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Mishra P, Sadananthan SA, Yaligar J, Tan KH, Chong YS, Gluckman PD, Godfrey KM, Fortier MV, Eriksson JG, Chan JKY, Chan SY, Wang D, Velan SS, Michael N. Even moderate liver fat accumulation below conventional fatty liver cutoffs is linked to multiple metabolomic alterations and gestational dysglycemia in Asian women of reproductive age. BMC Med 2024; 22:561. [PMID: 39605006 PMCID: PMC11600899 DOI: 10.1186/s12916-024-03779-0] [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: 07/24/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND It is not clear if conventional liver fat cutoff of 5.56% weight which has been used for identifying fatty liver in western populations is also applicable for Asians. In Asian women of reproductive age, we evaluate the optimum metabolic syndrome (MetS)-linked liver fat cutoff, the specific metabolomic alterations apparent at this cutoff, as well as prospective associations of preconception liver fat levels with gestational dysglycemia. METHODS Liver fat (measured by magnetic resonance spectroscopy), MetS, and nuclear magnetic resonance (NMR)-based plasma metabolomic profiles were assessed in 382 Asian women, who were planning to conceive. Ninety-eight women went on to become pregnant and received an oral glucose tolerance test at week 26 of gestation. RESULTS The optimum liver fat cutoff for diagnosing MetS was 2.07%weight. Preconception liver fat was categorized into Low (liver fat < 2.07%), Moderate (2.07% ≤ liver fat < 5.56%), and High (liver fat ≥ 5.56%) groups. Individual MetS traits showed worsening trends, going from Low to Moderate to High groups. Multiple plasma metabolomic alterations, previously linked to incident type 2 diabetes (T2D), were already evident in the Moderate group (adjusted for ethnicity, age, parity, educational attainment, and BMI). Both a cross-sectional multi-metabolite score for incident T2D and mid-gestational glucose area under the curve showed increasing trends, going from Low to Moderate to High groups (p < 0.001 for both). Gestational diabetes incidence was 2-fold (p = 0.23) and 7-fold (p < 0.001) higher in the Moderate and High groups relative to the Low group. CONCLUSIONS In Asian women of reproductive age, moderate liver fat accumulation below the conventional fatty liver cutoff was not metabolically benign and was linked to gestational dysglycemia. The newly derived cutoff can aid in screening individuals before adverse metabolic phenotypes have consolidated, which provides a longer window for preventive strategies.
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Affiliation(s)
- Priti Mishra
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
| | - Suresh Anand Sadananthan
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
| | - Jadegoud Yaligar
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
| | - Kok Hian Tan
- Academic Clinical Program in Obstetrics and Gynaecology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Department of Maternal-Fetal Medicine, KK Women's and Children's Hospital (KKH), Singapore, Singapore
| | - Yap Seng Chong
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Peter D Gluckman
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Keith M Godfrey
- NIHR Southampton Biomedical Research Centre, Southampton University Hospital NHS Foundation Trust and University of Southampton, Southampton, UK
- MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK
| | - Marielle V Fortier
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
- Department of Diagnostic and Interventional Imaging, KK Women's and Children's Hospital (KKH), Singapore, Singapore
| | - Johan G Eriksson
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Folkhalsan Research Centre, Helsinki, Finland
- Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
| | - Jerry Kok Yen Chan
- Academic Clinical Program in Obstetrics and Gynaecology, Duke-National University of Singapore Medical School, Singapore, Singapore
- Department of Reproductive Medicine, KK Women's and Children's Hospital (KKH), Singapore, Singapore
| | - Shiao-Yng Chan
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
- Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Dennis Wang
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore, 138671, Singapore
- National Heart and Lung Institute, Imperial College London, London, UK
| | - S Sendhil Velan
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore
| | - Navin Michael
- Institute for Human Development and Potential (IHDP), Agency for Science, Technology and Research (A*STAR), 30 Medical Drive, Singapore, 117609, Singapore.
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Li X, Li M. Unlocking Cholesterol Metabolism in Metabolic-Associated Steatotic Liver Disease: Molecular Targets and Natural Product Interventions. Pharmaceuticals (Basel) 2024; 17:1073. [PMID: 39204178 PMCID: PMC11358954 DOI: 10.3390/ph17081073] [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: 07/07/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Metabolic-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, represents a growing global health concern. The intricate pathogenesis of MASLD, driven by genetic, metabolic, epigenetic, and environmental factors, leads to considerable clinical variability. Dysregulation of hepatic lipid metabolism, particularly cholesterol homeostasis, is a critical factor in the progression of MASLD and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). This review elucidates the multifaceted roles of cholesterol metabolism in MASLD, focusing on its absorption, transportation, biosynthesis, efflux, and conversion. We highlight recent advancements in understanding these processes and explore the therapeutic potential of natural products such as curcumin, berberine, and resveratrol in modulating cholesterol metabolism. By targeting key molecular pathways, these natural products offer promising strategies for MASLD management. Finally, this review also covers the clinical studies of natural products in MASLD, providing new insights for future research and clinical applications.
