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Liu T, Wang L, Ji L, Mu L, Wang K, Xu G, Wang S, Ma Q. Plantaginis Semen Ameliorates Hyperuricemia Induced by Potassium Oxonate. Int J Mol Sci 2024; 25:8548. [PMID: 39126116 PMCID: PMC11313179 DOI: 10.3390/ijms25158548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Plantaginis semen is the dried ripe seed of Plantago asiatica L. or Plantago depressa Willd., which has a long history in alleviating hyperuricemia (HUA) and chronic kidney diseases. While the major chemical ingredients and mechanism remained to be illustrated. Therefore, this work aimed to elucidate the chemicals and working mechanisms of PS for HUA. UPLC-QE-Orbitrap-MS was applied to identify the main components of PS in vitro and in vivo. RNA sequencing (RNA-seq) was conducted to explore the gene expression profile, and the genes involved were further confirmed by real-time quantitative PCR (RT-qPCR). A total of 39 components were identified from PS, and 13 of them were detected in the rat serum after treating the rat with PS. The kidney tissue injury and serum uric acid (UA), xanthine oxidase (XOD), and cytokine levels were reversed by PS. Meanwhile, renal urate anion transporter 1 (Urat1) and glucose transporter 9 (Glut9) levels were reversed with PS treatment. RNA-seq analysis showed that the PPAR signaling pathway; glycine, serine, and threonine metabolism signaling pathway; and fatty acid metabolism signaling pathway were significantly modified by PS treatment. Further, the gene expression of Slc7a8, Pck1, Mgll, and Bhmt were significantly elevated, and Fkbp5 was downregulated, consistent with RNA-seq results. The PPAR signaling pathway involved Pparα, Pparγ, Lpl, Plin5, Atgl, and Hsl were elevated by PS treatment. URAT1 and PPARα proteins levels were confirmed by Western blotting. In conclusion, this study elucidates the chemical profile and working mechanisms of PS for prevention and therapy of HUA and provides a promising traditional Chinese medicine agency for HUA prophylaxis.
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Affiliation(s)
| | | | | | | | | | | | - Shifeng Wang
- Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China; (T.L.); (L.W.); (L.J.); (L.M.); (K.W.); (G.X.)
| | - Qun Ma
- Key Laboratory of TCM-Information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China; (T.L.); (L.W.); (L.J.); (L.M.); (K.W.); (G.X.)
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2
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Hoekstra M, Snip OSC, Janusz P, Bernabé Kleijn MNA, Truitt ER, Sullivan BD, Schmidt TA, Jay GD, Van Eck M. Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low-density lipoprotein receptor knockout mice. J Physiol 2024; 602:1939-1951. [PMID: 38606903 DOI: 10.1113/jp286354] [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: 01/29/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin-like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti-atherogenic potential of chronic rhPRG4 treatment. Female low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet for 6 weeks and injected three times per week intraperitoneally with 0.5 mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma-free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4-treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 103 μm2 compared with 339 ± 15 × 103 μm2 in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti-inflammatory M2-like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro-inflammatory/pro-atherogenic cytokine TNF-alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti-inflammatory agent. KEY POINTS: Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility. In this study we investigated the anti-atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low-density lipoprotein receptor knockout mice. We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro-inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF-alpha levels and a lowered atherosclerosis susceptibility. Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions.
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Affiliation(s)
- Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
| | - Olga S C Snip
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Philip Janusz
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Mireia N A Bernabé Kleijn
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | | | | | - Tannin A Schmidt
- Biomedical Engineering Department, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Gregory D Jay
- Department of Emergency Medicine, Warren Alpert Medical School and Division of Biomedical Engineering, School of Engineering, Brown University, Providence, Rhode Island, USA
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
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3
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Hoekstra M, de Jong LM, van der Geest R, de Leeuw LR, Krisnamurthi R, Geerling JJ, Van Eck M. LXR Agonist T0901317's Hepatic Impact Overrules Its Atheroprotective Action in Macrophages, Driving Early Atherogenesis in Chow-Diet-Fed Male Apolipoprotein E Knockout Mice. Biomolecules 2024; 14:429. [PMID: 38672446 PMCID: PMC11047872 DOI: 10.3390/biom14040429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism remains anti-atherogenic under dietary conditions with a low basal hepatic lipogenesis rate. Hereto, atherosclerosis-susceptible male apolipoprotein E knockout mice were fed a low-fat diet with or without 10 mg/kg/day LXR agonist T0901317 supplementation for 8 weeks. Importantly, T0901317 significantly stimulated atherosclerosis susceptibility, despite an associated increase in the macrophage gene expression levels of cholesterol efflux transporters ABCA1 and ABCG1. The pro-atherogenic effect of T0901317 coincided with exacerbated hypercholesterolemia, hypertriglyceridemia, and a significant rise in hepatic triglyceride stores and macrophage numbers. Furthermore, T0901317-treated mice exhibited elevated plasma MCP-1 levels and monocytosis. In conclusion, these findings highlight that the pro-atherogenic hepatic effects of LXR agonism are dominant over the anti-atherogenic effects in macrophages in determining the overall atherosclerosis outcome under low-fat diet feeding conditions. A low-fat diet experimental setting, as compared to the commonly used high-fat-diet-based preclinical setup, thus appears more sensitive in uncovering the potential relevance of the off-target liver effects of novel anti-atherogenic therapeutic approaches that target macrophage LXR.
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Affiliation(s)
- Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
| | - Laura M. de Jong
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Rick van der Geest
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Lidewij R. de Leeuw
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Rani Krisnamurthi
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Janine J. Geerling
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
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4
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Chen S, Kim JK. The Role of Cannabidiol in Liver Disease: A Systemic Review. Int J Mol Sci 2024; 25:2370. [PMID: 38397045 PMCID: PMC10888697 DOI: 10.3390/ijms25042370] [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: 01/22/2024] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Cannabidiol (CBD), a non-psychoactive phytocannabinoid abundant in Cannabis sativa, has gained considerable attention for its anti-inflammatory, antioxidant, analgesic, and neuroprotective properties. It exhibits the potential to prevent or slow the progression of various diseases, ranging from malignant tumors and viral infections to neurodegenerative disorders and ischemic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and viral hepatitis stand as prominent causes of morbidity and mortality in chronic liver diseases globally. The literature has substantiated CBD's potential therapeutic effects across diverse liver diseases in in vivo and in vitro models. However, the precise mechanism of action remains elusive, and an absence of evidence hinders its translation into clinical practice. This comprehensive review emphasizes the wealth of data linking CBD to liver diseases. Importantly, we delve into a detailed discussion of the receptors through which CBD might exert its effects, including cannabinoid receptors, CB1 and CB2, peroxisome proliferator-activated receptors (PPARs), G protein-coupled receptor 55 (GPR55), transient receptor potential channels (TRPs), and their intricate connections with liver diseases. In conclusion, we address new questions that warrant further investigation in this evolving field.
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Affiliation(s)
- Si Chen
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea;
| | - Jeon-Kyung Kim
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
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5
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Hong S, Hong S, Lee SH. Association of overexpressed carboxyl-terminal amyloid precursor protein in brains with altered glucose metabolism and liver toxicity. Anim Cells Syst (Seoul) 2023; 27:103-111. [PMID: 37033452 PMCID: PMC10075522 DOI: 10.1080/19768354.2023.2197761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. The deposition of amyloid plaques mainly composed of amyloid beta (Aβ) is observed in brain regions in AD patients. AD presents with similar pathophysiology to that of metabolic syndrome, including glucose and insulin resistance. In addition, epidemiological studies indicate diabetes, impaired glucose metabolism, and obesity increase the prevalence of AD. The liver is considered a key organ in the reciprocal relationship between AD and metabolic syndrome and is the major organ for the clearance of Aβ in the periphery. Furthermore, liver dysfunction aggravates Aβ-induced pathophysiology. Aβ is produced in the brain and peripheral tissues and penetrates the blood–brain barrier. However, in vivo evidence showing the effect of Aβ on the crosstalk between the brain and liver has not been reported yet. In the present study, we investigated the toxicity of brain-derived Aβ on glucose metabolism and the liver using transgenic mice overexpressing the carboxyl-terminal of amyloid precursor protein in the brain. The transgenic mice were overweight, which was associated with impaired glucose metabolism and insulin resistance, but not due to increased food intake. In addition, transgenic mice had enlarged livers and reduced gene expressions associated with glucose and lipid metabolism. Thus, overexpressed amyloid precursor protein in the brain may promote being overweight and glucose resistance, possibly through liver toxicity.
