May C, Ducheix S, Cariou B, Rimbert A. From Genetic Findings to new Intestinal Molecular Targets in Lipid Metabolism. Curr Atheroscler Rep 2025; 27:26. [PMID: 39798054 DOI: 10.1007/s11883-024-01264-w] [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] [Accepted: 12/03/2024] [Indexed: 01/13/2025]
Abstract
PURPOSE OF REVIEW While lipid-lowering therapies demonstrate efficacy, many patients still contend with significant residual risk of atherosclerotic cardiovascular diseases (ASCVD). The intestine plays a pivotal role in regulating circulating lipoproteins levels, thereby exerting influence on ASCVD pathogenesis. This review underscores recent genetic findings from the last six years that delineate new biological pathways and actors in the intestine which regulate lipid-related ASCVD risk. RECENT FINDINGS Specifically, we detail the role of LIMA1 in cholesterol absorption within enterocytes, the function of PLA2G12B in the expansion and lipidation of chylomicrons, the involvement of SURF4 in lipoprotein secretion, and the discovery of a gut-derived hormone named CHOLESIN that modulates cholesterol homeostasis through GPR146 via a gut-liver crosstalk. We further discuss the potential of these newly identified genes and pathways as novel targets for pharmaceutical intervention. Newly identified genetic and intestinal molecular mechanisms offer promising opportunities for preventing and treating ASCVD, but careful evaluation and further research are needed to optimize their clinical application.
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Affiliation(s)
- Cédric Le May
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Simon Ducheix
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Antoine Rimbert
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France.
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Alruhaimi RS, Hussein OE, Alnasser SM, Germoush MO, Alotaibi M, Hassanein EHM, El Mohtadi M, Mahmoud AM. Oxidative Stress, Inflammation, and Altered Lymphocyte E-NTPDase Are Implicated in Acute Dyslipidemia in Rats: Protective Role of Arbutin. Pharmaceuticals (Basel) 2024; 17:1343. [PMID: 39458984 PMCID: PMC11509952 DOI: 10.3390/ph17101343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Dyslipidemia is frequently linked to various disorders, and its clinical relevance is now recognized. The role of inflammation and oxidative stress (OS) in dyslipidemia has been acknowledged. This study assessed the potential of arbutin (ARB) to prevent dyslipidemia and its associated OS and inflammation in rats with acute hyperlipidemia. METHODS Rats received ARB orally for 14 days and a single intraperitoneal injection of poloxamer-407 on day 15. RESULTS Poloxamer-407 elevated circulating cholesterol (CHOL), triglycerides (TG), very low-density lipoprotein (vLDL), and LDL, and reduced high-density lipoprotein (HDL)-C and lipoprotein lipase (LPL). ARB ameliorated the circulating lipids and LPL, and suppressed 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) in rat liver and in vitro. Fatty acid synthase (FAS) in rat liver and its in vitro activity were suppressed by ARB, which also upregulated the LDL receptor (LDL-R) and ABCA1, and had no effect on ABCG5 and ABCG8 mRNA. ARB ameliorated liver malondialdehyde and nitric oxide and enhanced antioxidants in rats with dyslipidemia. Liver NF-κB p65 and blood inflammatory cytokines were increased in dyslipidemic rats, effects that were reversed by ARB. Moreover, ARB effectively suppressed lymphocyte E-NTPDase and E-ADA activities in dyslipidemic rats. The biochemical findings were supported by in silico data showing the affinity of ARB to bind LDL-R PCSK9 binding domain, HMGCR, FAS, and E-NTPDase. CONCLUSIONS ARB possessed anti-dyslipidemia, anti-inflammatory, and antioxidant effects mediated via the modulation of CHOL and TG synthesis, LPL, lymphocyte E-NTPDase and E-ADA, and cytokine release in rats. Thus, ARB could be an effective agent to attenuate dyslipidemia and its associated OS and inflammation, pending further studies as well as clinical trials.
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Affiliation(s)
- Reem S. Alruhaimi
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Omnia E. Hussein
- Higher Technological Institute for Applied Health Sciences, Beni-Suef 62764, Egypt
| | - Sulaiman M. Alnasser
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
| | - Mousa O. Germoush
- Biology Department, College of Science, Jouf University, Sakakah 72388, Saudi Arabia
| | - Meshal Alotaibi
- Department of Pharmacy Practice, College of Pharmacy, University of Hafr Albatin, Hafar Al Batin 39524, Saudi Arabia
| | - Emad H. M. Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University-Assiut Branch, Assiut 71524, Egypt
| | | | - Ayman M. Mahmoud
- Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK
- Molecular Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt
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Zhang X, van der Vorst EPC. High-Density Lipoprotein Modifications: Causes and Functional Consequences in Type 2 Diabetes Mellitus. Cells 2024; 13:1113. [PMID: 38994965 PMCID: PMC11240616 DOI: 10.3390/cells13131113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 06/22/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024] Open
Abstract
High-density lipoprotein (HDL) is a group of small, dense, and protein-rich lipoproteins that play a role in cholesterol metabolism and various cellular processes. Decreased levels of HDL and HDL dysfunction are commonly observed in individuals with type 2 diabetes mellitus (T2DM), which is also associated with an increased risk for cardiovascular disease (CVD). Due to hyperglycemia, oxidative stress, and inflammation that develop in T2DM, HDL undergoes several post-translational modifications such as glycation, oxidation, and carbamylation, as well as other alterations in its lipid and protein composition. It is increasingly recognized that the generation of HDL modifications in T2DM seems to be the main cause of HDL dysfunction and may in turn influence the development and progression of T2DM and its related cardiovascular complications. This review provides a general introduction to HDL structure and function and summarizes the main modifications of HDL that occur in T2DM. Furthermore, the potential impact of HDL modifications on the pathogenesis of T2DM and CVD, based on the altered interactions between modified HDL and various cell types that are involved in glucose homeostasis and atherosclerotic plaque generation, will be discussed. In addition, some perspectives for future research regarding the T2DM-related HDL modifications are addressed.
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Affiliation(s)
- Xiaodi Zhang
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany;
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), 80336 Munich, Germany
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8
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Hernández-Martín M, Garcimartín A, Bocanegra A, Redondo-Castillejo R, Quevedo-Torremocha C, Macho-González A, García Fernández RA, Bastida S, Benedí J, Sánchez-Muniz FJ, López-Oliva ME. Silicon as a Functional Meat Ingredient Improves Jejunal and Hepatic Cholesterol Homeostasis in a Late-Stage Type 2 Diabetes Mellitus Rat Model. Foods 2024; 13:1794. [PMID: 38928736 PMCID: PMC11203255 DOI: 10.3390/foods13121794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/02/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Silicon included in a restructured meat (RM) matrix (Si-RM) as a functional ingredient has been demonstrated to be a potential bioactive antidiabetic compound. However, the jejunal and hepatic molecular mechanisms by which Si-RM exerts its cholesterol-lowering effects remain unclear. Male Wistar rats fed an RM included in a high-saturated-fat high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection were used as late-stage type 2 diabetes mellitus (T2DM) model. Si-RM was included into the HSFHCD as a functional food. An early-stage TD2M group fed a high-saturated-fat diet (HSFD) was taken as reference. Si-RM inhibited the hepatic and intestinal microsomal triglyceride transfer protein (MTP) reducing the apoB-containing lipoprotein assembly and cholesterol absorption. Upregulation of liver X receptor (LXRα/β) by Si-RM turned in a higher low-density lipoprotein receptor (LDLr) and ATP-binding cassette transporters (ABCG5/8, ABCA1) promoting jejunal cholesterol efflux and transintestinal cholesterol excretion (TICE), and facilitating partially reverse cholesterol transport (RCT). Si-RM decreased the jejunal absorptive area and improved mucosal barrier integrity. Consequently, plasma triglycerides and cholesterol levels decreased, as well as the formation of atherogenic lipoprotein particles. Si-RM mitigated the dyslipidemia associated with late-stage T2DM by Improving cholesterol homeostasis. Silicon could be used as an effective nutritional approach in diabetic dyslipidemia management.
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Affiliation(s)
- Marina Hernández-Martín
- Departmental Section of Physiology, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Alba Garcimartín
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.G.); (R.R.-C.); (C.Q.-T.); (J.B.)
| | - Aránzazu Bocanegra
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.G.); (R.R.-C.); (C.Q.-T.); (J.B.)
| | - Rocío Redondo-Castillejo
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.G.); (R.R.-C.); (C.Q.-T.); (J.B.)
| | - Claudia Quevedo-Torremocha
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.G.); (R.R.-C.); (C.Q.-T.); (J.B.)
| | - Adrián Macho-González
- Nutrition and Food Science Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.M.-G.); (S.B.); (F.J.S.-M.)
| | - Rosa Ana García Fernández
- Animal Medicine and Surgery Department, Veterinary School, Complutense University of Madrid, 28040 Madrid, Spain;
| | - Sara Bastida
- Nutrition and Food Science Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.M.-G.); (S.B.); (F.J.S.-M.)
| | - Juana Benedí
- Pharmacology, Pharmacognosy and Botany Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.G.); (R.R.-C.); (C.Q.-T.); (J.B.)
| | - Francisco José Sánchez-Muniz
- Nutrition and Food Science Department, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain; (A.M.-G.); (S.B.); (F.J.S.-M.)
| | - María Elvira López-Oliva
- Departmental Section of Physiology, Pharmacy School, Complutense University of Madrid, 28040 Madrid, Spain;
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9
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Romo EZ, Hong BV, Patel RY, Agus JK, Harvey DJ, Maezawa I, Jin LW, Lebrilla CB, Zivkovic AM. Elevated lipopolysaccharide binding protein in Alzheimer's disease patients with APOE3/E3 but not APOE3/E4 genotype. Front Neurol 2024; 15:1408220. [PMID: 38882697 PMCID: PMC11177782 DOI: 10.3389/fneur.2024.1408220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 05/16/2024] [Indexed: 06/18/2024] Open
Abstract
Introduction The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood. Methods In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA. Results LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS). Discussion These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.