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Affiliation(s)
| | - Meng Li
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China;
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Liu N, Chen Y, An T, Tao S, Lv B, Dou J, Deng R, Zhen X, Zhang Y, Lu C, Chang Z, Jiang G. Lysophosphatidylcholine trigger myocardial injury in diabetic cardiomyopathy via the TLR4/ZNF480/AP-1/NF-kB pathway. Heliyon 2024; 10:e33601. [PMID: 39040275 PMCID: PMC11260982 DOI: 10.1016/j.heliyon.2024.e33601] [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: 08/17/2023] [Revised: 06/15/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Background Diabetic cardiomyopathy (DC), a frequent complication of type 2 diabetes mellitus (T2DM), is mainly associated with severe adverse outcomes. Previous research has highlighted the role of Lysophosphatidylcholine (LPC) in inducing myocardial injury; however, the specific mechanisms through which LPC mediate such injury in DC remain elusive. The existing knowledge gap underscores the need for additional clarification. Consequently, this study aimed to explore the impact and underlying mechanisms of LPC on myocardial injury in DC. Methods A total of 55 patients diagnosed with T2DM and 62 healthy controls were involved. A combination of 16s rRNA sequencing, metabolomic analysis, transcriptomic RNA-sequencing (RNA-seq), and whole exome sequencing (WES) was performed on fecal and peripheral blood samples collected from the participants. Following this, correlation analysis was carried out, and the results were further validated through the mouse model of T2DM. Results Four LPC variants distinguishing T2DM patients from healthy controls were identified, all of which were upregulated in T2DM patients. Specifically, Lysopc (16:0, 2 N isoform) and LPC (16:0) exhibited a positive correlation with nuclear factor kappa B subunit 2 (NFKB2) and a negative correlation with Zinc finger protein 480 (ZNF480) Furthermore, the expression levels of Toll-like receptor 4 (TLR4), c-Jun, c-Fos, and NFKB2 were upregulated in the peripheral blood of T2DM patients and in the myocardial tissue of T2DM mice, whereas ZNF480 expression level was downregulated. Lastly, myocardial injury was identified in T2DM mice. Conclusions The results indicated that LPC could induce myocardial injury in DC through the TLR4/ZNF480/AP-1/NF-kB pathway, providing a precise target for the clinical diagnosis and treatment of DC.
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Affiliation(s)
- Nannan Liu
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Chen
- College of Traditional Chinese Medicine, Xinjiang Medical University, City Urumqi, China
| | - Tian An
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Tao
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Bohan Lv
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Jinfang Dou
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Ruxue Deng
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Xianjie Zhen
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Yuelin Zhang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
| | - Caizhong Lu
- Guangming Traditional Chinese Medecine Hospital of Pudong New Area, Shanghai, China
| | - Zhongsheng Chang
- Guangming Traditional Chinese Medecine Hospital of Pudong New Area, Shanghai, China
| | - Guangjian Jiang
- Traditional Chinese Medicine School, Beijing University of Chinese Medicine, Beijing, China
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Wupperfeld D, Fricker G, Bois De Fer B, Popovic B. Essential phospholipids impact cytokine secretion and alter lipid-metabolizing enzymes in human hepatocyte cell lines. Pharmacol Rep 2024; 76:572-584. [PMID: 38664334 PMCID: PMC11126482 DOI: 10.1007/s43440-024-00595-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/03/2024] [Accepted: 04/05/2024] [Indexed: 05/09/2024]
Abstract
BACKGROUND Essential phospholipids (EPL) are hepatoprotective. METHODS The effects on interleukin (IL)-6 and -8 secretion and on certain lipid-metabolizing enzymes of non-cytotoxic concentrations of EPL (0.1 and 0.25 mg/ml), polyenylphosphatidylcholine (PPC), and phosphatidylinositol (PtdIns) (both at 0.1 and 1 mg/ml), compared with untreated controls, were assessed in human hepatocyte cell lines (HepG2, HepaRG, and steatotic HepaRG). RESULTS Lipopolysaccharide (LPS)-induced IL-6 secretion was significantly decreased in HepaRG cells by most phospholipids, and significantly increased in steatotic HepaRG cells with at least one concentration of EPL and PtdIns. LPS-induced IL-8 secretion was significantly increased in HepaRG and steatotic HepaRG cells with all phospholipids. All phospholipids significantly decreased amounts of fatty acid synthase in steatotic HepaRG cells and the amounts of acyl-CoA oxidase in HepaRG cells. Amounts of lecithin cholesterol acyltransferase were significantly decreased in HepG2 and HepaRG cells by most phospholipids, and significantly increased with 0.1 mg/ml PPC (HepaRG cells) and 1 mg/ml PtdIns (steatotic HepaRG cells). Glucose-6-phosphate dehydrogenase activity was unaffected by any phospholipid in any cell line. CONCLUSIONS EPL, PPC, and PtdIns impacted the secretion of pro-inflammatory cytokines and affected amounts of several key lipid-metabolizing enzymes in human hepatocyte cell lines. Such changes may help liver function improvement, and provide further insights into the EPL's mechanism of action.
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Affiliation(s)
- Dominik Wupperfeld
- Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany
| | - Gert Fricker
- Department of Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls University of Heidelberg, Heidelberg, Germany
| | | | - Branko Popovic
- Sanofi, Frankfurt am Main, K607, 65929, Industriepark Hoechst, Germany.
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Kaneva AM, Bojko ER. Fatty liver index (FLI): more than a marker of hepatic steatosis. J Physiol Biochem 2024; 80:11-26. [PMID: 37875710 DOI: 10.1007/s13105-023-00991-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/12/2023] [Indexed: 10/26/2023]
Abstract
Fatty liver index (FLI) was developed as a simple and accurate marker of hepatic steatosis. FLI is derived from an algorithm based on body mass index, waist circumference, and levels of triglycerides and gamma-glutamyltransferase, and it is widely used in clinical and epidemiological studies as a screening tool for discriminating between healthy and nonalcoholic fatty liver disease (NAFLD) subjects. However, a systematic review of the literature regarding FLI revealed that this index has more extensive relationships with biochemical and physiological parameters. FLI is associated with key parameters of lipid, protein and carbohydrate metabolism, hormones, vitamins and markers of inflammation, or oxidative stress. FLI can be a predictor or risk factor for a number of metabolic and nonmetabolic diseases and mortality. FLI is also used as an indicator for determining the effects of health-related prevention interventions, medications, and toxic substances on humans. Although in most cases, the exact mechanisms underlying these associations have not been fully elucidated, they are most often assumed to be mediated by insulin resistance, inflammation, and oxidative stress. Thus, FLI may be a promising marker of metabolic health due to its multiple associations with parameters of physiological and pathological processes. In this context, the present review summarizes the data from currently available literature on the associations between FLI and biochemical variables and physiological functions. We believe that this review will be of interest to researchers working in this area and can provide new perspectives and directions for future studies on FLI.