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Affiliation(s)
- Sungguan Hong
- Department of Chemistry, Chung-Ang University, Seoul, Republic of Korea
| | - Seungwoo Hong
- Department of Chemistry, Chung-Ang University, Seoul, Republic of Korea
| | - Sung Hoon Lee
- College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea
- Sung Hoon Lee College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul06974, Republic of Korea
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Rayego-Mateos S, Morgado-Pascual JL, García-Caballero C, Lazaro I, Sala-Vila A, Opazo-Rios L, Mas-Fontao S, Egido J, Ruiz-Ortega M, Moreno JA. Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade. J Pathol 2023; 261:169-183. [PMID: 37555366 DOI: 10.1002/path.6161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 05/30/2023] [Accepted: 06/14/2023] [Indexed: 08/10/2023]
Abstract
Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Sandra Rayego-Mateos
- Molecular and Cellular Biology in Renal and Vascular Pathology. IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain
| | - José Luis Morgado-Pascual
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
| | - Cristina García-Caballero
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain
| | - Iolanda Lazaro
- Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Aleix Sala-Vila
- Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Lucas Opazo-Rios
- Health Science Faculty, Universidad de Las Américas, Concepción-Talcahuano, Chile
| | - Sebastian Mas-Fontao
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), Madrid, Spain
- Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Jesús Egido
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain
| | - Marta Ruiz-Ortega
- Molecular and Cellular Biology in Renal and Vascular Pathology. IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain
| | - Juan Antonio Moreno
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
- Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), Madrid, Spain
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7
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van der Sluis RJ, van den Aardweg T, Sijsenaar TJP, Van Eck M, Hoekstra M. Metyrapone Treatment Protects Low-Density Lipoprotein Receptor Knockout Mice against Hypercorticosteronemia Development without Changing Atherosclerosis Susceptibility. Biomolecules 2023; 13:1287. [PMID: 37759687 PMCID: PMC10526766 DOI: 10.3390/biom13091287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 08/22/2023] [Indexed: 09/29/2023] Open
Abstract
The steroid 11beta-hydroxylase inhibitor metyrapone is able to effectively reverse the hypercortisolemia detected in human Cushing's Syndrome patients. In this current preclinical study, we investigated whether metyrapone monotherapy can also reverse the hypercortisolemia-associated increase in atherosclerotic cardiovascular disease risk. In this instance, female low-density lipoprotein receptor knockout mice fed a cholic acid-containing high cholesterol/high fat diet to induce the development of hypercorticosteronemia and atherosclerotic lesions were treated twice daily with 100 mg/kg metyrapone for 4 weeks. Metyrapone effectively protected against hypercorticosteronemia development with endpoint plasma corticosterone levels remaining 43% lower than in controls (p < 0.01). Gene expression analysis in livers and adrenals validated that glucocorticoid receptor signaling was also reduced. Importantly, metyrapone treatment did not impact plasma cholesterol levels or alter atherosclerotic plaque areas or lesional collagen contents. However, metyrapone induced significant systemic lymphocytopenia as evident from marked decreases in splenic white pulp contents and thymus weights (-48% and -41%, respectively; p < 0.001). In conclusion, we have shown that treatment with metyrapone diminishes hypercorticosteronemia without affecting atherosclerosis susceptibility in cholic acid-containing high cholesterol/high fat diet-fed low-density lipoprotein receptor knockout mice. These preclinical findings highlight that restoring plasma glucocorticoid levels to normal is not necessarily sufficient to overcome the cardiovascular co-morbidities associated with human Cushing's disease.
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Affiliation(s)
- Ronald J. van der Sluis
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands; (R.J.v.d.S.); (M.V.E.)
| | - Tim van den Aardweg
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands; (R.J.v.d.S.); (M.V.E.)
| | - Timothy J. P. Sijsenaar
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands; (R.J.v.d.S.); (M.V.E.)
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands; (R.J.v.d.S.); (M.V.E.)
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands; (R.J.v.d.S.); (M.V.E.)
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, 2333CC Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
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Shao C, Xu H, Sun X, Huang Y, Guo W, He Y, Ye L, Wang Z, Huang J, Liang X, Zhang J. New Perspectives on Chinese Medicine in Treating Hepatic Fibrosis: Lipid Droplets in Hepatic Stellate Cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2023; 51:1413-1429. [PMID: 37429706 DOI: 10.1142/s0192415x23500647] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
Hepatic fibrosis (HF) is a wound healing response featuring excessive deposition of the extracellular matrix (ECM) and activation of hepatic stellate cells (HSCs) that occurs during chronic liver injury. As an initial stage of various liver diseases, HF is a reversible pathological process that, if left unchecked, can escalate into cirrhosis, liver failure, and liver cancer. HF is a life-threatening disease presenting morbidity and mortality challenges to healthcare systems worldwide. There is no specific and effective anti-HF therapy, and the toxic side effects of the available drugs also impose a heavy financial burden on patients. Therefore, it is significant to study the pathogenesis of HF and explore effective prevention and treatment measures. Formerly called adipocytes, or fat storage cells, HSCs regulate liver growth, immunity, and inflammation, as well as energy and nutrient homeostasis. HSCs in a quiescent state do not proliferate and store abundant lipid droplets (LDs). Catabolism of LDs is characteristic of the activation of HSCs and morphological transdifferentiation of cells into contractile and proliferative myofibroblasts, resulting in the deposition of ECM and the development of HF. Recent studies have revealed that various Chinese medicines (e.g., Artemisia annua, turmeric, Scutellaria baicalensis Georgi, etc.) are able to effectively reduce the degradation of LDs in HSCs. Therefore, this study takes the modification of LDs in HSCs as an entry point to elaborate on the process of Chinese medicine intervening in the loss of LDs in HSCs and the mechanism of action for the treatment of HF.
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Affiliation(s)
- Chang Shao
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Huihui Xu
- The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, P. R. China
| | - Xiguang Sun
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Yan Huang
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Wenqin Guo
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Yi He
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Linmao Ye
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Zhili Wang
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Jiaxin Huang
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Xiaofan Liang
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
| | - Junjie Zhang
- School of Basic Medical Sciences, Hangzhou 310053, P. R. China
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9
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Moore JM, Bell EL, Hughes RO, Garfield AS. ABC transporters: human disease and pharmacotherapeutic potential. Trends Mol Med 2023; 29:152-172. [PMID: 36503994 DOI: 10.1016/j.molmed.2022.11.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/24/2022] [Accepted: 11/01/2022] [Indexed: 12/12/2022]
Abstract
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are a 48-member superfamily of membrane proteins that actively transport a variety of biological substrates across lipid membranes. Their functional diversity defines an expansive involvement in myriad aspects of human biology. At least 21 ABC transporters underlie rare monogenic disorders, with even more implicated in the predisposition to and symptomology of common and complex diseases. Such broad (patho)physiological relevance places this class of proteins at the intersection of disease causation and therapeutic potential, underlining them as promising targets for drug discovery, as exemplified by the transformative CFTR (ABCC7) modulator therapies for cystic fibrosis. This review will explore the growing relevance of ABC transporters to human disease and their potential as small-molecule drug targets.
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10
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Finney AC, Das S, Kumar D, McKinney MP, Cai B, Yurdagul A, Rom O. The interplay between nonalcoholic fatty liver disease and atherosclerotic cardiovascular disease. Front Cardiovasc Med 2023; 10:1116861. [PMID: 37200978 PMCID: PMC10185914 DOI: 10.3389/fcvm.2023.1116861] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/23/2023] [Indexed: 05/20/2023] Open
Abstract
Therapeutic approaches that lower circulating low-density lipoprotein (LDL)-cholesterol significantly reduced the burden of cardiovascular disease over the last decades. However, the persistent rise in the obesity epidemic is beginning to reverse this decline. Alongside obesity, the incidence of nonalcoholic fatty liver disease (NAFLD) has substantially increased in the last three decades. Currently, approximately one third of world population is affected by NAFLD. Notably, the presence of NAFLD and particularly its more severe form, nonalcoholic steatohepatitis (NASH), serves as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), thus, raising interest in the relationship between these two diseases. Importantly, ASCVD is the major cause of death in patients with NASH independent of traditional risk factors. Nevertheless, the pathophysiology linking NAFLD/NASH with ASCVD remains poorly understood. While dyslipidemia is a common risk factor underlying both diseases, therapies that lower circulating LDL-cholesterol are largely ineffective against NASH. While there are no approved pharmacological therapies for NASH, some of the most advanced drug candidates exacerbate atherogenic dyslipidemia, raising concerns regarding their adverse cardiovascular consequences. In this review, we address current gaps in our understanding of the mechanisms linking NAFLD/NASH and ASCVD, explore strategies to simultaneously model these diseases, evaluate emerging biomarkers that may be useful to diagnose the presence of both diseases, and discuss investigational approaches and ongoing clinical trials that potentially target both diseases.
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Affiliation(s)
- Alexandra C. Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Sandeep Das
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Dhananjay Kumar
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - M. Peyton McKinney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Bishuang Cai
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, United States
| | - Arif Yurdagul
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
| | - Oren Rom
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Correspondence: Arif Yurdagul Oren Rom
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11
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Natural PPARs agonists for the treatment of nonalcoholic fatty liver disease. Biomed Pharmacother 2022; 151:113127. [PMID: 35598367 DOI: 10.1016/j.biopha.2022.113127] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/12/2022] [Accepted: 05/13/2022] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a general term for a series of liver diseases including simple steatosis, non-alcoholic steatohepatitis, liver fibrosis, which is closely related to metabolic syndrome. The pathogenesis of NAFLD is relatively complex, which has gradually changed from the previous 'two-hit' hypothesis to the current "multiple hits" hypothesis. However, there is currently no approved treatment for NAFLD in clinic, highlighting the urgent need for drug development. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily, whose different subtypes have been proved to regulate different stages of NAFLD, thus becoming promising drug targets for NAFLD. As important sources of drug development, natural products have been proven to treat NAFLD through multiple pathways and multiple targets. In this paper, we outline the regulatory role of PPARs in NAFLD, and summarize some natural products that target PPARs to ameliorate NAFLD, in order to provide reference for drug development of NAFLD.