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Affiliation(s)
- Eduardo Z. Romo
- Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - Brian V. Hong
- Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - Rishi Y. Patel
- Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - Joanne K. Agus
- Department of Nutrition, University of California, Davis, Davis, CA, United States
| | - Danielle J. Harvey
- Department of Public Health Sciences, University of California, Davis, Davis, CA, United States
| | - Izumi Maezawa
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Lee-Way Jin
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Carlito B. Lebrilla
- Department of Chemistry, University of California, Davis, Davis, CA, United States
| | - Angela M. Zivkovic
- Department of Nutrition, University of California, Davis, Davis, CA, United States
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10
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Shi X, Chen Y, Shi M, Gao F, Huang L, Wang W, Wei D, Shi C, Yu Y, Xia X, Song N, Chen X, Distler JHW, Lu C, Chen J, Wang J. The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases. Lipids Health Dis 2024; 23:98. [PMID: 38570797 PMCID: PMC10988923 DOI: 10.1186/s12944-024-02062-8] [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] [Received: 12/26/2023] [Accepted: 02/27/2024] [Indexed: 04/05/2024] Open
Abstract
Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
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Affiliation(s)
- Xiangguang Shi
- Department of Dermatology, Huashan Hospital, and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Yahui Chen
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China
| | - Mengkun Shi
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Fei Gao
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
| | - Lihao Huang
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative Biology, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Wei Wang
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Dong Wei
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China
| | - Chenyi Shi
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuexin Yu
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China
| | - Xueyi Xia
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China
| | - Nana Song
- Department of Nephrology, Zhongshan Hospital, Fudan University, Fudan Zhangjiang Institute, Shanghai, People's Republic of China
| | - Xiaofeng Chen
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jörg H W Distler
- Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen, Nuremberg, Germany
| | - Chenqi Lu
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
| | - Jingyu Chen
- Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
- Center for Lung Transplantation, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jiucun Wang
- Department of Dermatology, Huashan Hospital, and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
- Human Phenome Institute, and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China Fudan University, Shanghai, China.
- Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Beijing, China.
- Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, China.
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11
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Wang J, Li J, Fu Y, Zhu Y, Lin L, Li Y. Research progress, challenges and perspectives of phospholipids metabolism in the LXR‑LPCAT3 signaling pathway and its relation to NAFLD (Review). Int J Mol Med 2024; 53:32. [PMID: 38362962 PMCID: PMC10903931 DOI: 10.3892/ijmm.2024.5356] [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: 09/22/2023] [Accepted: 01/16/2024] [Indexed: 02/17/2024] Open
Abstract
Phospholipids (PLs) are principle constituents of biofilms, with their fatty acyl chain composition significantly impacting the biophysical properties of membranes, thereby influencing biological processes. Recent studies have elucidated that fatty acyl chains, under the enzymatic action of lyso‑phosphatidyl‑choline acyltransferases (LPCATs), expedite incorporation into the sn‑2 site of phosphatidyl‑choline (PC), profoundly affecting pathophysiology. Accumulating evidence suggests that alterations in LPCAT activity are implicated in various diseases, including non‑alcoholic fatty liver disease (NAFLD), hepatitis C, atherosclerosis and cancer. Specifically, LPCAT3 is instrumental in maintaining systemic lipid homeostasis through its roles in hepatic lipogenesis, intestinal lipid absorption and lipoprotein secretion. The liver X receptor (LXR), pivotal in lipid homeostasis, modulates cholesterol, fatty acid (FA) and PL metabolism. LXR's capacity to modify PL composition in response to cellular sterol fluctuations is a vital mechanism for protecting biofilms against lipid stress. Concurrently, LXR activation enhances LPCAT3 expression on cell membranes and elevates polyunsaturated PL levels. This activation can ameliorate saturated free FA effects in vitro or endoplasmic reticulum stress in vivo due to lipid accumulation in hepatic cells. Pharmacological interventions targeting LXR, LPCAT and membrane PL components could offer novel therapeutic directions for NAFLD management. The present review primarily focused on recent advancements in understanding the LPCAT3 signaling pathway's role in lipid metabolism related to NAFLD, aiming to identify new treatment targets for the disease.
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Affiliation(s)
- Junmin Wang
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Jiacheng Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yugang Fu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yingying Zhu
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Liubing Lin
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Yong Li
- Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
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12
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Alruhaimi RS, Siddiq Abduh M, Ahmeda AF, Bin-Ammar A, Kamel EM, Hassanein EHM, Li C, Mahmoud AM. Berberine attenuates inflammation and oxidative stress and modulates lymphocyte E-NTPDase in acute hyperlipidemia. Drug Dev Res 2024; 85:e22166. [PMID: 38424708 DOI: 10.1002/ddr.22166] [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: 01/20/2024] [Accepted: 02/15/2024] [Indexed: 03/02/2024]
Abstract
Hyperlipidemia is a common clinically encountered health condition worldwide that promotes the development and progression of cardiovascular diseases, including atherosclerosis. Berberine (BBR) is a natural product with acknowledged anti-inflammatory, antioxidant, and metabolic effects. This study evaluated the effect of BBR on lipid alterations, oxidative stress, and inflammatory response in rats with acute hyperlipidemia induced by poloxamer-407 (P-407). Rats were pretreated with BBR (25 and 50 mg/kg) for 14 days and acute hyperlipidemia was induced by a single dose of P-407 (500 mg/kg). BBR ameliorated hypercholesterolemia, hypertriglyceridemia, and plasma lipoproteins in P-407-adminsitered rats. Plasma lipoprotein lipase (LPL) activity was decreased, and hepatic 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity was enhanced in hyperlipidemic rats. The expression of low-density lipoprotein receptor (LDL-R) and ATP-binding cassette transporter 1 (ABCA1) was downregulated in hyperlipidemic rats. BBR enhanced LPL activity, upregulated LDL-R, and ABCA1, and suppressed HMG-CoA reductase in P-407-administered rats. Pretreatment with BBR ameliorated lipid peroxidation, nitric oxide (NO), pro-inflammatory mediators (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon-γ, IL-4 and IL-18) and enhanced antioxidants. In addition, BBR suppressed lymphocyte ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and ecto-adenosine deaminase (E-ADA) as well as NO and TNF-α release by macrophages isolated from normal and hyperlipidemic rats. In silico investigations revealed the binding affinity of BBR toward LPL, HMG-CoA reductase, LDL-R, PSK9, ABCA1, and E-NTPDase. In conclusion, BBR effectively prevented acute hyperlipidemia and its associated inflammatory responses by modulating LPL, cholesterolgenesis, cytokine release, and lymphocyte E-NTPDase and E-ADA. Therefore, BBR is an effective and safe natural compound that might be employed as an adjuvant against hyperlipidemia and its associated inflammation.
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Affiliation(s)
- Reem S Alruhaimi
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Maisa Siddiq Abduh
- Department of Medical Laboratory Sciences, Immune Responses in Different Diseases Research Group, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ahmad F Ahmeda
- Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman, United Arab Emirates
- Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Albandari Bin-Ammar
- Department of Clinical Nutrition, College of Applied Medical Sciences, University of Hail, Ha'il, Saudi Arabia
| | - Emadeldin M Kamel
- Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Emad H M Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University-Assiut Branch, Assiut, Egypt
| | - Chen Li
- Department of Biology, Chemistry, Pharmacy, Free University of Berlin, Berlin, Germany
| | - Ayman M Mahmoud
- Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK
- Zoology Department, Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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13
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [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: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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14
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Sun J, Xie F, Wang J, Luo J, Chen T, Jiang Q, Xi Q, Liu GE, Zhang Y. Integrated meta-omics reveals the regulatory landscape involved in lipid metabolism between pig breeds. MICROBIOME 2024; 12:33. [PMID: 38374121 PMCID: PMC10877772 DOI: 10.1186/s40168-023-01743-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 12/19/2023] [Indexed: 02/21/2024]
Abstract
BACKGROUND Domesticated pigs serve as an ideal animal model for biomedical research and also provide the majority of meat for human consumption in China. Porcine intramuscular fat content associates with human health and diseases and is essential in pork quality. The molecular mechanisms controlling lipid metabolism and intramuscular fat accretion across tissues in pigs, and how these changes in response to pig breeds, remain largely unknown. RESULTS We surveyed the tissue-resident cell types of the porcine jejunum, colon, liver, and longissimus dorsi muscle between Lantang and Landrace breeds by single-cell RNA sequencing. Combining lipidomics and metagenomics approaches, we also characterized gene signatures and determined key discriminating markers of lipid digestibility, absorption, conversion, and deposition across tissues in two pig breeds. In Landrace, lean-meat swine mainly exhibited breed-specific advantages in lipid absorption and oxidation for energy supply in small and large intestinal epitheliums, nascent high-density lipoprotein synthesis for reverse cholesterol transport in enterocytes and hepatocytes, bile acid formation, and secretion for fat emulsification in hepatocytes, as well as intestinal-microbiota gene expression involved in lipid accumulation product. In Lantang, obese-meat swine showed a higher synthesis capacity of chylomicrons responsible for high serum triacylglycerol levels in small intestinal epitheliums, the predominant characteristics of lipid absorption in muscle tissue, and greater intramuscular adipcytogenesis potentials from muscular fibro-adipogenic progenitor subpopulation. CONCLUSIONS The findings enhanced our understanding of the cellular biology of lipid metabolism and opened new avenues to improve animal production and human diseases. Video Abstract.
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Affiliation(s)
- Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China
| | - Fang Xie
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China
| | - Jing Wang
- Institute of Animal Husbandry and Veterinary Medicine, Henan Academy of Agricultural Sciences, Zhengzhou, 450002, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
| | - George E Liu
- Animal Genomics and Improvement Laboratory, USDA-ARS, BARC-East, Beltsville, MD, 20705, USA.
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, 510642, China.