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Affiliation(s)
- Anastasiya M Kaneva
- Institute of Physiology of Кomi Science Centre of the Ural Branch of the Russian Academy of Sciences, FRC Komi SC UB RAS, 50 Pervomayskaya str., 167982, Syktyvkar, Russia.
| | - Evgeny R Bojko
- Institute of Physiology of Кomi Science Centre of the Ural Branch of the Russian Academy of Sciences, FRC Komi SC UB RAS, 50 Pervomayskaya str., 167982, Syktyvkar, Russia
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Abstract
PURPOSE OF REVIEW Obesity is accompanied by atherogenic dyslipidemia, a specific lipid disorder characterized by both quantitative and qualitative changes of plasma lipoproteins. The main alterations in the lipid profile include hypertriglyceridemia, reduced high-density lipoprotein (HDL) cholesterol level, and elevated small dense low-density lipoprotein (LDL) particles. Epidemiological data show that obesity is more common in women and is a frequent risk factor for reproductive disorders, metabolic complications in pregnancy, and cardiometabolic disease later in life. The aim of this narrative review is to discuss recent advances in the research of dyslipidemia in obesity, with an emphasis on female-specific disorders and cardiometabolic risk. RECENT FINDINGS The focus of current research on dyslipidemia in obesity is moving toward structurally and functionally modified plasma lipoproteins. Special attention is paid to the pro-atherogenic role of triglyceride-rich lipoproteins and their remnants. Introduction of advanced analytical techniques enabled identification of novel lipid biomarkers with potential clinical applications. In particular, proteomic and lipidomic studies have provided significant progress in the comprehensive research of HDL's alterations in obesity. Obesity-related dyslipidemia is a widespread metabolic disturbance in polycystic ovary syndrome patients and high-risk pregnancies, but is seldom evaluated with respect to its impact on future cardiometabolic health. Obesity and associated cardiometabolic diseases require a more depth insight into the quality of lipoprotein particles. Further application of omics-based techniques would enable a more comprehensive evaluation of dyslipidemia in order to reduce an excessive cardiovascular risk attributable to increased body weight. However, more studies on obesity-related female reproductive disorders are needed for this approach to be adopted in daily clinical practice.
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Affiliation(s)
- Jelena Vekic
- Department of Medical Biochemistry, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, P. Box 146, 11000, Belgrade, Serbia.
| | - Aleksandra Stefanovic
- Department of Medical Biochemistry, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, P. Box 146, 11000, Belgrade, Serbia
| | - Aleksandra Zeljkovic
- Department of Medical Biochemistry, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, P. Box 146, 11000, Belgrade, Serbia
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Li Z, Wen X, Li N, Zhong C, Chen L, Zhang F, Zhang G, Lyu A, Liu J. The roles of hepatokine and osteokine in liver-bone crosstalk: Advance in basic and clinical aspects. Front Endocrinol (Lausanne) 2023; 14:1149233. [PMID: 37091847 PMCID: PMC10117885 DOI: 10.3389/fendo.2023.1149233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/22/2023] [Indexed: 04/08/2023] Open
Abstract
Both the liver and bone are important secretory organs in the endocrine system. By secreting organ factors (hepatokines), the liver regulates the activity of other organs. Similarly, bone-derived factors, osteokines, are created during bone metabolism and act in an endocrine manner. Generally, the dysregulation of hepatokines is frequently accompanied by changes in bone mass, and osteokines can also disrupt liver metabolism. The crosstalk between the liver and bone, particularly the function and mechanism of hepatokines and osteokines, has increasingly gained notoriety as a topic of interest in recent years. Here, based on preclinical and clinical evidence, we summarize the potential roles of hepatokines and osteokines in liver-bone interaction, discuss the current shortcomings and contradictions, and make recommendations for future research.
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Affiliation(s)
- Zhanghao Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, Hong Kong SAR, China
| | - Xiaoxin Wen
- Department of Anatomy, Jinzhou Medical University, Jinzhou, China
| | - Nanxi Li
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, Hong Kong SAR, China
| | - Chuanxin Zhong
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, Hong Kong SAR, China
| | - Li Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, Hong Kong SAR, China
| | - Aiping Lyu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, Hong Kong SAR, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
- *Correspondence: Jin Liu, ; Aiping Lyu,
| | - Jin Liu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University (HKBU), Hong Kong, Hong Kong SAR, China
- Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
- *Correspondence: Jin Liu, ; Aiping Lyu,
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Shama S, Jang H, Wang X, Zhang Y, Shahin NN, Motawi TK, Kim S, Gawrieh S, Liu W. Phosphatidylethanolamines Are Associated with Nonalcoholic Fatty Liver Disease (NAFLD) in Obese Adults and Induce Liver Cell Metabolic Perturbations and Hepatic Stellate Cell Activation. Int J Mol Sci 2023; 24:ijms24021034. [PMID: 36674549 PMCID: PMC9861886 DOI: 10.3390/ijms24021034] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/28/2022] [Accepted: 01/03/2023] [Indexed: 01/07/2023] Open
Abstract
Pathogenesis roles of phospholipids (PLs) in nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This study investigated the role of PLs in the progression of NAFLD among obese individuals via studying the alterations in serum PL composition throughout the spectrum of disease progression and evaluating the effects of specific phosphatidylethanolamines (PEs) on FLD development in vitro. A total of 203 obese subjects, who were undergoing bariatric surgery, were included in this study. They were histologically classified into 80 controls (C) with normal liver histology, 93 patients with simple hepatic steatosis (SS), 16 with borderline nonalcoholic steatohepatitis (B-NASH) and 14 with progressive NASH (NASH). Serum PLs were profiled by automated electrospray ionization tandem mass spectrometry (ESI-MS/MS). HepG2 (hepatoma cells) and LX2 (immortalized hepatic stellate cells or HSCs) were used to explore the roles of PL in NAFLD/NASH development. Several PLs and their relative ratios were significantly associated with NAFLD progression, especially those involving PE. Incubation of HepG2 cells with two phosphatidylethanolamines (PEs), PE (34:1) and PE (36:2), resulted in significant inhibition of cell proliferation, reduction of mitochondrial mass and membrane potential, induction of lipid accumulation and mitochondrial ROS production. Meanwhile, treatment of LX2 cells with both PEs markedly increased cell activation and migration. These effects were associated with a significant change in the expression levels of genes involved in lipogenesis, lipid oxidation, autophagy, apoptosis, inflammation, and fibrosis. Thus, our study demonstrated that elevated level of PEs increases susceptibility to the disease progression of obesity associated NAFLD, likely through a causal cascade of impacts on the function of different liver cells.