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12
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de Jong LM, Zhang Z, den Hartog Y, Sijsenaar TJP, Martins Cardoso R, Manson ML, Hankemeier T, Lindenburg PW, Salvatori DCF, Van Eck M, Hoekstra M. PRMT3 inhibitor SGC707 reduces triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. Sci Rep 2022; 12:483. [PMID: 35013582 PMCID: PMC8748717 DOI: 10.1038/s41598-021-04524-w] [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: 11/08/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022] Open
Abstract
Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled.
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Affiliation(s)
- Laura M de Jong
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands
| | - Zhengzheng Zhang
- Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Yvette den Hartog
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands
| | - Timothy J P Sijsenaar
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands
| | - Renata Martins Cardoso
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands
| | - Martijn L Manson
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands
| | - Thomas Hankemeier
- Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands
| | - Peter W Lindenburg
- Analytical Biosciences and Metabolomics, Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.,Research Group Metabolomics, Leiden Center for Applied Bioscience, University of Applied Sciences Leiden, Leiden, The Netherlands
| | - Daniela C F Salvatori
- Central Laboratory Animal Facility, Leiden University Medical Center, Leiden, The Netherlands.,Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Gorlaeus Laboratories, 2333CC, Leiden, The Netherlands.
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13
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Kotlyarov S, Bulgakov A. Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease. Cells 2021; 10:2978. [PMID: 34831201 PMCID: PMC8616072 DOI: 10.3390/cells10112978] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/25/2021] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia;
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14
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Bone Marrow Ts65Dn Trisomy-Induced Changes in Platelet Functionality and Lymphocytopenia Do Not Impact Atherosclerosis Susceptibility in Mice. J Cardiovasc Dev Dis 2021; 8:jcdd8090110. [PMID: 34564128 PMCID: PMC8469845 DOI: 10.3390/jcdd8090110] [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: 07/27/2021] [Revised: 09/10/2021] [Accepted: 09/10/2021] [Indexed: 11/17/2022] Open
Abstract
The genetic disorder Down syndrome is associated with a decreased susceptibility for atherosclerotic cardiovascular disease. Hematological and immune abnormalities occur frequently in Down syndrome patients. We evaluated, in a preclinical setting, the impact of a Down syndrome-like hematological/immune phenotype on atherosclerosis susceptibility. Hereto, hypercholesterolemic low-density lipoprotein receptor knockout mice were transplanted with bone marrow from either a trisomic Ts65Dn mouse or euploid wild-type control and subsequently fed a Western-type diet to induce the development of atherosclerotic lesions. T and B cell concentrations were markedly reduced in blood of Ts65Dn bone marrow recipients (p < 0.001). Expression levels of the pro-atherogenic scavenger receptor CD36 were respectively 37% and 59% lower (p < 0.001) in trisomic monocytes and macrophages. However, these combined effects did not translate into an altered atherosclerosis susceptibility. Notably, blood platelet numbers were elevated in Ts65Dn bone marrow recipients (+57%; p < 0.001), which was paralleled by higher platelet GPVI protein expression (+35%; p < 0.001) and an enhanced collagen-induced platelet activation (p < 0.001). In conclusion, we have shown that providing mice with a Down syndrome-like hematological profile does not change the susceptibility to atherosclerosis. Furthermore, our studies have uncovered a novel effect of the trisomy on platelet functionality that may be relevant in human clinical settings.
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15
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Kumar V, Xin X, Ma J, Tan C, Osna N, Mahato RI. Therapeutic targets, novel drugs, and delivery systems for diabetes associated NAFLD and liver fibrosis. Adv Drug Deliv Rev 2021; 176:113888. [PMID: 34314787 PMCID: PMC8440458 DOI: 10.1016/j.addr.2021.113888] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/12/2021] [Accepted: 07/18/2021] [Indexed: 02/08/2023]
Abstract
Type 2 diabetes mellitus (T2DM) associated non-alcoholic fatty liver disease (NAFLD) is the fourth-leading cause of death. Hyperglycemia induces various complications, including nephropathy, cirrhosis and eventually hepatocellular carcinoma (HCC). There are several etiological factors leading to liver disease development, which involve insulin resistance and oxidative stress. Free fatty acid (FFA) accumulation in the liver exerts oxidative and endoplasmic reticulum (ER) stresses. Hepatocyte injury induces release of inflammatory cytokines from Kupffer cells (KCs), which are responsible for activating hepatic stellate cells (HSCs). In this review, we will discuss various molecular targets for treating chronic liver diseases, including homeostasis of FFA, lipid metabolism, and decrease in hepatocyte apoptosis, role of growth factors, and regulation of epithelial-to-mesenchymal transition (EMT) and HSC activation. This review will also critically assess different strategies to enhance drug delivery to different cell types. Targeting nanocarriers to specific liver cell types have the potential to increase efficacy and suppress off-target effects.
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Affiliation(s)
- Virender Kumar
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Xiaofei Xin
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jingyi Ma
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Natalia Osna
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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16
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Islam SMT, Won J, Khan M, Chavin KD, Singh I. Peroxisomal footprint in the pathogenesis of nonalcoholic steatohepatitis. Ann Hepatol 2021; 19:466-471. [PMID: 31870746 DOI: 10.1016/j.aohep.2019.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 11/08/2019] [Accepted: 11/20/2019] [Indexed: 02/08/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a form of fatty liver disease where benign hepatic steatosis leads to chronic inflammation in the steatotic liver of a patient without any history of alcohol abuse. Mechanisms underlying the progression of hepatic steatosis to NASH have long been investigated. This review outlines the potential role of peroxisomal dysfunctions in exacerbating the disease in NASH. Loss of peroxisomes as well as impaired peroxisomal functions have been demonstrated to occur in inflammatory conditions including NASH. Because peroxisomes and mitochondria co-operatively perform many metabolic functions including O2 and lipid metabolisms, a compromised peroxisomal biogenesis and function can potentially contribute to defective lipid and reactive oxygen species metabolism which in turn can lead the progression of disease in NASH. Impaired peroxisomal biogenesis and function may be due to the decreased expression of peroxisomal proliferator-activated receptor-α (PPAR-α), the major transcription factor of peroxisomal biogenesis. Recent studies indicate that the reduced expression of PPAR-α in NASH is correlated with the activation of the toll-like receptor-4 pathway (TLR-4). Further investigations are required to establish the mechanistic connection between the TLR-4 pathway and PPAR-α-dependent impaired biogenesis/function of peroxisomes in NASH.
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Affiliation(s)
- S M Touhidul Islam
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Jeseong Won
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Mushfiquddin Khan
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Kenneth D Chavin
- Department of Surgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Inderjit Singh
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
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17
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Cariello M, Piccinin E, Moschetta A. Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol 2021; 11:1519-1539. [PMID: 33545430 PMCID: PMC8042405 DOI: 10.1016/j.jcmgh.2021.01.012] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Elena Piccinin
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy; National Institute for Biostructures and Biosystems (INBB), Rome, Italy; Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy.
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18
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Francque S, Szabo G, Abdelmalek MF, Byrne CD, Cusi K, Dufour JF, Roden M, Sacks F, Tacke F. Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors. Nat Rev Gastroenterol Hepatol 2021; 18:24-39. [PMID: 33093663 DOI: 10.1038/s41575-020-00366-5] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2020] [Indexed: 02/06/2023]
Abstract
The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease.
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Affiliation(s)
- Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium. .,Translational Research in Inflammation and Immunology (TWI2N), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Health System, Durham, NC, USA
| | - Christopher D Byrne
- Nutrition & Metabolism, Human Development & Health, Faculty of Medicine, University Hospital Southampton, Southampton, UK
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research, University Hospital of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
| | - Michael Roden
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, University Clinics Düsseldorf, Düsseldorf, Germany.,Institute for Clinical Diabetology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Frank Sacks
- Departments of Nutrition and Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Channing Division, Department of Medicine Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité University Medical Center, Berlin, Germany
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19
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Mammalian ABCG-transporters, sterols and lipids: To bind perchance to transport? Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1866:158860. [PMID: 33309976 DOI: 10.1016/j.bbalip.2020.158860] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/15/2020] [Accepted: 12/08/2020] [Indexed: 02/08/2023]
Abstract
Members of the ATP binding cassette (ABC) transporter family perform a critical function in maintaining lipid homeostasis in cells as well as the transport of drugs. In this review, we provide an update on the ABCG-transporter subfamily member proteins, which include the homodimers ABCG1, ABCG2 and ABCG4 as well as the heterodimeric complex formed between ABCG5 and ABCG8. This review focusses on progress made in this field of research with respect to their function in health and disease and the recognised transporter substrates. We also provide an update on post-translational regulation, including by transporter substrates, and well as the involvement of microRNA as regulators of transporter expression and activity. In addition, we describe progress made in identifying structural elements that have been recognised as important for transport activity. We furthermore discuss the role of lipids such as cholesterol on the transport function of ABCG2, traditionally thought of as a drug transporter, and provide a model of potential cholesterol binding sites for ABCG2.