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15
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Liu L, Yan R, Guo P, Ji J, Gong W, Xue F, Yuan Z, Zhou X. Conditional transcriptome-wide association study for fine-mapping candidate causal genes. Nat Genet 2024; 56:348-356. [PMID: 38279040 DOI: 10.1038/s41588-023-01645-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 12/08/2023] [Indexed: 01/28/2024]
Abstract
Transcriptome-wide association studies (TWASs) aim to integrate genome-wide association studies with expression-mapping studies to identify genes with genetically predicted expression (GReX) associated with a complex trait. In the present report, we develop a method, GIFT (gene-based integrative fine-mapping through conditional TWAS), that performs conditional TWAS analysis by explicitly controlling for GReX of all other genes residing in a local region to fine-map putatively causal genes. GIFT is frequentist in nature, explicitly models both expression correlation and cis-single nucleotide polymorphism linkage disequilibrium across multiple genes and uses a likelihood framework to account for expression prediction uncertainty. As a result, GIFT produces calibrated P values and is effective for fine-mapping. We apply GIFT to analyze six traits in the UK Biobank, where GIFT narrows down the set size of putatively causal genes by 32.16-91.32% compared with existing TWAS fine-mapping approaches. The genes identified by GIFT highlight the importance of vessel regulation in determining blood pressures and lipid metabolism for regulating lipid levels.
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Affiliation(s)
- Lu Liu
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ran Yan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ping Guo
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiadong Ji
- Institute for Financial Studies, Shandong University, Jinan, China
| | - Weiming Gong
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fuzhong Xue
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
- Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhongshang Yuan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China.
- Institute for Medical Dataology, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
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16
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Cho KH, Baek SH, Nam HS, Bahuguna A, López-González LE, Rodríguez-Cortina I, Illnait-Ferrer J, Fernández-Travieso JC, Molina-Cuevas V, Pérez-Guerra Y, Oyarzabal Yera A, Mendoza-Castaño S. Beeswax Alcohol Prevents Low-Density Lipoprotein Oxidation and Demonstrates Antioxidant Activities in Zebrafish Embryos and Human Subjects: A Clinical Study. Curr Issues Mol Biol 2024; 46:409-429. [PMID: 38248328 PMCID: PMC10813917 DOI: 10.3390/cimb46010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
Oxidative stress is one of the primary instigators of the onset of various human ailments, including cancers, cardiovascular diseases, and dementia. Particularly, oxidative stress severely affects low-density lipid & protein (LDL) oxidation, leading to several detrimental health effects. Therefore, in this study, the effect of beeswax alcohol (BWA) was evaluated in the prevention of LDL oxidation, enhancement of paraoxonase 1 (PON-1) activity of high-density lipid & protein (HDL), and zebrafish embryo survivability. Furthermore, the implication of BWA consumption on the oxidative plasma variables was assessed by a preliminary clinical study on middle-aged and older human subjects (n = 50). Results support BWA augmentation of PON-1 activity in a dose-dependent manner (10-30 μM), which was significantly better than the effect exerted by coenzyme Q10 (CoQ10). Moreover, BWA significantly curtails LDL/apo-B oxidation evoked by CuSO4 (final 0.5 μM) and a causes a marked reduction in lipid peroxidation in LDL. The transmission electron microscopy (TEM) analysis revealed a healing effect of BWA towards the restoration of LDL morphology and size impaired by the exposure of Cu2+ ions (final 0.5 μM). Additionally, BWA counters the toxicity induced by carboxymethyllysine (CML, 500 ng) and rescues zebrafish embryos from development deformities and apoptotic cell death. A completely randomized, double-blinded, placebo-controlled preliminary clinical study on middle- and older-aged human subjects (n = 50) showed that 12 weeks of BWA (100 mg/day) supplementation efficiently diminished serum malondialdehyde (MDA) and total hydroperoxides and enhanced total antioxidant status by 25%, 27%, and 22%, respectively, compared to the placebo-control and baseline values. Furthermore, the consumption of BWA did not exhibit any noteworthy changes in physical variables, lipid profile, glucose levels, and biomarkers pertinent to kidney and liver function, thus confirming the safety of BWA for consumption. Conclusively, in vitro, BWA prevents LDL oxidation, enhances PON-1 activity in HDL, and positively influences oxidative variables in human subjects.
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Affiliation(s)
- Kyung-Hyun Cho
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Seung-Hee Baek
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Hyo-Seon Nam
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
| | - Ashutosh Bahuguna
- Raydel Research Institute, Medical Innovation Complex, Daegu 41061, Republic of Korea
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17
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Wang Y, Guo M, Tang CK. History and Development of ABCA1. Curr Probl Cardiol 2024; 49:102036. [PMID: 37595859 DOI: 10.1016/j.cpcardiol.2023.102036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 08/15/2023] [Indexed: 08/20/2023]
Abstract
ATP-binding cassette protein A1 (ABCA1) is a key protein in the transport of intracellular cholesterol to the extracellular and plays an important role in reducing cholesterol accumulation in surrounding tissues. Bibliometric analysis refers to the cross-science of quantitative analysis of a variety of documents by mathematical and statistical methods. It combines an analysis of structural and temporal patterns in scholarly publications with a description of topic concentration and types of uncertainty. This paper analyzes the history, hotspot, and development trend of ABCA1 through bibliometrics. It will provide readers with the research status and development trend of ABCA1 and help the hot research in this field explore new research directions. After screening, the research on ABCA1 is still in a hot phase in the past 20 years. ABCA1 is emerging in previously unrelated disciplines such as cancer. There were 551 keywords and 6888 breakout citations counted by CiteSpace. The relationship between cancer and cardiovascular disease has been linked by ABCA1. This review will guide readers who are not familiar with ABCA1 research to quickly understand the development process of ABCA1 and provide researchers with a possible future research focus on ABCA1.
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Affiliation(s)
- Yang Wang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Min Guo
- Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Chao-Ke Tang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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18
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Liu X, Zhang J, Chen Z, Xiao J, Zhou A, Fu Y, Cao Y. Cluster-determinant 36 (CD36) mediates intestinal absorption of dietary astaxanthin and affects its secretion. Food Res Int 2023; 173:113328. [PMID: 37803639 DOI: 10.1016/j.foodres.2023.113328] [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] [Received: 05/16/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 10/08/2023]
Abstract
The functional activity of dietary astaxanthin is closely related to its absorption, and the absorption of dietary carotenoids mainly mediated by transmembrane transport protein (TTP) has become the mainstream research direction in recent years. However, the main TTP mediating astaxanthin absorption and its potential mechanisms are still unclear. Hence, based on the preliminary screening results, this study aims to elucidate the role of cluster-determinant 36 (CD36) mediating astaxanthin absorption from the perspective of expression levels through in vitro cell model, in situ single-pass intestinal perfusion model and in vivo mice model. The results showed that astaxanthin uptake was significantly increased by 45.13% in CD36 overexpressing cells and decreased by 20.92% in the case of sulfo-N-succinimidyl oleate (SSO) inhibition. A similar trend also appeared in the duodenum and jejunum by in situ model. Moreover, astaxanthin uptake in the small intestine of CD36 knockout mice was significantly reduced by 88.22%. Furthermore, the inhibition or knockout of CD36 suppressed the expression of other transporters (SR-BI and NPC1L1). Interestingly, CD36 was also involved in the downstream secretion pathway, which is manifested by interfering with the expression of related proteins (ERK1/2, MTP, ApoB48, and ApoAI). Therefore, these results indicate the important role of CD36 in astaxanthin transmembrane transport for the first time, providing vital exploration way for the absorption of dietary fat-soluble substances.
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Affiliation(s)
- Xiaojuan Liu
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
| | - Junlin Zhang
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Zhiqing Chen
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Jie Xiao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Aimei Zhou
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
| | - Yongshui Fu
- Institute of Blood Transfusion, Guangzhou Blood Center, Guangzhou 510095, China
| | - Yong Cao
- Guangdong Provincial Key Laboratory of Nutraceuticals and Functional Foods, College of Food Science, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China
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19
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Xu H, Xin Y, Wang J, Liu Z, Cao Y, Li W, Zhou Y, Wang Y, Liu P. The TICE Pathway: Mechanisms and Potential Clinical Applications. Curr Atheroscler Rep 2023; 25:653-662. [PMID: 37736845 DOI: 10.1007/s11883-023-01147-6] [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] [Accepted: 08/28/2023] [Indexed: 09/23/2023]
Abstract
PURPOSE OF REVIEW Transintestinal cholesterol excretion (TICE) is a non-biliary pathway that excretes excess cholesterol from the body through feces. This article focuses on the research progress of the TICE pathway in the last few years, including the discovery process of the TICE pathway, its molecular mechanism, and potential clinical applications. RECENT FINDINGS Cholesterol homeostasis is vital for cardiovascular diseases, stroke, and neurodegenerative diseases. Beyond the cholesterol excretion via hepatobiliary pathway, TICE contributes significantly to reverse cholesterol transport ex vivo and in vivo. Nuclear receptors are ligand-activated transcription factors that regulate cholesterol metabolism. The farnesoid X receptor (FXR) and liver X receptor (LXR) activated, respectively, by oxysterols and bile acids promote intestinal cholesterol secretion through ABCG5/G8. Nutrient regulators and intestinal flora also modulate cholesterol secretion through the TICE pathway. TICE allows direct elimination of plasma cholesterol, which may provide an attractive therapeutic targets. TICE pathway may provide a potential target to stimulate cholesterol elimination and reduce the risk of cardiovascular diseases.
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Affiliation(s)
- Huimin Xu
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China
| | - Yiyang Xin
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China
| | - Jiaxin Wang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China
| | - Zixin Liu
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China
| | - Yutong Cao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China
| | - Weiguo Li
- People's Hospital of Hebi, Henan University, Henan, China
| | - Yun Zhou
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, Henan University, Henan, China.
| | - Yandong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
| | - Peng Liu
- People's Hospital of Hebi, Henan University, Henan, China.