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Affiliation(s)
- Samaa Shama
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Cell-Based Analysis Unit, Reference Laboratory, Egyptian Drug Authority, Cairo 12618, Egypt
| | - Hyejeong Jang
- Biostatistics and Bioinformatics Core, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Xiaokun Wang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Yang Zhang
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
| | - Nancy Nabil Shahin
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| | - Tarek Kamal Motawi
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Correspondence: (T.K.M.); (W.L.); Tel.: +20-122-313-8667 (T.K.M.); +1-313-577-3375 (W.L.)
| | - Seongho Kim
- Biostatistics and Bioinformatics Core, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Wanqing Liu
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Correspondence: (T.K.M.); (W.L.); Tel.: +20-122-313-8667 (T.K.M.); +1-313-577-3375 (W.L.)
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Gao H, Wu J, Sun Z, Zhang F, Shi T, Lu K, Qian D, Yin Z, Zhao Y, Qin J, Xue B. Influence of lecithin cholesterol acyltransferase alteration during different pathophysiologic conditions: A 45 years bibliometrics analysis. Front Pharmacol 2022; 13:1062249. [PMID: 36588724 PMCID: PMC9795195 DOI: 10.3389/fphar.2022.1062249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 12/06/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Lecithin cholesterol acyltransferase (LCAT) is an important enzyme responsible for free cholesterol (FC) esterification, which is critical for high density lipoprotein (HDL) maturation and the completion of the reverse cholesterol transport (RCT) process. Plasma LCAT activity and concentration showed various patterns under different physiological and pathological conditions. Research on LCAT has grown rapidly over the past 50 years, but there are no bibliometric studies summarizing this field as a whole. This study aimed to use the bibliometric analysis to demonstrate the trends in LCAT publications, thus offering a brief perspective with regard to future developments in this field. Methods: We used the Web of Science Core Collection to retrieve LCAT-related studies published from 1975 to 2020. The data were further analyzed in the number of studies, the journal which published the most LCAT-related studies, co-authorship network, co-country network, co-institute network, co-reference and the keywords burst by CiteSpace V 5.7. Results: 2584 publications contained 55,311 references were used to analyzed. The number of included articles fluctuated in each year. We found that Journal of lipid research published the most LCAT-related studies. Among all the authors who work on LCAT, they tend to collaborate with a relatively stable group of collaborators to generate several major authors clusters which Albers, J. published the most studies (n = 53). The United States of America contributed the greatest proportion (n = 1036) of LCAT-related studies. The LCAT-related studies have been focused on the vascular disease, lecithin-cholesterol acyltransferase reaction, phospholipid, cholesterol efflux, chronic kidney disease, milk fever, nephrotic syndrome, platelet-activating factor acetylhydrolase, reconstituted lpa-i, reverse cholesterol transport. Four main research frontiers in terms of burst strength for LCAT-related studies including "transgenic mice", "oxidative stress", "risk", and "cholesterol metabolism "need more attention. Conclusion: This is the first study that demonstrated the trends and future development in LCAT publications. Further studies should focus on the accurate metabolic process of LCAT dependent or independent of RCT using metabolic marker tracking techniques. It was also well worth to further studying the possibility that LCAT may qualify as a biomarker for risk prediction and clinical treatment.