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20
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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21
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Sven M F, Pierre B, Manal F A, Quentin M A, Elisabetta B, Vlad R, Philippe HM, Bruno S, Jean-Louis J, Pierre B, Jean-Louis A. A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study. Contemp Clin Trials 2020; 98:106170. [PMID: 33038502 DOI: 10.1016/j.cct.2020.106170] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/10/2020] [Accepted: 08/27/2020] [Indexed: 12/17/2022]
Abstract
Background Non-alcoholic steatohepatitis (NASH), a multifactorial disease, can progress to hepatic fibrosis and cirrhosis. The Peroxysomal Proliferator-Activated Receptors, PPARα, β/δ and γ, play a central role in the regulation of glucose and lipid metabolism and of the inflammatory and fibrogenic pathways in liver and in other organs that all contribute to NASH pathogenesis. Lanifibranor (IVA337), a panPPAR agonist, by acting on these three different PPAR isotypes, combines pharmacological effects that could address the different components of the disease as demonstrated in preclinical models. Objectives NATIVE study (EudraCT: 2016-001979-70, NCT: NCT03008070) aims to assess the safety and the efficacy of a 24-week treatment with lanifibranor (800 and 1200 mg/day) in adult non-cirrhotic NASH patients. The primary efficacy endpoint is a 2-point reduction in the activity part of the Steatosis Activity Fibrosis (SAF) histological score (combining inflammation and ballooning) without worsening of fibrosis. Design NATIVE is a Phase 2b randomised, placebo-controlled, double-blind, parallel-assignment, dose-range study. Eligible adult patients with a confirmed histological diagnosis of NASH should have a SAF Activity score of 3 or 4 (>2) and a SAF Steatosis score ≥ 1. There is no specific criterion related to the fibrosis score except that patients with cirrhosis (F4) were excluded. Summary This study will evaluate the efficacy of a 24-week treatment of NASH with lanifibranor based on histological evaluations (SAF score) by biopsy. The number of responders according to the SAF Activity score-based definition from baseline to 24 weeks will be compared between groups and serves as primary endpoint.
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Affiliation(s)
- Francque Sven M
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, 2610 Wilrijk, Belgium; Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
| | - Bedossa Pierre
- Liverpat, 28 rue de l'Amiral Hamelin, 75116 Paris, France.; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, Upon Tyne, UK
| | - Abdelmalek Manal F
- Division of Gastroenterology and Hepatology, Duke University, 40 Duke Medicine Circle, Durham, NC 27710, USA
| | - Anstee Quentin M
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, Upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne, UK; Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Bugianesi Elisabetta
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Torino, A.O. Città della Salute e della Scienza di Torino, Corso Bramante, 88 I-10126 Torino, Italy
| | - Ratziu Vlad
- AP-HP Hopital Pitié-Salpetrière, 47 Boulevard de L'Hôpital, 75013 Paris, France
| | | | - Scherrer Bruno
- Bruno Scherrer Conseil S.A.R.L., 15 rue Beethoven, 78730 Saint Arnoult en Yvelines, France
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22
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Seyfried AN, Maloney JM, MacNamara KC. Macrophages Orchestrate Hematopoietic Programs and Regulate HSC Function During Inflammatory Stress. Front Immunol 2020; 11:1499. [PMID: 32849512 PMCID: PMC7396643 DOI: 10.3389/fimmu.2020.01499] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/08/2020] [Indexed: 12/14/2022] Open
Abstract
The bone marrow contains distinct cell types that work in coordination to generate blood and immune cells, and it is the primary residence of hematopoietic stem cells (HSCs) and more committed multipotent progenitors (MPPs). Even at homeostasis the bone marrow is a dynamic environment where billions of cells are generated daily to replenish short-lived immune cells and produce the blood factors and cells essential for hemostasis and oxygenation. In response to injury or infection, the marrow rapidly adapts to produce specific cell types that are in high demand revealing key insight to the inflammatory nature of "demand-adapted" hematopoiesis. Here we focus on the role that resident and monocyte-derived macrophages play in driving these hematopoietic programs and how macrophages impact HSCs and downstream MPPs. Macrophages are exquisite sensors of inflammation and possess the capacity to adapt to the environment, both promoting and restraining inflammation. Thus, macrophages hold great potential for manipulating hematopoietic output and as potential therapeutic targets in a variety of disease states where macrophage dysfunction contributes to or is necessary for disease. We highlight essential features of bone marrow macrophages and discuss open questions regarding macrophage function, their role in orchestrating demand-adapted hematopoiesis, and mechanisms whereby they regulate HSC function.
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Affiliation(s)
- Allison N Seyfried
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United States
| | - Jackson M Maloney
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United States
| | - Katherine C MacNamara
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United States
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23
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Castaño D, Rattanasopa C, Monteiro-Cardoso VF, Corlianò M, Liu Y, Zhong S, Rusu M, Liehn EA, Singaraja RR. Lipid efflux mechanisms, relation to disease and potential therapeutic aspects. Adv Drug Deliv Rev 2020; 159:54-93. [PMID: 32423566 DOI: 10.1016/j.addr.2020.04.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023]
Abstract
Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms. Since most peripheral cells do not catabolize cholesterol, efflux (extra-cellular transport) of cholesterol is vital for lipid homeostasis. Defective efflux contributes to atherosclerotic plaque development, impaired β-cell insulin secretion, and neuropathology. Of these, defective lipid efflux in macrophages in the arterial walls leading to foam cell and atherosclerotic plaque formation has been the most well studied, likely because a leading global cause of death is cardiovascular disease. Circulating high density lipoprotein particles play critical roles as acceptors of effluxed cellular lipids, suggesting their importance in disease etiology. We review here mechanisms and pathways that modulate lipid efflux, the role of lipid efflux in disease etiology, and therapeutic options aimed at modulating this critical process.
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VLDL/LDL serves as the primary source of cholesterol in the adrenal glucocorticoid response to food deprivation. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158682. [PMID: 32169652 DOI: 10.1016/j.bbalip.2020.158682] [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: 12/20/2019] [Revised: 02/28/2020] [Accepted: 03/07/2020] [Indexed: 11/23/2022]
Abstract
The contribution of individual lipoprotein species to the generation of the adrenal cholesterol pool used for the synthesis of anti-inflammatory glucocorticoid species remains unknown. Here we examined the impact of specific lowering of very low-density lipoprotein (VLDL) and low-density (LDL) levels on adrenal cholesterol and glucocorticoid homeostasis. Hereto, lethally-irradiated hypercholesterolemic apolipoprotein E (APOE) knockout mice received APOE-containing bone marrow from wild-type mice (n = 6) or APOE knockout control bone marrow (n = 10) and were subsequently fed a regular chow diet. Transplantation with wild-type bone marrow was associated with a 10-fold decrease in VLDL/LDL-cholesterol levels. No changes were observed in adrenal weights, adrenal cholesterol content, or basal plasma corticosterone levels. However, food deprivation-induced corticosterone secretion was 64% lower (P < 0.05) in wild-type bone marrow recipients as compared to APOE knockout bone marrow recipients, in the context of similar plasma adrenocorticotropic hormone (ACTH) levels. A parallel 19-29% decrease in adrenal relative mRNA expression levels of ACTH-responsive genes SR-BI (P < 0.01), STAR (P < 0.05), and CYP11A1 (P < 0.05) was detected. In support of relative glucocorticoid insufficiency, blood lymphocyte and eosinophil concentrations were respectively 2.4-fold (P < 0.01) and 8-fold (P < 0.001) higher in wild-type bone marrow recipients under food deprivation stress conditions. In conclusion, we have shown that a selective lowering of VLDL/LDL levels in APOE knockout mice through a transplantation with APOE-containing wild-type bone marrow is associated with a decreased maximal adrenal glucocorticoid output. Our studies provide experimental support for the hypothesis that, in vivo, VLDL/LDL serves as the primary source of cholesterol used for glucocorticoid synthesis during food deprivation stress.
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Hoekstra M, van der Sluis RJ, Hildebrand RB, Lammers B, Zhao Y, Praticò D, van Berkel TJC, Rensen PCN, Kooijman S, Jauhiainen M, van Eck M. Disruption of Phospholipid Transfer Protein-Mediated High-Density Lipoprotein Maturation Reduces Scavenger Receptor BI Deficiency-Driven Atherosclerosis Susceptibility Despite Unexpected Metabolic Complications. Arterioscler Thromb Vasc Biol 2020; 40:611-623. [PMID: 31941380 DOI: 10.1161/atvbaha.119.313862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was-however-only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet-fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [14C]cholesteryl oleate after intravenous VLDL-like particle injection. CONCLUSIONS We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.