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20
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Hong BV, Agus JK, Tang X, Zheng JJ, Romo EZ, Lei S, Zivkovic AM. Precision Nutrition and Cardiovascular Disease Risk Reduction: the Promise of High-Density Lipoproteins. Curr Atheroscler Rep 2023; 25:663-677. [PMID: 37702886 PMCID: PMC10564829 DOI: 10.1007/s11883-023-01148-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2023] [Indexed: 09/14/2023]
Abstract
PURPOSE OF REVIEW Emerging evidence supports the promise of precision nutritional approaches for cardiovascular disease (CVD) prevention. Here, we discuss current findings from precision nutrition trials and studies reporting substantial inter-individual variability in responses to diets and dietary components relevant to CVD outcomes. We highlight examples where early precision nutrition research already points to actionable intervention targets tailored to an individual's biology and lifestyle. Finally, we make the case for high-density lipoproteins (HDL) as a compelling next generation target for precision nutrition aimed at CVD prevention. HDL possesses complex structural features including diverse protein components, lipids, size distribution, extensive glycosylation, and interacts with the gut microbiome, all of which influence HDL's anti-inflammatory, antioxidant, and cholesterol efflux properties. Elucidating the nuances of HDL structure and function at an individual level may unlock personalized dietary and lifestyle strategies to optimize HDL-mediated atheroprotection and reduce CVD risk. RECENT FINDINGS Recent human studies have demonstrated that HDL particles are key players in the reduction of CVD risk. Our review highlights the role of HDL and the importance of personalized therapeutic approaches to improve their potential for reducing CVD risk. Factors such as diet, genetics, glycosylation, and gut microbiome interactions can modulate HDL structure and function at the individual level. We emphasize that fractionating HDL into size-based subclasses and measuring particle concentration are necessary to understand HDL biology and for developing the next generation of diagnostics and biomarkers. These discoveries underscore the need to move beyond a one-size-fits-all approach to HDL management. Precision nutrition strategies that account for personalized metabolic, genetic, and lifestyle data hold promise for optimizing HDL therapies and function to mitigate CVD risk more potently. While human studies show HDL play a key role in reducing CVD risk, recent findings indicate that factors such as diet, genetics, glycosylation, and gut microbes modulate HDL function at the individual level, underscoring the need for precision nutrition strategies that account for personalized variability to optimize HDL's potential for mitigating CVD risk.
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Affiliation(s)
- Brian V Hong
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Joanne K Agus
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Xinyu Tang
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Jack Jingyuan Zheng
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Eduardo Z Romo
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Susan Lei
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Angela M Zivkovic
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA.
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21
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Ahmed RO, Ali A, Leeds T, Salem M. RNA-Seq analysis of the pyloric caecum, liver, and muscle reveals molecular mechanisms regulating fillet color in rainbow trout. BMC Genomics 2023; 24:579. [PMID: 37770878 PMCID: PMC10537910 DOI: 10.1186/s12864-023-09688-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 09/20/2023] [Indexed: 09/30/2023] Open
Abstract
BACKGROUND The characteristic pink-reddish color in the salmonids fillet is an important, appealing quality trait for consumers and producers. The color results from diet supplementation with carotenoids, which accounts for up to 20-30% of the feed cost. Pigment retention in the muscle is a highly variable phenotype. In this study, we aimed to understand the molecular basis for the variation in fillet color when rainbow trout (Oncorhynchus mykiss) fish families were fed an Astaxanthin-supplemented diet. We used RNA-Seq to study the transcriptome profile in the pyloric caecum, liver, and muscle from fish families with pink-reddish fillet coloration (red) versus those with lighter pale coloration (white). RESULTS More DEGs were identified in the muscle (5,148) and liver (3,180) than in the pyloric caecum (272). Genes involved in lipid/carotenoid metabolism and transport, ribosomal activities, mitochondrial functions, and stress homeostasis were uniquely enriched in the muscle and liver. For instance, the two beta carotene genes (BCO1 and BCO2) were significantly under-represented in the muscle of the red fillet group favoring more carotenoid retention. Enriched genes in the pyloric caecum were involved in intestinal absorption and transport of carotenoids and lipids. In addition, the analysis revealed the modulation of several genes with immune functions in the pyloric caecum, liver, and muscle. CONCLUSION The results from this study deepen our understanding of carotenoid dynamics in rainbow trout and can guide us on strategies to improve Astaxanthin retention in the rainbow trout fillet.
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Affiliation(s)
- Ridwan O Ahmed
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA
| | - Ali Ali
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA
| | - Tim Leeds
- Department of Agriculture Kearneysville, National Center for Cool and Cold Water Aquaculture, United States, Agricultural Research Service, Kearneysville, WV, 25430, USA
| | - Mohamed Salem
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD, 20742, USA.
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22
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Abstract
Cholesterol is an essential lipid species of mammalian cells. Cells acquire it through synthesis in the endoplasmic reticulum (ER) and uptake from lipoprotein particles. Newly synthesized cholesterol is efficiently distributed from the ER to other organelles via lipid-binding/transfer proteins concentrated at membrane contact sites (MCSs) to reach the trans-Golgi network, endosomes, and plasma membrane. Lipoprotein-derived cholesterol is exported from the plasma membrane and endosomal compartments via a combination of vesicle/tubule-mediated membrane transport and transfer through MCSs. In this review, we provide an overview of intracellular cholesterol trafficking pathways, including cholesterol flux from the ER to other membranes, cholesterol uptake from lipoprotein donors and transport from the plasma membrane to the ER, cellular cholesterol efflux to lipoprotein acceptors, as well as lipoprotein cholesterol secretion from enterocytes, hepatocytes, and astrocytes. We also briefly discuss human diseases caused by defects in these processes and therapeutic strategies available in such conditions.
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Affiliation(s)
- Elina Ikonen
- Department of Anatomy and Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, 00290 Helsinki, Finland
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23
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Burnap SA, Ortega-Prieto AM, Jimenez-Guardeño JM, Ali H, Takov K, Fish M, Shankar-Hari M, Giacca M, Malim MH, Mayr M. Cross-Linking Mass Spectrometry Uncovers Interactions Between High-Density Lipoproteins and the SARS-CoV-2 Spike Glycoprotein. Mol Cell Proteomics 2023; 22:100600. [PMID: 37343697 PMCID: PMC10279469 DOI: 10.1016/j.mcpro.2023.100600] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 06/23/2023] Open
Abstract
High-density lipoprotein (HDL) levels are reduced in patients with coronavirus disease 2019 (COVID-19), and the extent of this reduction is associated with poor clinical outcomes. While lipoproteins are known to play a key role during the life cycle of the hepatitis C virus, their influence on coronavirus (CoV) infections is poorly understood. In this study, we utilize cross-linking mass spectrometry (XL-MS) to determine circulating protein interactors of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoprotein. XL-MS of plasma isolated from patients with COVID-19 uncovered HDL protein interaction networks, dominated by acute-phase serum amyloid proteins, whereby serum amyloid A2 was shown to bind to apolipoprotein (Apo) D. XL-MS on isolated HDL confirmed ApoD to interact with SARS-CoV-2 spike but not SARS-CoV-1 spike. Other direct interactions of SARS-CoV-2 spike upon HDL included ApoA1 and ApoC3. The interaction between ApoD and spike was further validated in cells using immunoprecipitation-MS, which uncovered a novel interaction between both ApoD and spike with membrane-associated progesterone receptor component 1. Mechanistically, XL-MS coupled with data-driven structural modeling determined that ApoD may interact within the receptor-binding domain of the spike. However, ApoD overexpression in multiple cell-based assays had no effect upon viral replication or infectivity. Thus, SARS-CoV-2 spike can bind to apolipoproteins on HDL, but these interactions do not appear to alter infectivity.
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Affiliation(s)
- Sean A Burnap
- Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK; The Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, Oxford, UK; King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK.
| | - Ana Maria Ortega-Prieto
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Jose M Jimenez-Guardeño
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Hashim Ali
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK; Division of Virology, Department of Pathology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Kaloyan Takov
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Matthew Fish
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK; Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Manu Shankar-Hari
- Centre for Inflammation Research, Institute of Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK
| | - Mauro Giacca
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK
| | - Michael H Malim
- Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Manuel Mayr
- King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, UK.
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24
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Trites MJ, Stebbings BM, Aoki H, Phanse S, Akl MG, Li L, Babu M, Widenmaier SB. HDL functionality is dependent on hepatocyte stress defense factors Nrf1 and Nrf2. Front Physiol 2023; 14:1212785. [PMID: 37501930 PMCID: PMC10369849 DOI: 10.3389/fphys.2023.1212785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/30/2023] [Indexed: 07/29/2023] Open
Abstract
High density lipoproteins (HDL) promote homeostasis and counteract stressful tissue damage that underlie cardiovascular and other diseases by mediating reverse cholesterol transport, reducing inflammation, and abrogating oxidative damage. However, metabolically stressful conditions associated with atherosclerosis can impair these effects. Hepatocytes play a major role in the genesis and maturation of circulating HDL, and liver stress elicits marked regulatory changes to circulating HDL abundance and composition, which affect its functionality. The mechanisms linking liver stress to HDL function are incompletely understood. In this study, we sought to determine whether stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) promote hepatocyte production of functional HDL. Using genetically engineered mice briefly fed a mild metabolically stressful diet, we investigated the effect of hepatocyte-specific deletion of Nrf1, Nrf2, or both on circulating HDL cholesterol, protein composition, and function. Combined deletion, but not single gene deletion, reduced HDL cholesterol and apolipoprotein A1 levels as well as the capacity of HDL to accept cholesterol undergoing efflux from cultured macrophages and to counteract tumor necrosis factor α-induced inflammatory effect on cultured endothelial cells. This coincided with substantial alteration to the HDL proteome, which correlated with liver gene expression profiles of corresponding proteins. Thus, our findings show complementary actions by hepatocyte Nrf1 and Nrf2 play a role in shaping HDL abundance and composition to promote production of functionally viable HDL. Consequently, our study illuminates the possibility that enhancing stress defense programming in the liver may improve atheroprotective and perhaps other health promoting actions of HDL.
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Affiliation(s)
- Michael J. Trites
- Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Brynne M. Stebbings
- Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hiroyuki Aoki
- Department of Biochemistry, University of Regina, Regina, SK, Canada
| | - Sadhna Phanse
- Department of Biochemistry, University of Regina, Regina, SK, Canada
| | - May G. Akl
- Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Lei Li
- Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Mohan Babu
- Department of Biochemistry, University of Regina, Regina, SK, Canada
| | - Scott B. Widenmaier
- Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
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25
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Abstract
Kidney disease is associated with adverse consequences in many organs beyond the kidney, including the heart, lungs, brain, and intestines. The kidney-intestinal cross talk involves intestinal epithelial damage, dysbiosis, and generation of uremic toxins. Recent studies reveal that kidney injury expands the intestinal lymphatics, increases lymphatic flow, and alters the composition of mesenteric lymph. The intestinal lymphatics, like blood vessels, are a route for transporting potentially harmful substances generated by the intestines. The lymphatic architecture and actions are uniquely suited to take up and transport large macromolecules, functions that differentiate them from blood vessels, allowing them to play a distinct role in a variety of physiological and pathological processes. Here, we focus on the mechanisms by which kidney diseases result in deleterious changes in intestinal lymphatics and consider a novel paradigm of a vicious cycle of detrimental organ cross talk. This concept involves kidney injury-induced modulation of intestinal lymphatics that promotes production and distribution of harmful factors, which in turn contributes to disease progression in distant organ systems.