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Affiliation(s)
- Hongliang Gao
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China,School of Clinical Medicine, Wannan Medical College, Wuhu, China,Collaborative Innovation Center of Sustainable Forestry in Southern China, College of Forestry, Nanjing Forestry University, Nanjing, China
| | - Jing Wu
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Zhenyu Sun
- School of Health Policy and Management, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Furong Zhang
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Tianshu Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ke Lu
- Research Center for Computer-Aided Drug Discovery, Chinese Academy of Sciences, Shenzhen, China
| | - Dongfu Qian
- School of Health Policy and Management, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Zicheng Yin
- Nanjing Foreign Language School, Nanjing, China
| | - Yinjuan Zhao
- Collaborative Innovation Center of Sustainable Forestry in Southern China, College of Forestry, Nanjing Forestry University, Nanjing, China,*Correspondence: Bin Xue, ; Jian Qin, ; Yinjuan Zhao,
| | - Jian Qin
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China,*Correspondence: Bin Xue, ; Jian Qin, ; Yinjuan Zhao,
| | - Bin Xue
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China,*Correspondence: Bin Xue, ; Jian Qin, ; Yinjuan Zhao,
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Martin M, Gaete L, Tetzlaff W, Ferraro F, Lozano Chiappe E, Botta EE, Osta V, Saez MS, Lorenzon Gonzalez MV, Palenque P, Ballerini G, Sorroche P, Boero L, Triffone L, Brites F. Vascular inflammation and impaired reverse cholesterol transport and lipid metabolism in obese children and adolescents. Nutr Metab Cardiovasc Dis 2022; 32:258-268. [PMID: 34895801 DOI: 10.1016/j.numecd.2021.09.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 09/08/2021] [Accepted: 09/28/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND AIMS Childhood obesity is associated to complications such as insulin resistance and dyslipidemia. High density lipoproteins (HDL) constitute the only lipoprotein fraction with ateroprotective properties. The aim of the present study was to analyze inflammatory markers, carbohydrate metabolism, lipid profile and HDL functionality in obese children and adolescents compared to healthy controls. METHODS AND RESULTS Twenty obese children and adolescents (Body mass index z score >3.0) (9-15 years old) and 20 age and sex similar controls were included in the study. Triglyceride (TG), total cholesterol (TC), HDL-C, LDL-C, apolipoproteins (apo) A-I and B, glucose and insulin levels were quantified. Lipid indexes and HOMA-IR were calculated. Cholesterol efflux (CEC), lipoprotein associated phospholipase A2 (Lp-PLA2), lecithin-cholesterol acyl transferase (LCAT) and cholesteryl ester transfer protein, plus paraoxonase and arylesterase (ARE) activities were evaluated. Obese children and adolescents showed significantly higher TG [69 (45-95) vs 96 (76-121); p < 0.05], non-HDL-C [99 ± 34 vs 128 ± 26; p < 0.01], TC/HDL-C [2.8 ± 0.6 vs 4.7 ± 1.5; p < 0.01], TG/HDL-C [1.1 (1.0-1.8) vs 2,2 (1.4-3.2); p < 0.01], and HOMA-IR [1.5 (1.1-1.9) vs. 2.6 (2.0-4.5); p < 0.01] values, plus Lp-PLA2 activity [8.3 ± 1.9 vs 7.1 ± 1.7 umol/ml.h; p < 0,05] in addition to lower HDL-C [57 ± 10 vs 39 ± 9; p < 0.01], apo A-I [143 ± 25 vs 125 ± 19; p < 0.05], and CEC [6.4 (5.1-6.8) vs. 7.8 (5.7-9.5); p < 0.01] plus LCAT [12.6 ± 3.3 vs 18.7 ± 2.6; p < 0.05] and ARE [96 ± 19 vs. 110 ± 19; p < 0.05] activities. Lp-PLA2 activity correlated with LDL-C (r = 0.72,p < 0.01), non-HDL-C (r = 0.76,p < 0.01), and apo B (r = 0.60,p < 0.01). LCAT activity correlated with triglycerides (r = -0.78,p < 0.01), HDL-C (r = 0.64,p < 0.01), and apo A-I (r = 0.62, p < 0.05). ARE activity correlated with HDL-C (r = 0.32,p < 0.05) and apoA-I (r = 0.43,p < 0.01). CEC was negatively associated with BMI z-score (r = -0.36,p < 0.05), and triglycerides (r = -0.28,p < 0.05), and positively with LCAT activity (r = 0.65,p < 0.05). In multivariate analysis, BMI z-score was the only parameter significantly associated to CEC (r2 = 0.43, beta = -0.38, p < 0.05). CONCLUSION The obese group showed alterations in carbohydrate and lipid metabolism, which were associated to the presence of vascular specific inflammation and impairment of HDL atheroprotective capacity. These children and adolescents would present qualitative alterations in their lipoproteins which would determine higher risk of suffering premature cardiovascular disease.
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Affiliation(s)
- Maximiliano Martin
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina.
| | - Laura Gaete
- Servicio de Nutrición y Diabetes, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
| | - Walter Tetzlaff
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | - Florencia Ferraro
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | - Ezequiel Lozano Chiappe
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | - Eliana E Botta
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | - Viviana Osta
- Laboratorio Central, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
| | - Maria S Saez
- Laboratorio Central, Hospital Italiano de Buenos Aires, Argentina
| | | | - Patricia Palenque
- Servicio de Nutrición y Diabetes, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
| | - Gabriela Ballerini
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | | | - Laura Boero
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
| | - Liliana Triffone
- Servicio de Nutrición y Diabetes, Hospital de Niños "Ricardo Gutiérrez", Buenos Aires, Argentina
| | - Fernando Brites
- Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
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Di Sessa A, Riccio S, Pirozzi E, Verde M, Passaro AP, Umano GR, Guarino S, Miraglia del Giudice E, Marzuillo P. Advances in paediatric nonalcoholic fatty liver disease: Role of lipidomics. World J Gastroenterol 2021; 27:3815-3824. [PMID: 34321846 PMCID: PMC8291022 DOI: 10.3748/wjg.v27.i25.3815] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/06/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Due its close relationship with obesity, nonalcoholic fatty liver disease (NAFLD) has become a major worldwide health issue even in childhood. The most accepted pathophysiological hypothesis is represented by the "multiple hits" theory, in which both hepatic intracellular lipid accumulation and insulin resistance mainly contribute to liver injury through several factors. Among these, lipotoxicity has gained particular attention. In this view, the pathogenic role of different lipid classes in NAFLD (e.g., sphingolipids, fatty acids, ceramides, etc.) has been highlighted in recent lipidomics studies. Although there is some contrast between plasma and liver findings, lipidomic profile in the NAFLD context provides novel insights by expanding knowledge in the intricate field of NAFLD pathophysiology as well as by suggesting innovative therapeutic approaches in order to improve both NAFLD prevention and treatment strategies. Selective changes of distinct lipid species might be an attractive therapeutic target for treating NAFLD. Herein the most recent evidence in this attractive field has been summarized to provide a comprehensive overview of the lipidomic scenario in paediatric NAFLD.