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Affiliation(s)
- Menno Hoekstra
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Ronald J van der Sluis
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Reeni B Hildebrand
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Bart Lammers
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Ying Zhao
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | - Domenico Praticò
- Alzheimer's Center at Temple, Department of Pharmacology, Philadelphia, PA (D.P.)
| | - Theo J C van Berkel
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
| | | | - Sander Kooijman
- Division of Endocrinology, Department of Medicine (P.C.N.R., S.K.)
| | - Matti Jauhiainen
- Einthoven Laboratory for Experimental Vascular and Regenerative Medicine, Leiden University Medical Center, The Netherlands (P.C.N.R., S.K)
| | - Miranda van Eck
- From the Division of BioTherapeutics, Leiden Academic Centre for Drug Research, The Netherlands (M.H., R.J.v.d.S., R.B.H., B.L., Y.Z., T.J.C.v.B., M.v.E.)
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26
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d'Angelo M, Castelli V, Tupone MG, Catanesi M, Antonosante A, Dominguez-Benot R, Ippoliti R, Cimini AM, Benedetti E. Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs. Int J Mol Sci 2019; 20:ijms20215422. [PMID: 31683535 PMCID: PMC6862628 DOI: 10.3390/ijms20215422] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease.
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Affiliation(s)
- Michele d'Angelo
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Maria Grazia Tupone
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Mariano Catanesi
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Andrea Antonosante
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Reyes Dominguez-Benot
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Rodolfo Ippoliti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
| | - Anna Maria Cimini
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
- Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, PA 19122, USA.
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
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Chen J, Zhuang Y, Sng MK, Tan NS, Wahli W. The Potential of the FSP1cre- Pparb/d-/- Mouse Model for Studying Juvenile NAFLD. Int J Mol Sci 2019; 20:ijms20205115. [PMID: 31618976 PMCID: PMC6830345 DOI: 10.3390/ijms20205115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 10/14/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) can progress from steatosis to non-alcoholic steatohepatitis (NASH) characterized by liver inflammation, possibly leading to cirrhosis and hepatocellular carcinoma (HCC). Mice with impaired macrophage activation, when fed a high-fat diet, develop severe NASH. Evidence is mounting that Kupffer cells are implicated. However, it is unknown whether the resident CD68+ or bone marrow-derived CD11b+ Kupffer cells are involved. Characterization of the FSP1cre-Pparb/d-/- mouse liver revealed that FSP1 is expressed in CD11b+ Kupffer cells. Although these cells only constitute a minute fraction of the liver cell population, Pparb/d deletion in these cells led to remarkable hepatic phenotypic changes. We report that a higher lipid content was present in postnatal day 2 (P2) FSP1cre-Pparb/d-/- livers, which diminished after weaning. Quantification of total lipids and triglycerides revealed that P2 and week 4 of age FSP1cre-Pparb/d-/- livers have higher levels of both. qPCR analysis also showed upregulation of genes involved in fatty acid β-oxidation, and fatty acid and triglyceride synthesis pathways. This result is further supported by western blot analysis of proteins in these pathways. Hence, we propose that FSP1cre-Pparb/d-/- mice, which accumulate lipids in their liver in early life, may represent a useful animal model to study juvenile NAFLD.
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Affiliation(s)
- Jiapeng Chen
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Yan Zhuang
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
| | - Ming Keat Sng
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (J.C.); (Y.Z.); (M.K.S.); (N.S.T.)
- INRA UMR1331, ToxAlim, 180 Chemin de Tournefeuille, 31300 Toulouse, France
- Center for Integrative Genomics, University of Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
- Correspondence: ; Tel.: +65-6904-7012
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28
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Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism. Molecules 2019; 24:molecules24142545. [PMID: 31336903 PMCID: PMC6680900 DOI: 10.3390/molecules24142545] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/08/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
It has been more than 36 years since peroxisome proliferator-activated receptors (PPARs) were first recognized as enhancers of peroxisome proliferation. Consequently, many studies in different fields have illustrated that PPARs are nuclear receptors that participate in nutrient and energy metabolism and regulate cellular and whole-body energy homeostasis during lipid and carbohydrate metabolism, cell growth, cancer development, and so on. With increasing challenges to human health, PPARs have attracted much attention for their ability to ameliorate metabolic syndromes. In our previous studies, we found that the complex functions of PPARs may be used as future targets in obesity and atherosclerosis treatments. Here, we review three types of PPARs that play overlapping but distinct roles in nutrient and energy metabolism during different metabolic states and in different organs. Furthermore, research has emerged showing that PPARs also play many other roles in inflammation, central nervous system-related diseases, and cancer. Increasingly, drug development has been based on the use of several selective PPARs as modulators to diminish the adverse effects of the PPAR agonists previously used in clinical practice. In conclusion, the complex roles of PPARs in metabolic networks keep these factors in the forefront of research because it is hoped that they will have potential therapeutic effects in future applications.
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Affiliation(s)
- Fan Hong
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Shijia Pan
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yuan Guo
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Pengfei Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Yonggong Zhai
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
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29
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Ghanem CI, Manautou JE. Modulation of Hepatic MRP3/ABCC3 by Xenobiotics and Pathophysiological Conditions: Role in Drug Pharmacokinetics. Curr Med Chem 2019; 26:1185-1223. [PMID: 29473496 DOI: 10.2174/0929867325666180221142315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 01/17/2018] [Accepted: 02/05/2018] [Indexed: 12/13/2022]
Abstract
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistanceassociated proteins (MRPs). The MRP-related proteins can collectively confer resistance to natural, synthetic drugs and their conjugated metabolites, including platinum-containing compounds, folate anti-metabolites, nucleoside and nucleotide analogs, among others. MRPs can be also catalogued into "long" (MRP1/ABCC1, -2/C2, -3/C3, -6/C6, and -7/C10) and "short" (MRP4/C4, -5/C5, -8/C11, -9/C12, and -10/C13) categories. While MRP2/ABCC2 is expressed in the canalicular pole of hepatocytes, all others are located in the basolateral membrane. In this review, we summarize information from studies examining the changes in expression and regulation of the basolateral hepatic transporter MPR3/ABCC3 by xenobiotics and during various pathophysiological conditions. We also focus, primarily, on the consequences of such changes in the pharmacokinetic, pharmacodynamic and/or toxicity of different drugs of clinical use transported by MRP3.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacologicas (ININFA), Facultad de Farmacia y Bioquimica. CONICET. Universidad de Buenos Aires, Buenos Aires, Argentina.,Catedra de Fisiopatologia. Facultad de Farmacia y Bioquimica. Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jose E Manautou
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States
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30
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van der Sluis RJ, Depuydt MAC, Verwilligen RAF, Hoekstra M, Van Eck M. Elimination of adrenocortical apolipoprotein E production does not impact glucocorticoid output in wild-type mice. Mol Cell Endocrinol 2019; 490:21-27. [PMID: 30953750 DOI: 10.1016/j.mce.2019.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 01/07/2019] [Accepted: 04/02/2019] [Indexed: 12/26/2022]
Abstract
Apolipoprotein E (APOE) deficient mice exhibit unexplained hypercorticosteronemia. Given that APOE is also produced locally within the adrenals, we evaluated the effect of adrenal-specific APOE deficiency on the glucocorticoid function. Hereto, one adrenal containing or lacking APOE was transplanted into adrenalectomized wild-type mice. Adrenal APOE deficiency did not impact adrenal total cholesterol levels. Importantly, the ability of the two adrenal types to produce glucocorticoids was also not different as judged from the similar plasma corticosterone levels. Adrenal mRNA expression levels of HMG-CoA reductase and the LDL receptor were decreased by respectively 72% (p < 0.01) and 65% (p = 0.07), suggesting that cholesterol acquisition pathways were inhibited to possibly compensate the lack of APOE. In support, a parallel increase in the expression level of the cholesterol accumulation-associated ER stress marker CHOP was detected (+117%; p < 0.05). In conclusion, our studies show that elimination of adrenocortical APOE production does not impact glucocorticoid output in wild-type mice.
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Affiliation(s)
- Ronald J van der Sluis
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, 2333CC, Leiden, the Netherlands.
| | - Marie A C Depuydt
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, 2333CC, Leiden, the Netherlands
| | - Robin A F Verwilligen
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, 2333CC, Leiden, the Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, 2333CC, Leiden, the Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, 2333CC, Leiden, the Netherlands
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31
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Endocannabinoid System in Hepatic Glucose Metabolism, Fatty Liver Disease, and Cirrhosis. Int J Mol Sci 2019; 20:ijms20102516. [PMID: 31121839 PMCID: PMC6566399 DOI: 10.3390/ijms20102516] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/18/2019] [Accepted: 05/19/2019] [Indexed: 12/18/2022] Open
Abstract
There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1 promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.