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Affiliation(s)
- Jianyong Zhong
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Annet Kirabo
- Department of Molecular Physiology and Biophysics (A.K.), Vanderbilt University Medical Center, Nashville, TN
- Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN (A.K.)
| | - Hai-Chun Yang
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Agnes B. Fogo
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology and Immunology (J.Z., H.-C.Y., A.B.F.), Vanderbilt University Medical Center, Nashville, TN
- Department of Medicine (A.B.F.), Vanderbilt University Medical Center, Nashville, TN
| | - Elaine L. Shelton
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
| | - Valentina Kon
- Department of Pediatrics (J.Z., H.-C.Y., A.B.F., E.L.S., V.K.), Vanderbilt University Medical Center, Nashville, TN
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26
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Choi HY, Choi S, Iatan I, Ruel I, Genest J. Biomedical Advances in ABCA1 Transporter: From Bench to Bedside. Biomedicines 2023; 11:561. [PMID: 36831097 PMCID: PMC9953649 DOI: 10.3390/biomedicines11020561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
ATP-binding cassette transporter A1 (ABCA1) has been identified as the molecular defect in Tangier disease. It is biochemically characterized by absence of high-density lipoprotein cholesterol (HDL-C) in the circulation, resulting in the accumulation of cholesterol in lymphoid tissues. Accumulation of cholesterol in arteries is an underlying cause of atherosclerosis, and HDL-C levels are inversely associated with the presence of atherosclerotic cardiovascular disease (ASCVD). ABCA1 increases HDL-C levels by driving the generation of new HDL particles in cells, and cellular cholesterol is removed in the process of HDL generation. Therefore, pharmacological strategies that promote the HDL biogenic process by increasing ABCA1 expression and activity have been intensively studied to reduce ASCVD. Many ABCA1-upregulating agents have been developed, and some have shown promising effects in pre-clinical studies, but no clinical trials have met success yet. ABCA1 has long been an attractive drug target, but the failed clinical trials have indicated the difficulty of therapeutic upregulation of ABCA1, as well as driving us to: improve our understanding of the ABCA1 regulatory system; to develop more specific and sophisticated strategies to upregulate ABCA1 expression; and to search for novel druggable targets in the ABCA1-dependent HDL biogenic process. In this review, we discuss the beginning, recent advances, challenges and future directions in ABCA1 research aimed at developing ABCA1-directed therapies for ASCVD.
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Affiliation(s)
- Hong Y. Choi
- Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Senna Choi
- Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Iulia Iatan
- Centre for Heart Lung Innovation, Department of Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Isabelle Ruel
- Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Jacques Genest
- Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
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27
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Is microRNA-33 an Appropriate Target in the Treatment of Atherosclerosis? Nutrients 2023; 15:nu15040902. [PMID: 36839260 PMCID: PMC9958916 DOI: 10.3390/nu15040902] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open
Abstract
The maintenance of cholesterol homeostasis is a complicated process involving regulation of cholesterol synthesis, dietary uptake and bile acid synthesis and excretion. Reverse cholesterol transport, described as the transfer of cholesterol from non-hepatic cells, including foam cells in atherosclerotic plaques, to the liver and then its excretion in the feces is important part of this regulation. High-density lipoproteins are the key mediators of reverse cholesterol transport. On the other hand, microRNA-33 was identified as a key regulator of cholesterol homeostasis. Recent studies indicate the impact of microRNA-33 not only on cellular cholesterol efflux and HDL production but also on bile metabolism in the liver. As proper coordination of cholesterol metabolism is essential to human health, discussion of recent findings in this field may open new perspectives in the microRNA-dependent treatment of a cholesterol imbalance.
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28
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Calzada C, Vors C, Penhoat A, Cheillan D, Michalski MC. Role of circulating sphingolipids in lipid metabolism: Why dietary lipids matter. Front Nutr 2023; 9:1108098. [PMID: 36712523 PMCID: PMC9874159 DOI: 10.3389/fnut.2022.1108098] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 12/21/2022] [Indexed: 01/13/2023] Open
Abstract
Sphingolipids are structural components of cell membranes and lipoproteins but also act as signaling molecules in many pathophysiological processes. Although sphingolipids comprise a small part of the plasma lipidome, some plasma sphingolipids are recognized as implicated in the development of metabolic diseases and cardiovascular diseases. Plasma sphingolipids are mostly carried out into lipoproteins and may modulate their functional properties. Lipids ingested from the diet contribute to the plasma lipid pool besides lipids produced by the liver and released from the adipose tissue. Depending on their source, quality and quantity, dietary lipids may modulate sphingolipids both in plasma and lipoproteins. A few human dietary intervention studies investigated the impact of dietary lipids on circulating sphingolipids and lipid-related cardiovascular risk markers. On the one hand, dietary saturated fatty acids, mainly palmitic acid, may increase ceramide concentrations in plasma, triglyceride-rich lipoproteins and HDL. On the other hand, milk polar lipids may decrease some molecular species of sphingomyelins and ceramides in plasma and intestine-derived chylomicrons. Altogether, different dietary fatty acids and lipid species can modulate circulating sphingolipids vehicled by postprandial lipoproteins, which should be part of future nutritional strategies for prevention of cardiovascular diseases.
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Affiliation(s)
- Catherine Calzada
- Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Pierre Bénite, France,*Correspondence: Catherine Calzada ✉
| | - Cécile Vors
- Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Pierre Bénite, France
| | - Armelle Penhoat
- Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Pierre Bénite, France
| | - David Cheillan
- Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Pierre Bénite, France,Service de Biochimie et de Biologie Moléculaire, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France
| | - Marie-Caroline Michalski
- Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRAE UMR1397, Université Claude Bernard Lyon 1, Pierre Bénite, France
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29
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Reboul E. Proteins involved in fat-soluble vitamin and carotenoid transport across the intestinal cells: New insights from the past decade. Prog Lipid Res 2023; 89:101208. [PMID: 36493998 DOI: 10.1016/j.plipres.2022.101208] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
It is now well established that vitamins D, E, and K and carotenoids are not absorbed solely through passive diffusion. Broad-specificity membrane transporters such as SR-BI (scavenger receptor class B type I), CD36 (CD36 molecule), NPC1L1 (Niemann Pick C1-like 1) or ABCA1 (ATP-binding cassette A1) are involved in the uptake of these micronutrients from the lumen to the enterocyte cytosol and in their secretion into the bloodstream. Recently, the existence of efflux pathways from the enterocyte back to the lumen or from the bloodstream to the lumen, involving ABCB1 (P-glycoprotein/MDR1) or the ABCG5/ABCG8 complex, has also been evidenced for vitamins D and K. Surprisingly, no membrane proteins have been involved in dietary vitamin A uptake so far. After an overview of the metabolism of fat-soluble vitamins and carotenoids along the gastrointestinal tract (from the mouth to the colon where interactions with microbiota may occur), a focus is placed on the identified and candidate proteins participating in the apical uptake, intracellular transport, basolateral secretion and efflux back to the lumen of fat-soluble vitamins and carotenoids in enterocytes. This review also highlights the mechanisms that remain to be identified to fully unravel the pathways involved in fat-soluble vitamin and carotenoid intestinal absorption.
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30
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Zhao Y, Zhang L, Liu L, Zhou X, Ding F, Yang Y, Du S, Wang H, Van Eck M, Wang J. Specific Loss of ABCA1 (ATP-Binding Cassette Transporter A1) Suppresses TCR (T-Cell Receptor) Signaling and Provides Protection Against Atherosclerosis. Arterioscler Thromb Vasc Biol 2022; 42:e311-e326. [PMID: 36252122 DOI: 10.1161/atvbaha.122.318226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux to apo AI to maintain cellular cholesterol homeostasis. The current study aims to investigate whether T-cell-specific deletion of ABCA1 modulates the phenotype/function of T cells and the development of atherosclerosis. METHODS Mice with T-cell-specific deletion of ABCA1 on low-density lipoprotein receptor knockout (Ldlr-/-) background (Abca1CD4-/CD4-Ldlr-/-) were generated by multiple steps of (cross)-breedings among Abca1flox/flox, CD4-Cre, and Ldlr-/- mice. RESULTS Deletions of ABCA1 greatly suppressed cholesterol efflux to apo AI but slightly reduced membrane lipid rafts on T cells probably due to the upregulation of ABCG1. Moreover, ABCA1 deficiency impaired TCR (T-cell receptor) signaling and inhibited the survival and proliferation of T cells as well as the formation of effector memory T cells. Despite the comparable levels of plasma total cholesterol after Western-type diet feeding, Abca1CD4-/CD4-Ldlr-/- mice showed significantly attenuated arterial accumulations of T cells and smaller atherosclerotic lesions than Abca1+/+Ldlr-/-controls, which were associated with reduced surface CCR5 (CC motif chemokine receptor 5) and CXCR3 (CXC motif chemokine receptor 3), decreased antiapoptotic Bcl-2 (B-cell lymphoma 2) and Bcl-xL (B-cell lymphoma extra-large), and hampered abilities to produce IL (interleukin)-2 and IFN (interferon)-γ by ABCA1-deficient T cells. CONCLUSIONS ABCA1 is essential for T-cell cholesterol homeostasis. Deletion of ABCA1 in T cells impairs TCR signaling, suppresses the survival, proliferation, differentiation, and function of T cells, thereby providing atheroprotection in vivo.