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Affiliation(s)
- Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Simona Riccio
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emilia Pirozzi
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Martina Verde
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Antonio Paride Passaro
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Giuseppina Rosaria Umano
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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12
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Bedi S, Garcia E, Jeyarajah EJ, Shalaurova I, Perez-Matos MC, Jiang ZG, Dullaart RPF, Matyus SP, Kirk WJ, Otvos JD, Davidson WS, Connelly MA. Characterization of LP-Z Lipoprotein Particles and Quantification in Subjects with Liver Disease Using a Newly Developed NMR-Based Assay. J Clin Med 2020; 9:jcm9092915. [PMID: 32927635 PMCID: PMC7564541 DOI: 10.3390/jcm9092915] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/03/2020] [Accepted: 09/08/2020] [Indexed: 12/11/2022] Open
Abstract
Background: Lipoprotein particles with abnormal compositions, such as lipoprotein X (LP-X) and lipoprotein Z (LP-Z), have been described in cases of obstructive jaundice and cholestasis. The study objectives were to: (1) develop an NMR-based assay for quantification of plasma/serum LP-Z particles, (2) evaluate the assay performance, (3) isolate LP-Z particles and characterize them by lipidomic and proteomic analysis, and (4) quantify LP-Z in subjects with various liver diseases. Methods: Assay performance was assessed for linearity, sensitivity, and precision. Mass spectroscopy was used to characterize the protein and lipid content of isolated LP-Z particles. Results: The assay showed good linearity and precision (2.5–6.3%). Lipid analyses revealed that LP-Z particles exhibit lower cholesteryl esters and higher free cholesterol, bile acids, acylcarnitines, diacylglycerides, dihexosylceramides, lysophosphatidylcholines, phosphatidylcholines, triacylglycerides, and fatty acids than low-density lipoprotein (LDL) particles. A proteomic analysis revealed that LP-Z have one copy of apolipoprotein B per particle such as LDL, but less apolipoprotein (apo)A-I, apoC3, apoA-IV and apoC2 and more complement C3. LP-Z were not detected in healthy volunteers or subjects with primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, or type 2 diabetes. LP-Z were detected in some, but not all, subjects with hypertriglyceridemia, and were high in some subjects with alcoholic liver disease. Conclusions: LP-Z differ significantly in their lipid and protein content from LDL. Further studies are needed to fully understand the pathophysiological reason for the enhanced presence of LP-Z particles in patients with cholestasis and alcoholic liver disease.
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Affiliation(s)
- Shimpi Bedi
- Center for Lipid and Arteriosclerosis Science, Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237-0507, USA; (S.B.); (W.S.D.)
| | - Erwin Garcia
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
| | - Elias J. Jeyarajah
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
| | - Irina Shalaurova
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
| | - Maria Camila Perez-Matos
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.C.P.-M.); (Z.G.J.)
| | - Z. Gordon Jiang
- Division of Gastroenterology & Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (M.C.P.-M.); (Z.G.J.)
| | - Robin P. F. Dullaart
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands;
| | - Steven P. Matyus
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
| | - William J. Kirk
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
| | - James D. Otvos
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
| | - W. Sean Davidson
- Center for Lipid and Arteriosclerosis Science, Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45237-0507, USA; (S.B.); (W.S.D.)
| | - Margery A. Connelly
- Laboratory Corporation of America Holdings (LabCorp), Burlington, NC 27560, USA; (E.G.); (E.J.J.); (I.S.); (S.P.M.); (W.J.K.); (J.D.O.)
- Correspondence: ; Tel.: +1-919-388-5534
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Kartsoli S, Kostara CE, Tsimihodimos V, Bairaktari ET, Christodoulou DK. Lipidomics in non-alcoholic fatty liver disease. World J Hepatol 2020; 12:436-450. [PMID: 32952872 PMCID: PMC7475773 DOI: 10.4254/wjh.v12.i8.436] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/03/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.
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Affiliation(s)
- Sofia Kartsoli
- Department of Gastroenterology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece
| | - Christina E Kostara
- Laboratory of Clinical Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece
| | - Vasilis Tsimihodimos
- Department of Internal Medicine, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece
| | - Eleni T Bairaktari
- Laboratory of Clinical Chemistry, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece
| | - Dimitrios K Christodoulou
- Department of Gastroenterology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece
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van Dijk PR, Abdulle AE, Bulthuis ML, Perton FG, Connelly MA, van Goor H, Dullaart RP. The Systemic Redox Status Is Maintained in Non-Smoking Type 2 Diabetic Subjects Without Cardiovascular Disease: Association with Elevated Triglycerides and Large VLDL. J Clin Med 2019; 9:jcm9010049. [PMID: 31878321 PMCID: PMC7019670 DOI: 10.3390/jcm9010049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/10/2019] [Accepted: 12/22/2019] [Indexed: 12/11/2022] Open
Abstract
Decreased circulating levels of free thiols (R-SH, sulfhydryl groups) reflect enhanced oxidative stress, which plays an important role in the pathogenesis of cardiometabolic diseases. Since hyperglycemia causes oxidative stress, we questioned whether plasma free thiols are altered in patients with type 2 diabetes mellitus (T2DM) without cardiovascular disease or renal function impairment. We also determined their relationship with elevated triglycerides and very low density lipoproteins (VLDL), a central feature of diabetic dyslipidemia. Fasting plasma free thiols (colorimetric method), lipoproteins, VLDL (nuclear magnetic resonance spectrometry), free fatty acids (FFA), phospholipid transfer protein (PLTP) activity and adiponectin were measured in 79 adult non-smoking T2DM subjects (HbA1c 51 ± 8 mmol/mol, no use of insulin or lipid lowering drugs), and in 89 non-smoking subjects without T2DM. Plasma free thiols were univariately correlated with glucose (r = 0.196, p < 0.05), but were not decreased in T2DM subjects versus non-diabetic subjects (p = 0.31). Free thiols were higher in subjects with (663 ± 84 µmol/L) versus subjects without elevated triglycerides (619 ± 91 µmol/L; p = 0.002). Age- and sex-adjusted multivariable linear regression analysis demonstrated that plasma triglycerides were positively and independently associated with free thiols (β = 0.215, p = 0.004), FFA (β = 0.168, p = 0.029) and PLTP activity (β = 0.228, p = 0.002), inversely with adiponectin (β = −0.308, p < 0.001) but not with glucose (β = 0.052, p = 0.51). Notably, the positive association of free thiols with (elevated) triglycerides appeared to be particularly evident in men. Additionally, large VLDL were independently associated with free thiols (β = 0.188, p = 0.029). In conclusion, circulating free thiols are not decreased in this cohort of non-smoking and generally well-controlled T2DM subjects. Paradoxically, higher triglycerides and more large VLDL particles are likely associated with higher plasma levels of thiols, reflecting lower systemic oxidative stress.