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Sahebi R, Hassanian SM, Ghayour‐Mobarhan M, Farrokhi E, Rezayi M, Samadi S, Bahramian S, Ferns GA, Avan A. Scavenger receptor Class B type I as a potential risk stratification biomarker and therapeutic target in cardiovascular disease. J Cell Physiol 2019; 234:16925-16932. [DOI: 10.1002/jcp.28393] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Reza Sahebi
- Department of Modern Sciences and Technologies, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
- Department of Molecular Medicine, School of Advanced Technologies Shahrekord University of Medical Sciences Shahrekord Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Majid Ghayour‐Mobarhan
- Department of Modern Sciences and Technologies, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Effat Farrokhi
- Department of Molecular Medicine, School of Advanced Technologies Shahrekord University of Medical Sciences Shahrekord Iran
| | - Majid Rezayi
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Sara Samadi
- Department of Modern Sciences and Technologies, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
| | - Shabbou Bahramian
- Stem Cell Research Center Golestan University of Medical Sciences Gorgan Iran
| | - Gordon A. Ferns
- Division of Medical Education Brighton & Sussex Medical School, Falmer Brighton Sussex
| | - Amir Avan
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
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Hoekstra M, Nahon JE, de Jong LM, Kröner MJ, de Leeuw LR, Van Eck M. Inhibition of PRMT3 activity reduces hepatic steatosis without altering atherosclerosis susceptibility in apoE knockout mice. Biochim Biophys Acta Mol Basis Dis 2019; 1865:1402-1409. [PMID: 30776415 DOI: 10.1016/j.bbadis.2019.02.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 02/07/2019] [Accepted: 02/12/2019] [Indexed: 12/22/2022]
Abstract
The nuclear receptor liver X receptor (LXR) impacts on cholesterol metabolism as well as hepatic lipogenesis via transcriptional regulation. It is proposed that inhibition of the protein arginine methyltransferase 3 (PRMT3) uncouples these two transcriptional pathways in vivo by acting as a specific lipogenic coactivator of LXR. Here we validated the hypothesis that treatment with the allosteric PRMT3 inhibitor SGC707 will diminish the hepatic steatosis extent, while leaving global cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. For this purpose, 12-week old hyperlipidemic apolipoprotein E knockout mice were fed a Western-type diet for six weeks to induce both hepatic steatosis and atherosclerosis. The mice received 3 intraperitoneal injections with SGC707 or solvent control per week. Mice chronically treated with SGC707 developed less severe hepatic steatosis as exemplified by the 51% reduced (P < 0.05) liver triglyceride levels. In contrast, the extent of in vivo macrophage foam cell formation and aortic root atherosclerosis was not affected by SGC707 treatment. Interestingly, SGC707-treated mice gained 94% less body weight (P < 0.05), which was paralleled by changes in white adipose tissue morphology, i.e. reduction in adipocyte size and browning. In conclusion, we have shown that through PRMT3 inhibitor treatment specific functions of LXR involved in respectively the development of fatty liver disease and atherosclerosis can be uncoupled, resulting in an overall diminished hepatic steatosis extent without a negative impact on atherosclerosis susceptibility. As such, our studies highlight that PRMT3 inhibition may constitute a novel therapeutic approach to limit the development of fatty liver disease in humans.
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Affiliation(s)
- Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands..
| | - Joya E Nahon
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Laura M de Jong
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Mara J Kröner
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Lidewij R de Leeuw
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, the Netherlands
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Ishikawa H, Guo X, Sugawara S, Iwagaki Y, Yamamoto K, Konno A, Nishiuchi M, Tsuduki T. Influence of Japanese diet consumption during pregnancy and lactation on lipid metabolism in offspring. Nutrition 2019; 58:69-76. [DOI: 10.1016/j.nut.2018.06.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 05/26/2018] [Accepted: 06/10/2018] [Indexed: 01/26/2023]
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35
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Proteoglycan 4 deficiency protects against glucose intolerance and fatty liver disease in diet-induced obese mice. Biochim Biophys Acta Mol Basis Dis 2019; 1865:494-501. [DOI: 10.1016/j.bbadis.2018.11.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 11/09/2018] [Accepted: 11/13/2018] [Indexed: 02/06/2023]
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36
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Wang F, Ye X, Wu Y, Wang H, Sheng C, Peng D, Chen W. Time Interval of Two Injections and First-Dose Dependent of Accelerated Blood Clearance Phenomenon Induced by PEGylated Liposomal Gambogenic Acid: The Contribution of PEG-Specific IgM. J Pharm Sci 2018; 108:641-651. [PMID: 30595169 DOI: 10.1016/j.xphs.2018.10.027] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/04/2018] [Accepted: 10/16/2018] [Indexed: 01/11/2023]
Abstract
Repeated injection of PEGylated liposomes can cause the disappearance of long circulating property because of the induction of anti-PEG IgM antibody referred to as "accelerated blood clearance (ABC) phenomenon." Although ABC phenomenon typically occurs when entrapped drugs are chemotherapeutic agent with low cytotoxic, there is little evidence of accelerated blood clearance of PEGylated herbal-derived compound on repeated injection. Herein, we investigated the blood concentration of PEGylated liposomal gambogenic acid (PEG-GEA-L), a model PEGylated liposomal herbal extract, on its repeated injection to rats. We found time interval between injections had considerable impact on the magnitude of ABC phenomenon induced by PEG-GEA-L. When time interval was prolonged from 3 days to 7 days, ABC phenomenon could be attenuated. Furthermore, its magnitude was enhanced accompanied by a marked rise in the accumulation of PEG-GEA-L in the liver and spleen in a first-dose-dependent manner. Consistently, the level of anti-PEG IgM significantly increased with the first dose of PEG-GEA-L and decreased with the extended time interval between injections, which implies anti-PEG IgM is a major contributor to the ABC phenomenon. Notably, the increased expression of liver anti-PEG IgM was accompanied by an increased expression of efflux transporters in the induction process of the ABC phenomenon.
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Affiliation(s)
- Fengling Wang
- Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China; Department of Pharmacy, The Second People's Hospital of Hefei, Hefei 230011, Anhui, China
| | - Xi Ye
- Department of Pharmacy, The Second People's Hospital of Hefei, Hefei 230011, Anhui, China
| | - Yifan Wu
- Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China
| | - Huihui Wang
- Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China
| | - Chengming Sheng
- Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China
| | - Daiyin Peng
- Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China.
| | - Weidong Chen
- Institute of Drug Metabolism, School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, Anhui, China.
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van der Sluis RJ, Verwilligen RAF, Lendvai Z, Wever R, Hoekstra M, Van Eck M. HDL is essential for atherosclerotic lesion regression in Apoe knockout mice by bone marrow Apoe reconstitution. Atherosclerosis 2018; 278:240-249. [PMID: 30340108 DOI: 10.1016/j.atherosclerosis.2018.09.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 09/05/2018] [Accepted: 09/26/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND AND AIMS Although studies in mice have suggested that lesion regression is feasible, the underlying mechanisms remain largely unknown. Here we determined the impact of high-density lipoprotein (HDL) on atherosclerosis regression outcome. METHODS Atherosclerotic lesion dynamics were studied upon bone marrow transplantation-mediated re-introduction of apolipoprotein E (Apoe) in Apoe knockout mice. Probucol was used to pharmacologically deplete HDL. RESULTS Restoration of Apoe function was associated with an initial growth of atherosclerotic lesions and parallel decrease in lesional macrophage foam cell content (47 ± 4% at 4 weeks versus 72 ± 2% at baseline: p < 0.001), despite the fact that cholesterol levels were markedly reduced. Notably, significant lesion regression was detected from 4 weeks onwards, when plasma cholesterol levels had returned to the normolipidemic range. As a result, lesions were 41% smaller (p < 0.05) at 8 weeks than at 4 weeks after bone marrow transplantation. Regressed lesions contained an even lower level of macrophage foam cells (33 ± 5%: p < 0.001) and were rich in collagen. Probucol co-treatment was associated with a 3.2-fold lower (p < 0.05) plasma HDL-cholesterol level and a more pro-inflammatory (CCR2+) monocyte phenotype. Importantly, probucol-treated mice exhibited atherosclerotic lesions that were larger than those of regular chow diet-fed bone marrow transplanted mice at 8 weeks (186 ± 15*103 μm2 for probucol-treated versus 120 ± 19*103 μm2 for controls: p < 0.05). CONCLUSIONS We have shown that probucol-induced HDL deficiency impairs the ability of established lesions to regress in response to reversal of the genetic hypercholesterolemia in Apoe knockout mice. Our studies thus highlight a crucial role for HDL in the process of atherosclerosis regression.