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Affiliation(s)
- Ying Zhao
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Lili Zhang
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Limin Liu
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Xuan Zhou
- Department of Immunology (X.Z.), Soochow Medical College of Soochow University, Suzhou, China
| | - Fangfang Ding
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Yan Yang
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Shiyu Du
- Department of Pathophysiology (Y.Z., L.Z., L.L., F.D., Y.Y., S.D.), Soochow Medical College of Soochow University, Suzhou, China
| | - Hongmin Wang
- School of Biology & Basic Medical Sciences, and Institutes of Biology & Medical Sciences (H.W., J.W.), Soochow Medical College of Soochow University, Suzhou, China
| | - Miranda Van Eck
- Division of BioTherapeutics (M.V.E.), Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.,Division of Systems Pharmacology and Pharmacy (M.V.E.), Leiden Academic Centre for Drug Research, Leiden University, the Netherlands.,Pharmacy Leiden, the Netherlands (M.V.E.)
| | - Jun Wang
- School of Biology & Basic Medical Sciences, and Institutes of Biology & Medical Sciences (H.W., J.W.), Soochow Medical College of Soochow University, Suzhou, China
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31
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Meszaros M, Bikov A. Obstructive Sleep Apnoea and Lipid Metabolism: The Summary of Evidence and Future Perspectives in the Pathophysiology of OSA-Associated Dyslipidaemia. Biomedicines 2022; 10:2754. [PMID: 36359273 PMCID: PMC9687681 DOI: 10.3390/biomedicines10112754] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 09/29/2023] Open
Abstract
Obstructive sleep apnoea (OSA) is associated with cardiovascular and metabolic comorbidities, including hypertension, dyslipidaemia, insulin resistance and atherosclerosis. Strong evidence suggests that OSA is associated with an altered lipid profile including elevated levels of triglyceride-rich lipoproteins and decreased levels of high-density lipoprotein (HDL). Intermittent hypoxia; sleep fragmentation; and consequential surges in the sympathetic activity, enhanced oxidative stress and systemic inflammation are the postulated mechanisms leading to metabolic alterations in OSA. Although the exact mechanisms of OSA-associated dyslipidaemia have not been fully elucidated, three main points have been found to be impaired: activated lipolysis in the adipose tissue, decreased lipid clearance from the circulation and accelerated de novo lipid synthesis. This is further complicated by the oxidisation of atherogenic lipoproteins, adipose tissue dysfunction, hormonal changes, and the reduced function of HDL particles in OSA. In this comprehensive review, we summarise and critically evaluate the current evidence about the possible mechanisms involved in OSA-associated dyslipidaemia.
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Affiliation(s)
- Martina Meszaros
- Department of Pulmonology and Sleep Disorders Centre, University Hospital Zurich, 8091 Zurich, Switzerland
- Department of Pulmonology, Semmelweis University, 1083 Budapest, Hungary
| | - Andras Bikov
- North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK
- Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester M13 9MT, UK
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32
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Wang H, Reddy ST, Fogelman AM. The role of gut-derived oxidized lipids and bacterial lipopolysaccharide in systemic inflammation and atherosclerosis. Curr Opin Lipidol 2022; 33:277-282. [PMID: 35979993 PMCID: PMC9581106 DOI: 10.1097/mol.0000000000000841] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW This review explores mechanisms by which gut-derived bacteriallipopolysaccharide (LPS) and oxidized phospholipids contribute to chronic systemic inflammation and atherosclerosis. RECENT FINDINGS Gut-derived LPS enters through the small intestine via two distinct pathways that involve high density lipoproteins (HDL) and chylomicrons. Gut-derived LPS can bind to the LPS-binding protein (LBP) and to HDL 3 in the small intestine and travel through the portal vein to the liver where it does not elicit an inflammatory reaction, and is inactivated or it can bind to HDL 2 and travel through the portal vein to the liver where it elicits an inflammatory reaction. Alternatively, in the small intestine, LPS can bind to LBP and chylomicrons and travel through the lymphatics to the systemic circulation and enhance inflammatory processes including atherosclerosis. Oxidized phospholipids formed in the small intestine regulate the levels and uptake of LPS in small intestine by regulating antimicrobial proteins such as intestinal alkaline phosphatase. Gut-derived LPS and oxidized phospholipids may be responsible for the persistent inflammation seen in some persons with human immunodeficiency virus on potent antiretroviral therapy with undetectable virus levels. SUMMARY By targeting gut-derived oxidized phospholipids, the uptake of gut-derived LPS may be reduced to decrease systemic inflammation and atherosclerosis.
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Affiliation(s)
- Huan Wang
- Department of Medicine, Division of Cardiology
| | - Srinivasa T. Reddy
- Department of Medicine, Division of Cardiology
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles California, USA
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33
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Noguchi M, Shimizu M, Lu P, Takahashi Y, Yamauchi Y, Sato S, Kiyono H, Kishino S, Ogawa J, Nagata K, Sato R. Lactic acid bacteria-derived γ-linolenic acid metabolites are PPARδ ligands that reduce lipid accumulation in human intestinal organoids. J Biol Chem 2022; 298:102534. [PMID: 36162507 PMCID: PMC9636582 DOI: 10.1016/j.jbc.2022.102534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/17/2022] Open
Abstract
Gut microbiota regulate physiological functions in various hosts, such as energy metabolism and immunity. Lactic acid bacteria, including Lactobacillus plantarum, have a specific polyunsaturated fatty acid saturation metabolism that generates multiple fatty acid species, such as hydroxy fatty acids, oxo fatty acids, conjugated fatty acids, and trans-fatty acids. How these bacterial metabolites impact host physiology is not fully understood. Here, we investigated the ligand activity of lactic acid bacteria–produced fatty acids in relation to nuclear hormone receptors expressed in the small intestine. Our reporter assays revealed two bacterial metabolites of γ-linolenic acid (GLA), 13-hydroxy-cis-6,cis-9-octadecadienoic acid (γHYD), and 13-oxo-cis-6,cis-9-octadecadienoic acid (γKetoD) activated peroxisome proliferator-activated receptor delta (PPARδ) more potently than GLA. We demonstrate that both γHYD and γKetoD bound directly to the ligand-binding domain of human PPARδ. A docking simulation indicated that four polar residues (T289, H323, H449, and Y473) of PPARδ donate hydrogen bonds to these fatty acids. Interestingly, T289 does not donate a hydrogen bond to GLA, suggesting that bacterial modification of GLA introducing hydroxy and oxo group determines ligand selectivity. In human intestinal organoids, we determined γHYD and γKetoD increased the expression of PPARδ target genes, enhanced fatty acid β-oxidation, and reduced intracellular triglyceride accumulation. These findings suggest that γHYD and γKetoD, which gut lactic acid bacteria could generate, are naturally occurring PPARδ ligands in the intestinal tract and may improve lipid metabolism in the human intestine.
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Affiliation(s)
- Makoto Noguchi
- Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo
| | - Makoto Shimizu
- Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo.
| | - Peng Lu
- Food Biotechnology and Structural Biology Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo
| | - Yu Takahashi
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo
| | - Yoshio Yamauchi
- Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo; Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo
| | - Shintaro Sato
- Department of Microbiology and Immunology, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama
| | - Hiroshi Kiyono
- Mucosal Immunology and Allergy Therapeutics, Institute for Global Prominent Research, Future Medicine Education and Research Organization, Chiba University, Chiba
| | - Shigenobu Kishino
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto
| | - Jun Ogawa
- Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto
| | - Koji Nagata
- Food Biotechnology and Structural Biology Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo
| | - Ryuichiro Sato
- Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo.
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Liu Y, Liu Y. Construction of lipid-biomacromolecular compounds for loading and delivery of carotenoids: Preparation methods, structural properties, and absorption-enhancing mechanisms. Crit Rev Food Sci Nutr 2022; 64:1653-1676. [PMID: 36062817 DOI: 10.1080/10408398.2022.2118229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Due to the unstable chemical properties and poor water solubility of carotenoids, their processing adaptation and oral bioavailability are poor, limiting their application in hydrophilic food systems. Lipid-biomacromolecular compounds can be excellent carriers for carotenoid delivery by taking full advantage of the solubilization of lipids to non-polar nutrients and the water dispersion and gastrointestinal controlled release properties of biomacromolecules. This paper reviewed the research progress of lipid-biomacromolecular compounds as encapsulation and delivery carriers of carotenoids and summarized the material selection and preparation methods for biomacromolecular compounds. By considering the interaction between the two, this paper briefly discussed the effect of these compounds on carotenoid water solubility, stability, and bioavailability, emphasizing their delivery effect on carotenoids. Finally, various challenges and future trends of lipid-biomacromolecular compounds as carotenoid delivery carriers were discussed, providing new insight into efficient loading and delivery of carotenoids.
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Affiliation(s)
- Yunjun Liu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, Fujian, People's Republic of China
| | - Yixiang Liu
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen, Fujian, People's Republic of China
- Collaborative Innovation Center of Provincial and Ministerial Co-construction for Marine Food Deep Processing, Dalian Polytechnic University, Dalian, China
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35
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HDL, cholesterol efflux, and ABCA1: Free from good and evil dualism. J Pharmacol Sci 2022; 150:81-89. [DOI: 10.1016/j.jphs.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/15/2022] [Accepted: 07/25/2022] [Indexed: 11/19/2022] Open
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36
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HDL as Bidirectional Lipid Vectors: Time for New Paradigms. Biomedicines 2022; 10:biomedicines10051180. [PMID: 35625916 PMCID: PMC9138557 DOI: 10.3390/biomedicines10051180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 02/06/2023] Open
Abstract
The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.
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37
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Li L, Zhong S, Li R, Liang N, Zhang L, Xia S, Xu X, Chen X, Chen S, Tao Y, Yin H. Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression. JCI Insight 2022; 7:155869. [PMID: 35393951 PMCID: PMC9057588 DOI: 10.1172/jci.insight.155869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 02/18/2022] [Indexed: 11/17/2022] Open
Abstract
HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR-double KO (ALKO), and ALDH2 rs671-knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency-induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.