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Affiliation(s)
- Peter R. van Dijk
- Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
- Correspondence:
| | - Amaal Eman Abdulle
- Department of Internal Medicine, division vascular medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
| | - Marian L.C. Bulthuis
- Department of Pathology and Medical, Biology, Section Pathology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (H.v.G.)
| | - Frank G. Perton
- Laboratory Center, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - Margery A. Connelly
- Laboratory Corporation of America® Holdings (LabCorp), Morrisville, NC 27560, USA;
| | - Harry van Goor
- Department of Pathology and Medical, Biology, Section Pathology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands (H.v.G.)
| | - Robin P.F. Dullaart
- Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
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15
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Robert C, Couëdelo L, Vaysse C, Michalski MC. Vegetable lecithins: A review of their compositional diversity, impact on lipid metabolism and potential in cardiometabolic disease prevention. Biochimie 2019; 169:121-132. [PMID: 31786232 DOI: 10.1016/j.biochi.2019.11.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Abstract
Vegetable lecithins, widely used in the food industry as emulsifiers, are a mixture of naturally occurring lipids containing more than 50% of phospholipids (PL). PL exert numerous important physiological effects. Their amphiphilic nature notably enables them to stabilise endogenous lipid droplets, conferring them an important role in lipoprotein transport, functionality and metabolism. In addition, beneficial effects of dietary lecithin on metabolic disorders have been reported since the 1990s. This review attempts to summarize the effects of various vegetable lecithins on lipid and lipoprotein metabolism, as well as their potential application in the treatment of dyslipidemia associated with metabolic disorders. Despite controversial data concerning the impact of vegetable lecithins on lipid digestion and intestinal absorption, the beneficial effect of lecithin supplementation on plasma and hepatic lipoprotein and cholesterol levels is unequivocal. This is especially true in hyperlipidemic patients. Furthermore, the immense compositional diversity of vegetable lecithins endows them with a vast range of biochemical and biological properties, which remain to be explored in detail. Data on the effects of vegetable lecithins alternative to soybean, both as supplements and as ingredients in different foods, is undoubtedly lacking. Given the exponential demand for vegetable products alternative to those of animal origin, it is of primordial importance that future research is undertaken in order to elucidate the mechanisms by which individual fatty acids and PL from various vegetable lecithins modulate lipid metabolism. The extent to which they may influence parameters associated with metabolic disorders, such as intestinal integrity, low-grade inflammation and gut microbiota must also be assessed.
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Affiliation(s)
- Chloé Robert
- Univ Lyon, CarMeN Laboratory, Inserm, INRAE, INSA Lyon, Université Claude Bernard Lyon 1, Lyon-Sud Medical School, Pierre-Bénite, FR-69310, France; ITERG, Equipe Nutrition, Santé et Biochimie des Lipides, Canéjan, FR-33610, Canéjan, France
| | - Leslie Couëdelo
- ITERG, Equipe Nutrition, Santé et Biochimie des Lipides, Canéjan, FR-33610, Canéjan, France
| | - Carole Vaysse
- ITERG, Equipe Nutrition, Santé et Biochimie des Lipides, Canéjan, FR-33610, Canéjan, France
| | - Marie-Caroline Michalski
- Univ Lyon, CarMeN Laboratory, Inserm, INRAE, INSA Lyon, Université Claude Bernard Lyon 1, Lyon-Sud Medical School, Pierre-Bénite, FR-69310, France.
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16
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Janac J, Zeljkovic A, Jelic-Ivanovic Z, Dimitrijevic-Sreckovic V, Miljkovic M, Stefanovic A, Munjas J, Vekic J, Kotur-Stevuljevic J, Spasojević-Kalimanovska V. The association between lecithin-cholesterol acyltransferase activity and fatty liver index. Ann Clin Biochem 2019; 56:583-592. [PMID: 31084205 DOI: 10.1177/0004563219853596] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Background Non-alcoholic fatty liver disease is a frequent ailment with known complications, including those within the cardiovascular system. Associations between several indicators of high-density lipoprotein metabolism and function with clinical and laboratory parameters for the assessment of fatty liver index, a surrogate marker of non-alcoholic fatty liver disease, were evaluated. Methods The study comprised 130 patients classified according to fatty liver index values: fatty liver index < 30, fatty liver index 30–59 (the intermediate group) and fatty liver index ⩾ 60. Lecithin–cholesterol acyltransferase and cholesteryl ester transfer protein activities were determined. Paraoxonase 1 concentration and its activity, paraoxonase 3 concentration and high-density lipoprotein subclass distribution were assessed. Results Increased lecithin–cholesterol acyltransferase activity correlated with increased fatty liver index ( P < 0.001). Paraoxonase 3 concentration was lower in the fatty liver index ⩾ 60 group compared with the fatty liver index < 30 group ( P < 0.05). Cholesteryl ester transfer protein activity, paraoxonase 1 concentration and its activity did not significantly differ across the fatty liver index groups. The relative proportion of small-sized high-density lipoprotein 3 subclass was higher in the fatty liver index ⩾ 60 group compared with the other two fatty liver index groups ( P < 0.01). Lecithin–cholesterol acyltransferase activity positively associated with the fatty liver index ⩾ 60 group and remained significant after adjustment for other potential confounders. Only the triglyceride concentration remained significantly associated with lecithin–cholesterol acyltransferase activity when the parameters that constitute the fatty liver index equation were examined. Conclusions Higher lecithin–cholesterol acyltransferase activity is associated with elevated fatty liver index values. Significant independent association between triglycerides and lecithin–cholesterol acyltransferase activity might indicate a role of hypertriglyceridaemia in alterations of lecithin–cholesterol acyltransferase activity in individuals with elevated fatty liver index.