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Affiliation(s)
- Ronald J van der Sluis
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, the Netherlands.
| | - Robin A F Verwilligen
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, the Netherlands
| | - Zsuzsanna Lendvai
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, the Netherlands
| | - Robbert Wever
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, the Netherlands
| | - Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, the Netherlands
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, the Netherlands
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38
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Rahmati-Ahmadabad S, Shirvani H, Ghanbari-Niaki A, Rostamkhani F. The effects of high-intensity interval training on reverse cholesterol transport elements: A way of cardiovascular protection against atherosclerosis. Life Sci 2018; 209:377-382. [PMID: 30125578 DOI: 10.1016/j.lfs.2018.08.036] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 08/11/2018] [Accepted: 08/16/2018] [Indexed: 12/11/2022]
Abstract
AIMS Reverse cholesterol transport (RCT) is a process that prevents atherosclerosis. Studies showed that exercise training for strengthening cardiac muscle, increasing heart lipid metabolism and its potency against risk factors could protect cardiovascular health. Thus, the present study aims to investigate the effects of high intensity interval training (HIIT) on RCT and its related elements in plasma and tissues (liver and intestine) of rats. MATERIALS AND METHODS Twenty adult male Wistar rats were randomly divided into control (n = 10) and trained (n = 10) groups. The trained group undertook HIIT (90%-95% of VO2max, five days/week, for 10 weeks) on a treadmill. The rats were killed five days after the last training session to minimize the effects of the last training session. KEY FINDINGS A higher and significant ABCA1 mRNA was observed in the liver and intestine of trained rats. However, ABCG1 and LXR expressions only increased in the liver following the HIIT. These changes in the expression of the trained rats were accompanied by higher changes in plasma LCAT and HDL levels. SIGNIFICANCE The responses of ABCA1, as a key player in plasma HDL biogenesis, are similar in liver and intestine tissues after the HIIT program. However, different responses of ABCG1 and LXR in the liver and intestine tissues of the trained rats confirm the main role of the liver than the intestine in HDL biogenes. Therefore, HIIT modality result in cardiovascular protection by increasing the expression of genes involved in RCT and biogenesis of HDL.
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Affiliation(s)
| | - Hossein Shirvani
- Exercise Physiology Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Abbass Ghanbari-Niaki
- Exercise Biochemistry Division, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Mazandaran, Iran
| | - Fatemeh Rostamkhani
- Department of Biology, College of Basic Sciences, Yadegar-e-Imam Khomeini (RAH) Shahre Rey Branch, Islamic Azad University, Tehran, Iran
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39
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Chen J, Montagner A, Tan NS, Wahli W. Insights into the Role of PPARβ/δ in NAFLD. Int J Mol Sci 2018; 19:ijms19071893. [PMID: 29954129 PMCID: PMC6073272 DOI: 10.3390/ijms19071893] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/13/2018] [Accepted: 06/23/2018] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue in developed countries. Although usually associated with obesity, NAFLD is also diagnosed in individuals with low body mass index (BMI) values, especially in Asia. NAFLD can progress from steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by liver damage and inflammation, leading to cirrhosis and hepatocellular carcinoma (HCC). NAFLD development can be induced by lipid metabolism alterations; imbalances of pro- and anti-inflammatory molecules; and changes in various other factors, such as gut nutrient-derived signals and adipokines. Obesity-related metabolic disorders may be improved by activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)β/δ, which is involved in metabolic processes and other functions. This review is focused on research findings related to PPARβ/δ-mediated regulation of hepatic lipid and glucose metabolism and NAFLD development. It also discusses the potential use of pharmacological PPARβ/δ activation for NAFLD treatment.
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Affiliation(s)
- Jiapeng Chen
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
| | - Alexandra Montagner
- ToxAlim, Research Center in Food Toxicology, National Institute for Agricultural Research (INRA), 180 Chemin de Tournefeuille, 31300 Toulouse, France.
- Institut National de La Santé et de La Recherche Médicale (INSERM), UMR1048, Institute of Metabolic and Cardiovascular Diseases, 31027 Toulouse, France.
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
- KK Research Centre, KK Women's and Children Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
- Institute of Molecular and Cell Biology, Agency for Science Technology & Research, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
- ToxAlim, Research Center in Food Toxicology, National Institute for Agricultural Research (INRA), 180 Chemin de Tournefeuille, 31300 Toulouse, France.
- Center for Integrative Genomics, University of Lausanne, Génopode, CH-1015 Lausanne, Switzerland.
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40
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Franko J, McCall JL, Barnett JB. Evaluating Macrophages in Immunotoxicity Testing. Methods Mol Biol 2018; 1803:255-296. [PMID: 29882145 DOI: 10.1007/978-1-4939-8549-4_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
Macrophages are a heterogeneous group of cells that have a multitude of functions depending on their differentiation state. While classically known for their phagocytic and antigen presentation abilities, it is now evident that these cells fulfill homeostatic functions beyond the elimination of invading pathogens. In addition, macrophages have also been implicated in the downregulation of inflammatory responses following pathogen removal, tissue remodeling, repair, and angiogenesis. Alterations in macrophage differentiation and/or activity due to xenobiotic exposure can have grave consequences on organismal homeostasis, potentially contributing to disease due to immunosuppression or chronic inflammatory responses, depending upon the pathways affected. In this chapter, we provide an overview of the macrophages subtypes, their origin and a general discussion of several different assays used to assess their functional status.
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Affiliation(s)
- Jennifer Franko
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Jamie L McCall
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, USA
| | - John B Barnett
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, USA.
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41
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van der Tuin SJL, Li Z, Berbée JFP, Verkouter I, Ringnalda LE, Neele AE, van Klinken JB, Rensen SS, Fu J, de Winther MPJ, Groen AK, Rensen PCN, Willems van Dijk K, Wang Y. Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80 +Clec4f +Vsig4 +Ly6C - Kupffer Cell Subsets. J Am Heart Assoc 2018. [PMID: 29525783 PMCID: PMC5907564 DOI: 10.1161/jaha.117.008105] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. METHODS AND RESULTS In CETP-transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C-type lectin domain family 4, member f (Clec4f) and V-set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high-density lipoprotein-cholesterol over non-high-density lipoprotein-cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double-immunofluorescence staining showed that CETP co-localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene-expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor-mediated CETP expression. CONCLUSIONS Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C-). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high-density lipoprotein (HDL)-cholesterol. This sequence of events is consistent with the anti-inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections.
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Affiliation(s)
- Sam J L van der Tuin
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Zhuang Li
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jimmy F P Berbée
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Inge Verkouter
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Linda E Ringnalda
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Annette E Neele
- Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
| | - Jan B van Klinken
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Sander S Rensen
- Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jingyuan Fu
- Department of Pediatrics, University of Groningen, The Netherlands.,Department of Genetics, University Medical Center Groningen University of Groningen, The Netherlands
| | - Menno P J de Winther
- Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University, Munich, Germany
| | - Albert K Groen
- Amsterdam Diabetes Center, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.,Department of Pediatrics, University of Groningen, The Netherlands
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Ko Willems van Dijk
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Yanan Wang
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands .,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.,Department of Pediatrics, University of Groningen, The Netherlands
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42
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Ishikawa H, Guo X, Sugawara S, Iwagaki Y, Yamamoto K, Tsuduki T. Effect of the Japanese diet during pregnancy and lactation or post-weaning on the risk of metabolic syndrome in offspring. Biosci Biotechnol Biochem 2018; 82:515-524. [DOI: 10.1080/09168451.2018.1428788] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Abstract
We examined the effects on offspring of ingestion of the 1975 Japanese diet during pregnancy and lactation and after weaning in mice. Pregnant dams were divided into groups that were fed the Japanese diet or a control diet and raised until offspring were weaned. The offspring after weaning were further divided into groups that were raised on the Japanese diet or the control diet. Ingestion of the Japanese diet after weaning suppressed accumulation of visceral fat in offspring, and reduced the amount of lipids in serum and liver. This effect was weakened if the Japanese diet was only ingested during pregnancy and lactation. Therefore, it was suggested that ingestion of the Japanese diet of mothers during pregnancy and lactation weakens the lipid accumulation inhibitory effect of the Japanese diet in children.
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Affiliation(s)
- Haruna Ishikawa
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, Sendai, Japan
| | - Xiaoxu Guo
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, Sendai, Japan
| | - Saeko Sugawara
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, Sendai, Japan
| | - Yui Iwagaki
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, Sendai, Japan
| | - Kazushi Yamamoto
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, Sendai, Japan
| | - Tsuyoshi Tsuduki
- Laboratory of Food and Biomolecular Science, Graduate School of Agriculture, Tohoku University, Sendai, Japan
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43
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Critical Role of the Human ATP-Binding Cassette G1 Transporter in Cardiometabolic Diseases. Int J Mol Sci 2017; 18:ijms18091892. [PMID: 28869506 PMCID: PMC5618541 DOI: 10.3390/ijms18091892] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 08/30/2017] [Accepted: 08/30/2017] [Indexed: 12/15/2022] Open
Abstract
ATP-binding cassette G1 (ABCG1) is a member of the large family of ABC transporters which are involved in the active transport of many amphiphilic and lipophilic molecules including lipids, drugs or endogenous metabolites. It is now well established that ABCG1 promotes the export of lipids, including cholesterol, phospholipids, sphingomyelin and oxysterols, and plays a key role in the maintenance of tissue lipid homeostasis. Although ABCG1 was initially proposed to mediate cholesterol efflux from macrophages and then to protect against atherosclerosis and cardiovascular diseases (CVD), it becomes now clear that ABCG1 exerts a larger spectrum of actions which are of major importance in cardiometabolic diseases (CMD). Beyond a role in cellular lipid homeostasis, ABCG1 equally participates to glucose and lipid metabolism by controlling the secretion and activity of insulin and lipoprotein lipase. Moreover, there is now a growing body of evidence suggesting that modulation of ABCG1 expression might contribute to the development of diabetes and obesity, which are major risk factors of CVD. In order to provide the current understanding of the action of ABCG1 in CMD, we here reviewed major findings obtained from studies in mice together with data from the genetic and epigenetic analysis of ABCG1 in the context of CMD.