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Affiliation(s)
- Luxiao Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Shanshan Zhong
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Rui Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Ningning Liang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Lili Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Shen Xia
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Xiaodong Xu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Xin Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Shiting Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Yongzhen Tao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China
| | - Huiyong Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), University of the Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Shanghai, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China
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38
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Hafiane A, Gianopoulos I, Sorci-Thomas MG, Daskalopoulou SS. Current models of apolipoprotein A-I lipidation by adenosine triphosphate binding cassette transporter A1. Curr Opin Lipidol 2022; 33:139-145. [PMID: 34581311 DOI: 10.1097/mol.0000000000000786] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW The primary cardioprotective function of high-density lipoprotein (HDL) is to remove excess cellular free cholesterol (FC) from peripheral tissues and deliver it to the liver. Here, we summarize recent research that examines apolipoprotein A-I (apoA-I) lipidation models by adenosine triphosphate binding cassette transporter A1 (ABCA1) and discuss its relevance in atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS The first step in HDL formation involves the interaction between apoA-I and ABCA1, where ABCA1 mediates the removal of FC and phospholipids from lipid-laden macrophages to form discoidal nascent HDL (nHDL). However, there are currently no clear-cut systematic models that characterize HDL formation. A number of recent studies have investigated the importance of apoA-I C- and N-terminal domains required for optimal cholesterol efflux and nHDL production. Furthermore, functional ABCA1 is required for direct or indirect binding to apoA-I where ABCA1 dimer-monomer interconversion facilitates apoA-I lipidation from plasma membrane microdomains. Microparticles are also another lipid source for apoA-I solubilization into nHDL. SUMMARY ApoA-I and ABCA1 are key factors in macrophage-mediated cholesterol efflux and nHDL production. Understanding of the key steps in HDL formation may unlock the therapeutic potential of HDL and improve clinical management of ASCVD.
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Affiliation(s)
- Anouar Hafiane
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
| | - Ioanna Gianopoulos
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
| | - Mary G Sorci-Thomas
- Division of Endocrinology, Metabolism and Clinical Nutrition, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Stella S Daskalopoulou
- Division of Experimental Medicine, Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada
- Division of Internal Medicine, Department of Medicine, Faculty of Medicine, McGill University Health Centre, McGill University Montreal, Montreal, Canada
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39
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Amentoflavone-Enriched Selaginella rossii Warb. Suppresses Body Weight and Hyperglycemia by Inhibiting Intestinal Lipid Absorption in Mice Fed a High-Fat Diet. Life (Basel) 2022; 12:life12040472. [PMID: 35454963 PMCID: PMC9024644 DOI: 10.3390/life12040472] [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: 02/11/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 11/17/2022] Open
Abstract
Many Selaginellaceae species are used as traditional medicines in Asia. This study is the first to investigate the anti-obesity and anti-diabetic effects of Selaginella rossii (SR) in high-fat diet (HFD)–fed C57BL/6J mice. Seven-day oral administration of ethanol extract (100 mg/kg/day) or ethyl acetate (EtOAc) extract (50 mg/kg/day) from SR improved oral fat tolerance by inhibiting intestinal lipid absorption; 10-week long-term administration of the EtOAc extract markedly reduced HFD-induced body weight gain and hyperglycemia by reducing adipocyte hypertrophy, glucose levels, HbA1c, and plasma insulin levels. Treatment with SR extracts reduced the expression of intestinal lipid absorption-related genes, including Cd36, fatty acid-binding protein 6, ATP-binding cassette subfamily G member 8, NPC1 like intracellular cholesterol transporter 1, and ATP-binding cassette subfamily A member 1. In addition, the EtOAc extract increased the expression of protein absorption–related solute carrier family genes, including Slc15a1, Slc8a2, and Slc6a9. SR extracts reduced HFD-induced hepatic steatosis by suppressing fatty acid transport to hepatocytes and hepatic lipid accumulation. Furthermore, amentoflavone (AMF), the primary compound in SR extracts, reduced intestinal lipid absorption by inhibiting fatty acid transport in HFD-fed mice. AMF-enriched SR extracts effectively protected against HFD-induced body weight gain and hyperglycemia by inhibiting intestinal lipid absorption.
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40
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Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159121. [PMID: 35150895 DOI: 10.1016/j.bbalip.2022.159121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 02/01/2022] [Indexed: 11/24/2022]
Abstract
Enterocytes of the small intestine (SI) play an important role in maintaining systemic lipid levels by regulating dietary lipid absorption and postprandial lipoprotein secretion. An excessive amount of dietary-derived triglycerides (TGs) taken up by the apical side of enterocytes or basolaterally internalized lipoprotein remnants can be transiently stored in cytosolic lipid droplets (cLDs). As mice lacking adipose TG lipase (ATGL) in the SI display massive accumulation of cLDs but also delayed cholesterol absorption, we hypothesized that SI-specific overexpression of ATGL (Atgl iTg) might have beneficial effects on lipid homeostasis in the gut and possibly throughout the body. Here, we demonstrate that Atgl iTg mice had only modestly increased enzymatic activity despite drastically elevated Atgl mRNA levels (up to 120-fold) on chow diet, and was highly induced upon high-fat/high-cholesterol diet (HF/HCD) feeding. Atgl iTg mice showed markedly reduced intestinal TG concentrations after acute and chronic lipid challenge without affecting chylomicron TG secretion. Circulating plasma cholesterol levels were significantly lower in Atgl iTg mice under different feeding conditions, contrasting the accelerated uptake of dietary cholesterol into the circulation after HF/HCD feeding. In the fasted state, gene expression analysis revealed modulation of PPARα and liver X receptor (LXR) target genes by an increased fatty acid release, whereas the decreased plasma cholesterol concentrations in refed mice were more likely due to changes in HDL synthesis and secretion. We conclude that ATGL, in addition to its role in TG catabolism, plays a critical role in whole-body cholesterol homeostasis by modulating PPARα and LXR signaling in intestinal enterocytes.
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41
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Liu W, Liu J, Zhou Y, Cao D, Lei Q, Han H, Wang J, Li D, Gao J, Li H, Li F. Genome-Wide Association Study of Abdominal Fat in Wenshang Barred Chicken Based on the Slaf-Seq Technology. BRAZILIAN JOURNAL OF POULTRY SCIENCE 2022. [DOI: 10.1590/1806-9061-2021-1612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- W Liu
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - J Liu
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - Y Zhou
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - D Cao
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - Q Lei
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - H Han
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - J Wang
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - D Li
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - J Gao
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
| | - H Li
- Shandong Academy of Agricultural Sciences, P. R. China
| | - F Li
- Shandong Academy of Agricultural Sciences, P. R. China; Poultry Breeding Engineering Technology Center of Shandong Province, China
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42
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Bieczynski F, Painefilú JC, Venturino A, Luquet CM. Expression and Function of ABC Proteins in Fish Intestine. Front Physiol 2021; 12:791834. [PMID: 34955897 PMCID: PMC8696203 DOI: 10.3389/fphys.2021.791834] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 11/17/2021] [Indexed: 12/15/2022] Open
Abstract
In fish, the intestine is fundamental for digestion, nutrient absorption, and other functions like osmoregulation, acid-base balance, and excretion of some metabolic products. These functions require a large exchange surface area, which, in turn, favors the absorption of natural and anthropogenic foreign substances (xenobiotics) either dissolved in water or contained in the food. According to their chemical nature, nutrients, ions, and water may cross the intestine epithelium cells' apical and basolateral membranes by passive diffusion or through a wide array of transport proteins and also through endocytosis and exocytosis. In the same way, xenobiotics can cross this barrier by passive diffusion or taking advantage of proteins that transport physiological substrates. The entry of toxic substances is counterbalanced by an active efflux transport mediated by diverse membrane proteins, including the ATP binding cassette (ABC) proteins. Recent advances in structure, molecular properties, and functional studies have shed light on the importance of these proteins in cellular and organismal homeostasis. There is abundant literature on mammalian ABC proteins, while the studies on ABC functions in fish have mainly focused on the liver and, to a minor degree, on the kidney and other organs. Despite their critical importance in normal physiology and as a barrier to prevent xenobiotics incorporation, fish intestine's ABC transporters have received much less attention. All the ABC subfamilies are present in the fish intestine, although their functionality is still scarcely studied. For example, there are few studies of ABC-mediated transport made with polarized intestinal preparations. Thus, only a few works discriminate apical from basolateral transport activity. We briefly describe the main functions of each ABC subfamily reported for mammals and other fish organs to help understand their roles in the fish intestine. Our study considers immunohistochemical, histological, biochemical, molecular, physiological, and toxicological aspects of fish intestinal ABC proteins. We focus on the most extensively studied fish ABC proteins (subfamilies ABCB, ABCC, and ABCG), considering their apical or basolateral location and distribution along the intestine. We also discuss the implication of fish intestinal ABC proteins in the transport of physiological substrates and aquatic pollutants, such as pesticides, cyanotoxins, metals, hydrocarbons, and pharmaceutical products.
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Affiliation(s)
- Flavia Bieczynski
- Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue – Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional del Comahue, Neuquén, Argentina
| | - Julio C. Painefilú
- Instituto Patagónico de Tecnologías Biológicas y Geoambientales, Consejo Nacional de Investigaciones Científicas y Técnicas – Universidad Nacional del Comahue, Bariloche, Argentina
| | - Andrés Venturino
- Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue – Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional del Comahue, Neuquén, Argentina
| | - Carlos M. Luquet
- Laboratorio de Ecotoxicología Acuática, Subsede INIBIOMA-CEAN (CONICET – UNCo), Junín de los Andes, Argentina
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43
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Kjeldsen EW, Thomassen JQ, Frikke-Schmidt R. HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease - Insights from randomized clinical trials and human genetics. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1867:159063. [PMID: 34637926 DOI: 10.1016/j.bbalip.2021.159063] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/12/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.
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Affiliation(s)
- Emilie Westerlin Kjeldsen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jesper Qvist Thomassen
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Ruth Frikke-Schmidt
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Van Valkenburgh J, Meuret C, Martinez AE, Kodancha V, Solomon V, Chen K, Yassine HN. Understanding the Exchange of Systemic HDL Particles Into the Brain and Vascular Cells Has Diagnostic and Therapeutic Implications for Neurodegenerative Diseases. Front Physiol 2021; 12:700847. [PMID: 34552500 PMCID: PMC8450374 DOI: 10.3389/fphys.2021.700847] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/29/2021] [Indexed: 12/02/2022] Open
Abstract
High-density lipoproteins (HDLs) are complex, heterogenous lipoprotein particles, consisting of a large family of apolipoproteins, formed in subspecies of distinct shapes, sizes, and functions and are synthesized in both the brain and the periphery. HDL apolipoproteins are important determinants of Alzheimer’s disease (AD) pathology and vascular dementia, having both central and peripheral effects on brain amyloid-beta (Aβ) accumulation and vascular functions, however, the extent to which HDL particles (HLD-P) can exchange their protein and lipid components between the central nervous system (CNS) and the systemic circulation remains unclear. In this review, we delineate how HDL’s structure and composition enable exchange between the brain, cerebrospinal fluid (CSF) compartment, and vascular cells that ultimately affect brain amyloid metabolism and atherosclerosis. Accordingly, we then elucidate how modifications of HDL-P have diagnostic and therapeutic potential for brain vascular and neurodegenerative diseases.