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Affiliation(s)
- Jelena Janac
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Zeljkovic
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Zorana Jelic-Ivanovic
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Vesna Dimitrijevic-Sreckovic
- 2 Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milica Miljkovic
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Aleksandra Stefanovic
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Jelena Munjas
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Jelena Vekic
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Jelena Kotur-Stevuljevic
- 1 Department of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
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Law SH, Chan ML, Marathe GK, Parveen F, Chen CH, Ke LY. An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases. Int J Mol Sci 2019; 20:ijms20051149. [PMID: 30845751 PMCID: PMC6429061 DOI: 10.3390/ijms20051149] [Citation(s) in RCA: 489] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 02/27/2019] [Accepted: 02/28/2019] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A2 (PLA2). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA2 increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A1 activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.
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Affiliation(s)
- Shi-Hui Law
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Mei-Lin Chan
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
- Division of Thoracic Surgery, Department of Surgery, MacKay Memorial Hospital, MacKay Medical College, Taipei 10449, Taiwan.
| | - Gopal K Marathe
- Department of Studies in Biochemistry, Manasagangothri, University of Mysore, Mysore-570006, India.
| | - Farzana Parveen
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
| | - Chu-Huang Chen
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 77030, USA.
| | - Liang-Yin Ke
- Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
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van den Berg EH, Gruppen EG, James RW, Bakker SJL, Dullaart RPF. Serum paraoxonase 1 activity is paradoxically maintained in nonalcoholic fatty liver disease despite low HDL cholesterol. J Lipid Res 2019; 60:168-175. [PMID: 30455362 PMCID: PMC6314263 DOI: 10.1194/jlr.p088997] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 11/05/2018] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by low HDL cholesterol, but the activity of the HDL-associated antioxidative enzyme paraoxonase-1 (PON-1) remains unclear. To determine the association of PON-1 with suspected NAFLD, we measured serum enzyme activity in 7,622 participants of the Prevention of Renal and Vascular End-Stage Disease cohort. A fatty liver index (FLI) ≥60, a proxy of NAFLD, was present in 2,083 participants (27.3%) and coincided with increased prevalence of T2D, metabolic syndrome (MetS), (central) obesity, elevated triglycerides, and low HDL cholesterol (all P < 0.001). In men and women combined, serum PON-1 activity did not vary according to elevated FLI (P = 0.98), whereas in men with elevated FLI PON-1 activity was increased (P = 0.016). In multivariable linear regression analyses (adjusted for age, sex, T2D, MetS, alcohol use, and smoking), PON-1 activity was unexpectedly associated with elevated FLI (β = 0.083; P < 0.001). In a sensitivity analysis (n = 5,126) that excluded subjects with positive cardiovascular history, impaired estimated glomerular filtration rate, elevated urinary albumin excretion, and drug use, PON-1 activity was also independently associated with elevated FLI (β = 0.045; P = 0.017). These results indicate that PON-1 is paradoxically maintained and may even be increased in NAFLD despite inverse associations with metabolic disorders and low HDL cholesterol.
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Affiliation(s)
- Eline H van den Berg
- Departments of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Departments of Gastroenterology and Hepatology University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eke G Gruppen
- Departments of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Departments of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Richard W James
- Departments of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Stephan J L Bakker
- Departments of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robin P F Dullaart
- Departments of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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19
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Zheng Y, Liu Y, Zhao S, Zheng Z, Shen C, An L, Yuan Y. Large-scale analysis reveals a novel risk score to predict overall survival in hepatocellular carcinoma. Cancer Manag Res 2018; 10:6079-6096. [PMID: 30538557 PMCID: PMC6252784 DOI: 10.2147/cmar.s181396] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a major cause of cancer mortality and an increasing incidence worldwide; however, there are very few effective diagnostic approaches and prognostic biomarkers. Materials and methods One hundred forty-nine pairs of HCC samples from Gene Expression Omnibus (GEO) were obtained to screen differentially expressed genes (DEGs) between HCC and normal samples. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene ontology enrichment analyses, and protein–protein interaction network were used. Cox proportional hazards regression analysis was used to identify significant prognostic DEGs, with which a gene expression signature prognostic prediction model was identified in The Cancer Genome Atlas (TCGA) project discovery cohort. The robustness of this panel was assessed in the GSE14520 cohort. We verified details of the gene expression level of the key molecules through TCGA, GEO, and qPCR and used immunohistochemistry for substantiation in HCC tissues. The methylation states of these genes were also explored. Results Ninety-eight genes, consisting of 13 upregulated and 85 downregulated genes, were screened out in three datasets. KEGG and Gene ontology analysis for the DEGs revealed important biological features of each subtype. Protein–protein interaction network analysis was constructed, consisting of 64 nodes and 115 edges. A subset of four genes (SPINK1, TXNRD1, LCAT, and PZP) that formed a prognostic gene expression signature was established from TCGA and validated in GSE14520. Next, the expression details of the four genes were validated with TCGA, GEO, and clinical samples. The expression panels of the four genes were closely related to methylation states. Conclusion This study identified a novel four-gene signature biomarker for predicting the prognosis of HCC. The biomarkers may also reveal molecular mechanisms underlying development of the disease and provide new insights into interventional strategies.
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Affiliation(s)
- Yujia Zheng
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yulin Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Songfeng Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,
| | - Zhetian Zheng
- School of Computer Science, Yangtze University, Jingzhou, Hubei, China
| | - Chunyi Shen
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Li An
- Institute of Quality Standard and Testing Technology for Agro-products, Henan Academy of Agricultural Sciences, Zhengzhou, China,
| | - Yongliang Yuan
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China,
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