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44
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Ouweneel AB, van der Sluis RJ, Nahon JE, Van Eck M, Hoekstra M. Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice. Atherosclerosis 2017; 261:99-104. [DOI: 10.1016/j.atherosclerosis.2017.02.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 01/30/2017] [Accepted: 02/17/2017] [Indexed: 11/26/2022]
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45
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Hoekstra M. SR-BI as target in atherosclerosis and cardiovascular disease - A comprehensive appraisal of the cellular functions of SR-BI in physiology and disease. Atherosclerosis 2017; 258:153-161. [DOI: 10.1016/j.atherosclerosis.2017.01.034] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 01/25/2017] [Accepted: 01/27/2017] [Indexed: 12/12/2022]
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46
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Mass E, Ballesteros I, Farlik M, Halbritter F, Günther P, Crozet L, Jacome-Galarza CE, Händler K, Klughammer J, Kobayashi Y, Gomez-Perdiguero E, Schultze JL, Beyer M, Bock C, Geissmann F. Specification of tissue-resident macrophages during organogenesis. Science 2016; 353:aaf4238. [PMID: 27492475 PMCID: PMC5066309 DOI: 10.1126/science.aaf4238] [Citation(s) in RCA: 597] [Impact Index Per Article: 66.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 07/20/2016] [Indexed: 12/28/2022]
Abstract
Tissue-resident macrophages support embryonic development and tissue homeostasis and repair. The mechanisms that control their differentiation remain unclear. We report here that erythro-myeloid progenitors in mice generate premacrophages (pMacs) that simultaneously colonize the whole embryo from embryonic day 9.5 in a chemokine-receptor-dependent manner. The core macrophage program initiated in pMacs is rapidly diversified as expression of transcriptional regulators becomes tissue-specific in early macrophages. This process appears essential for macrophage specification and maintenance, as inactivation of Id3 impairs the development of liver macrophages and results in selective Kupffer cell deficiency in adults. We propose that macrophage differentiation is an integral part of organogenesis, as colonization of organ anlagen by pMacs is followed by their specification into tissue macrophages, hereby generating the macrophage diversity observed in postnatal tissues.
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Affiliation(s)
- Elvira Mass
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ivan Ballesteros
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Matthias Farlik
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Florian Halbritter
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Patrick Günther
- Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Lucile Crozet
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
| | | | - Kristian Händler
- Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
| | - Johanna Klughammer
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Yasuhiro Kobayashi
- Institute for Oral Science, Matsumoto Dental University, 1780 Hiro-Oka Gobara Shiojiri, Nagano, 390-0781 Japan
| | - Elisa Gomez-Perdiguero
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK
| | - Joachim L. Schultze
- Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany
| | - Marc Beyer
- Genomics & Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
- Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
- Max Planck Institute for Informatics, 66123 Saarbrücken, Germany
| | - Frederic Geissmann
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK
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47
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Quercetin regulates hepatic cholesterol metabolism by promoting cholesterol-to-bile acid conversion and cholesterol efflux in rats. Nutr Res 2016; 36:271-9. [DOI: 10.1016/j.nutres.2015.11.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 11/02/2015] [Accepted: 11/04/2015] [Indexed: 01/11/2023]
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48
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Hoekstra M, Van Eck M. HDL is redundant for adrenal steroidogenesis in LDLR knockout mice with a human-like lipoprotein profile. J Lipid Res 2016; 57:631-7. [PMID: 26891738 DOI: 10.1194/jlr.m066019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Indexed: 11/20/2022] Open
Abstract
The contribution of HDL to adrenal steroidogenesis appears to be different between mice and humans. In the current study, we tested the hypothesis that a difference in lipoprotein profile may be the underlying cause. Hereto, we determined the impact of HDL deficiency on the adrenal glucocorticoid output in genetically modified mice with a human-like lipoprotein profile. Genetic deletion of APOA1 in LDL receptor (LDLR) knockout mice was associated with HDL deficiency and a parallel increase in the level of cholesterol associated with nonHDL fractions. Despite a compensatory increase in the adrenal relative mRNA expression levels of the cholesterol synthesis gene, HMG-CoA reductase, adrenals from APOA1/LDLR double knockout mice were severely depleted of neutral lipids, as compared with those of control LDLR knockout mice. However, basal corticosterone levels and the adrenal glucocorticoid response to stress were not different between the two types of mice. In conclusion, we have shown that HDL is not critical for proper adrenal glucocorticoid function when mice are provided with a human-like lipoprotein profile. Our findings provide the first experimental evidence that APOB-containing lipoproteins may facilitate adrenal steroidogenesis, in an LDLR-independent manner, in vivo in mice.
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Affiliation(s)
- Menno Hoekstra
- Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, 2333CC Leiden, The Netherlands
| | - Miranda Van Eck
- Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, 2333CC Leiden, The Netherlands
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Scavenger receptor B1, the HDL receptor, is expressed abundantly in liver sinusoidal endothelial cells. Sci Rep 2016; 6:20646. [PMID: 26865459 PMCID: PMC4749959 DOI: 10.1038/srep20646] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 01/07/2016] [Indexed: 02/08/2023] Open
Abstract
Cholesterol from peripheral tissue, carried by HDL, is metabolized in the liver after uptake by the HDL receptor, SR-B1. Hepatocytes have long been considered the only liver cells expressing SR-B1; however, in this study we describe two disparate immunofluorescence (IF) experiments that suggest otherwise. Using high-resolution confocal microscopy employing ultrathin (120 nm) sections of mouse liver, improving z-axis resolution, we identified the liver sinusoidal endothelial cells (LSEC), marked by FcγRIIb, as the cell within the liver expressing abundant SR-B1. In contrast, the hepatocyte, identified with β-catenin, expressed considerably weaker levels, although optical resolution of SR-B1 was inadequate. Thus, we moved to a different IF strategy, first separating dissociated liver cells by gradient centrifugation into two portions, hepatocytes (parenchymal cells) and LSEC (non-parenchymal cells). Characterizing both portions for the cellular expression of SR-B1 by flow cytometry, we found that LSEC expressed considerable amounts of SR-B1 while in hepatocytes SR-B1 expression was barely perceptible. Assessing mRNA of SR-B1 by real time PCR we found messenger expression in LSEC to be about 5 times higher than in hepatocytes.
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van der Sluis RJ, Van Eck M, Hoekstra M. Adrenocortical LDL receptor function negatively influences glucocorticoid output. J Endocrinol 2015; 226:145-54. [PMID: 26136384 DOI: 10.1530/joe-15-0023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/01/2015] [Indexed: 12/17/2022]
Abstract
Over 50% of the cholesterol needed by adrenocortical cells for the production of glucocorticoids is derived from lipoproteins. However, the overall contribution of the different lipoproteins and associated uptake pathways to steroidogenesis remains to be determined. Here we aimed to show the importance of LDL receptor (LDLR)-mediated cholesterol acquisition for adrenal steroidogenesis in vivo. Female total body LDLR knockout mice with a human-like lipoprotein profile were bilaterally adrenalectomized and subsequently provided with one adrenal either expressing or genetically lacking the LDLR under their renal capsule to solely modulate adrenocortical LDLR function. Plasma total cholesterol levels and basal plasma corticosterone levels were identical in the two types of adrenal transplanted mice. Strikingly, restoration of adrenal LDLR function significantly reduced the ACTH-mediated stimulation of adrenal steroidogenesis (P<0.001), with plasma corticosterone levels that were respectively 44-59% lower (P<0.01) as compared to adrenal LDLR negative controls. In addition, LDLR positive adrenal transplanted mice exhibited a significant decrease (-39%; P<0.001) in their plasma corticosterone level under fasting stress conditions. Biochemical analysis did not show changes in the expression of genes involved in cholesterol mobilization. However, LDLR expressing adrenal transplants displayed a marked 62% reduction (P<0.05) in the transcript level of the key steroidogenic enzyme HSD3B2. In conclusion, our studies in a mouse model with a human-like lipoprotein profile provide the first in vivo evidence for a novel inhibitory role of the LDLR in the control of adrenal glucocorticoid production.
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Affiliation(s)
- Ronald J van der Sluis
- Division of BiopharmaceuticsCluster BioTherapeutics, Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 CC Leiden, The Netherlands
| | - Miranda Van Eck
- Division of BiopharmaceuticsCluster BioTherapeutics, Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 CC Leiden, The Netherlands
| | - Menno Hoekstra
- Division of BiopharmaceuticsCluster BioTherapeutics, Gorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 CC Leiden, The Netherlands
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