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Affiliation(s)
- Juno Van Valkenburgh
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Cristiana Meuret
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Ashley E Martinez
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Vibha Kodancha
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Victoria Solomon
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Kai Chen
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Hussein N Yassine
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Abstract
The trafficking and function of intestine-derived high-density lipoprotein (HDL) have not been identified. In a recent issue of Science, Han et al. (2021) find that intestine-derived HDL neutralizes intestinal-leaked LPS in the portal vein, serving as a host disease tolerance strategy to restrain liver damage of enteric origin under physiological conditions.
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Affiliation(s)
- Sheng Chen
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China
| | - Di Wang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
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46
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Liu R, Hannon BA, Robinson KN, Raine LB, Hammond BR, Renzi-Hammond LM, Cohen NJ, Kramer AF, Hillman CH, Teran-Garcia M, Khan NA. Single Nucleotide Polymorphisms in CD36 Are Associated with Macular Pigment among Children. J Nutr 2021; 151:2533-2540. [PMID: 34049394 PMCID: PMC8417927 DOI: 10.1093/jn/nxab153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/03/2020] [Accepted: 04/28/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND High macular pigment optical density (MPOD) has been associated with improved eye health and better cognitive functions. Genetic variations have been associated with MPOD in adults. However, these associations between genetic variations and MPOD have not been studied in children. OBJECTIVES This was a secondary analysis of the FK2 (Fitness Improves Thinking in Kids 2) trial (n = 134, 41% male). The aim was to determine differences in MPOD among children (aged 7-9 y) based on genetic variants that either are biologically relevant to lutein (L) and zeaxanthin (Z) accumulation or have been associated with MPOD in adults. METHODS MPOD was measured using customized heterochromatic flicker photometry via a macular densitometer. DXA was used to assess whole-body and visceral adiposity. DNA was extracted from saliva samples and was genotyped for 26 hypothesis-driven single nucleotide polymorphisms and 75 ancestry-informative markers (AIMs). Habitual diet history was obtained via 3-d food logs completed by parents (n = 88). General linear models were used to compare MPOD between different genotypes. Principal component analysis was performed for the AIMs to account for ethnic heterogeneity. RESULTS Children carrying ≥1 minor allele on β-carotene-15,15'-monooxygenase (BCO1)-rs7501331 (T allele) (P = 0.045), cluster of differentiation 36(CD36)-rs1527483 (T allele) (P = 0.038), or CD36-rs3173798 (C allele) (P = 0.001) had significantly lower MPOD (range: 14.1%-26.4%) than those who were homozygotes for the major alleles. MPOD differences based on CD36-rs3173798 genotypes persisted after adjustment for dietary L and Z intake. CONCLUSIONS The findings indicate that genetic variations of CD36 and BCO1 contribute to MPOD in children. The influence of genetic variation in CD36-rs3173798 persisted after adjusting for variation in dietary intake.This trial was registered at clinicaltrials.gov as NCT01619826.
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Affiliation(s)
- Ruyu Liu
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Bridget A Hannon
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Katie N Robinson
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Lauren B Raine
- Department of Psychology, Northeastern University, Boston, MA, USA
| | - Billy R Hammond
- Department of Psychology, University of Georgia, Athens, GA, USA
| | - Lisa M Renzi-Hammond
- Department of Psychology, University of Georgia, Athens, GA, USA
- College of Public Health, Institute of Gerontology, University of Georgia, Athens, GA, USA
| | - Neal J Cohen
- Department of Psychology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Center for Nutrition, Learning, and Memory, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Arthur F Kramer
- Department of Psychology, Northeastern University, Boston, MA, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Charles H Hillman
- Department of Psychology, Northeastern University, Boston, MA, USA
- Department of Physical Therapy, Movement, & Rehabilitation Sciences, Northeastern University, Boston, MA, USA
| | - Margarita Teran-Garcia
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Human Development and Family Studies, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Naiman A Khan
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA
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Han YH, Onufer EJ, Huang LH, Sprung RW, Davidson WS, Czepielewski RS, Wohltmann M, Sorci-Thomas MG, Warner BW, Randolph GJ. Enterically derived high-density lipoprotein restrains liver injury through the portal vein. Science 2021; 373:eabe6729. [PMID: 34437091 PMCID: PMC8478306 DOI: 10.1126/science.abe6729] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 03/16/2021] [Accepted: 06/03/2021] [Indexed: 12/30/2022]
Abstract
The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL3 subspecies form, in complex with lipopolysaccharide (LPS)-binding protein (LBP). HDL3, but not HDL2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL.
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Affiliation(s)
- Yong-Hyun Han
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Emily J Onufer
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Li-Hao Huang
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Robert W Sprung
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - W Sean Davidson
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237, USA
| | - Rafael S Czepielewski
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mary Wohltmann
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Mary G Sorci-Thomas
- Department of Medicine, Division of Endocrinology, Pharmacology and Toxicology, and Blood Research Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Brad W Warner
- Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Gwendalyn J Randolph
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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Yang K, Xu M, Cao J, Zhu Q, Rahman M, Holmén BA, Fukagawa NK, Zhu J. Ultrafine particles altered gut microbial population and metabolic profiles in a sex-specific manner in an obese mouse model. Sci Rep 2021; 11:6906. [PMID: 33767227 PMCID: PMC7994449 DOI: 10.1038/s41598-021-85784-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Emerging evidence has highlighted the connection between exposure to air pollution and the increased risk of obesity, metabolic syndrome, and comorbidities. Given the recent interest in studying the effects of ultrafine particle (UFP) on the health of obese individuals, this study examined the effects of gastrointestinal UFP exposure on gut microbial composition and metabolic function using an in vivo murine model of obesity in both sexes. UFPs generated from light-duty diesel engine combustion of petrodiesel (B0) and a petrodiesel/biodiesel fuel blend (80:20 v/v, B20) were administered orally. Multi-omics approaches, including liquid chromatography-mass spectrometry (LC-MS) based targeted metabolomics and 16S rRNA gene sequence analysis, semi-quantitatively compared the effects of 10-day UFP exposures on obese C57B6 mouse gut microbial population, changes in diversity and community function compared to a phosphate buffer solution (PBS) control group. Our results show that sex-specific differences in the gut microbial population in response to UFP exposure can be observed, as UFPs appear to have a differential impact on several bacterial families in males and females. Meanwhile, the alteration of seventy-five metabolites from the gut microbial metabolome varied significantly (ANOVA p < 0.05) across the PBS control, B0, and B20 groups. Multivariate analyses revealed that the fuel-type specific disruption to the microbial metabolome was observed in both sexes, with stronger disruptive effects found in females in comparison to male obese mice. Metabolic signatures of bacterial cellular oxidative stress, such as the decreased concentration of nucleotides and lipids and increased concentrations of carbohydrate, energy, and vitamin metabolites were detected. Furthermore, blood metabolites from the obese mice were differentially affected by the fuel types used to generate the UFPs (B0 vs. B20).
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Affiliation(s)
- Kundi Yang
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA
| | - Mengyang Xu
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA
| | - Jingyi Cao
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA
| | - Qi Zhu
- Department of Biology, Miami University, Oxford, OH, 45056, USA
| | - Monica Rahman
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA
| | - Britt A Holmén
- School of Engineering, University of Vermont, Burlington, VT, 05405, USA
| | - Naomi K Fukagawa
- USDA ARS Beltsville Human Nutrition Research Center, Beltsville, MD, 20705, USA
| | - Jiangjiang Zhu
- Department of Human Sciences, The Ohio State University, 302D Wiseman Hall, 400 W 12th Ave, Columbus, OH, 43210, USA.
- James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
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49
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Vona R, Iessi E, Matarrese P. Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity? Front Cell Dev Biol 2021; 9:622908. [PMID: 33816471 PMCID: PMC8017202 DOI: 10.3389/fcell.2021.622908] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/15/2021] [Indexed: 12/11/2022] Open
Abstract
Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Elisabetta Iessi
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Istituto Superiore di Sanità [Italian National Institute of Health], Rome, Italy
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50
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Jacobo-Albavera L, Domínguez-Pérez M, Medina-Leyte DJ, González-Garrido A, Villarreal-Molina T. The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease. Int J Mol Sci 2021; 22:ijms22041593. [PMID: 33562440 PMCID: PMC7915494 DOI: 10.3390/ijms22041593] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 02/06/2023] Open
Abstract
Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.
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Affiliation(s)
- Leonor Jacobo-Albavera
- Laboratorio de Genómica de Enfermedades Cardiovasculares, Dirección de Investigación, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City CP14610, Mexico; (L.J.-A.); (M.D.-P.); (D.J.M.-L.); (A.G.-G.)
| | - Mayra Domínguez-Pérez
- Laboratorio de Genómica de Enfermedades Cardiovasculares, Dirección de Investigación, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City CP14610, Mexico; (L.J.-A.); (M.D.-P.); (D.J.M.-L.); (A.G.-G.)
| | - Diana Jhoseline Medina-Leyte
- Laboratorio de Genómica de Enfermedades Cardiovasculares, Dirección de Investigación, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City CP14610, Mexico; (L.J.-A.); (M.D.-P.); (D.J.M.-L.); (A.G.-G.)
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Coyoacán, Mexico City CP04510, Mexico
| | - Antonia González-Garrido
- Laboratorio de Genómica de Enfermedades Cardiovasculares, Dirección de Investigación, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City CP14610, Mexico; (L.J.-A.); (M.D.-P.); (D.J.M.-L.); (A.G.-G.)
| | - Teresa Villarreal-Molina
- Laboratorio de Genómica de Enfermedades Cardiovasculares, Dirección de Investigación, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City CP14610, Mexico; (L.J.-A.); (M.D.-P.); (D.J.M.-L.); (A.G.-G.)
- Correspondence:
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