|
1
|
Chen H, Mo P, Xu G. Potential function of hepatic Niemann-Pick C1-like 1: cholesterol homeostasis regulation of the canalicular lipid bilayer membrane. Gastroenterol Rep (Oxf) 2025; 13:goaf010. [PMID: 40060220 PMCID: PMC11889457 DOI: 10.1093/gastro/goaf010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 07/02/2024] [Accepted: 09/20/2024] [Indexed: 04/11/2025] Open
Abstract
Niemann-Pick C1-like 1 (NPC1L1) is distributed in the human liver and intestine but only slightly expressed in the mouse liver. While it is well established that intestinal NPC1L1 is crucial for the absorption of exogenous cholesterol, the physiological and pathological roles of canalicular membrane-localized NPC1L1 in human hepatic cholesterol transport remain unclear. In this review, we discussed the potential function of human hepatic NPC1L1 and proposed that the disparity in NPC1L1 abundance between humans and mice in the liver may be attributable to their distinct bile hydrophobicity. Human hepatic NPC1L1 might interact with other proteins in the canalicular membrane, regulate membrane cholesterol homeostasis, and contribute to the stability of the canalicular lipid bilayer membrane in response to the greater detergent properties of human bile salts. We hoped to provide novel perspectives on hepatic NPC1L1 for future investigations.
Collapse
Affiliation(s)
- Hongtan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Pingfan Mo
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Guoqiang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| |
Collapse
|
|
2
|
Aizawa H. Impact of micelle characteristics on cholesterol absorption and ezetimibe inhibition: Insights from Niemann-Pick C1-like 1 binding and molecular structure. J Liposome Res 2024; 34:386-398. [PMID: 37905576 DOI: 10.1080/08982104.2023.2274424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/18/2023] [Indexed: 11/02/2023]
Abstract
Yamanashi et al., conducted a study on the absorption of cholesterol and β-sitosterol, as well as the inhibitory effect of ezetimibe (EZE). They used CaCo-2 cells to simulate the intestines and investigated how different mixed micelles, acting as carriers, were absorbed into these cells through the Niemann-Pick C1-like 1 (NPC1L1) protein. The study focused on the impact of micelle shape, size, and zeta potential on absorption and the inhibitory effect of EZE. I utilized small-angle X-ray scattering and a zeta potential measuring device to measure these characteristics. The findings revealed a two-step mechanism: NPC1L1 selectively bound micelles based on their shape and size, and once bound, the absorption was regulated by the molecular structure of the micelle components. EZE's inhibitory effect changed with micelle composition, influencing micelle size and shape. EZE initially acted on the micelle's shape and size, and then NPC1L1 selectively bound micelles based on their shape and size, allowing EZE to directly inhibit absorption by interacting with NPC1L1. This groundbreaking discovery challenges existing concepts and holds significant implications for researchers in drug development, as well as physicians and pharmacists.
Collapse
Affiliation(s)
- Hideki Aizawa
- Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Japan
| |
Collapse
|
|
3
|
Sansri V, Sroyraya M, Phisalprapa P, Yosboonruang A, Ontawong A, Saokaew S, Goh BH, Trisat K, Phewchan P, Rawangkan A, Limpeanchob N, Duangjai A. Suppressive Effect of Coffee Leaves on Lipid Digestion and Absorption In Vitro. Foods 2024; 13:2445. [PMID: 39123636 PMCID: PMC11312072 DOI: 10.3390/foods13152445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/27/2024] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Coffee leaves are a major source of bioactive components and are used as ethnomedicine. However, despite their traditional medicinal use, information about their effects on antihyperlipidemia remains limited. METHODS The aims of this study were to evaluate the main components of leaf extracts from Arabica and Robusta coffees and to examine the potential of these coffee leaves in reducing lipid digestion and absorption in vitro. RESULTS Coffee leaf extracts from Arabica coffee contain a high amount of caffeine, whereas extracts from Robusta coffee contain high amounts of chlorogenic acid (CGA) and caffeine. Additionally, leaf extracts from Arabica and Robusta coffee demonstrated the inhibition of pancreatic lipase, decreased micellar cholesterol solubility, and reduced bile acid binding. Furthermore, these extracts resulted in a reduction in cholesterol uptake in Caco-2 cells. Molecular docking experiments supported this discovery, showing CGA and caffeine binding to Niemann-Pick C1-like 1 (NPC1L1), a key protein in cholesterol absorption. The results indicated that CGA and caffeine can competitively bind to NPC1L1 at the cholesterol binding pocket, reducing its cholesterol binding rate. These findings suggest that coffee leaves might help suppress lipid absorption and digestion, highlighting their potential use in preventing and treating hyperlipidemia.
Collapse
Affiliation(s)
- Veerawat Sansri
- Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok 10300, Thailand;
| | - Morakot Sroyraya
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Pochamana Phisalprapa
- Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Atchariya Yosboonruang
- Division of Microbiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Atcharaporn Ontawong
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Surasak Saokaew
- Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Unit of Excellence on Clinical Outcomes Research and Integration (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
- Division of Social and Administrative Pharmacy, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Bey-Hing Goh
- Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Bandar Sunway 47500, Malaysia
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Kanittaporn Trisat
- Department of Pharmacy Practice and Center of Excellence for Innovation in Chemistry, Pharmacological Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Premchirakorn Phewchan
- Department of Pharmacy Practice and Center of Excellence for Innovation in Chemistry, Pharmacological Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Anchalee Rawangkan
- Division of Microbiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| | - Nanteetip Limpeanchob
- Department of Pharmacy Practice and Center of Excellence for Innovation in Chemistry, Pharmacological Research Unit, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
| | - Acharaporn Duangjai
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand
| |
Collapse
|
|
4
|
Langhi C, Vallier M, Bron A, Otero YF, Maura M, Le Joubioux F, Blomberg N, Giera M, Guigas B, Maugard T, Chassaing B, Peltier S, Blanquet-Diot S, Bard JM, Sirvent P. A polyphenol-rich plant extract prevents hypercholesterolemia and modulates gut microbiota in western diet-fed mice. Front Cardiovasc Med 2024; 11:1342388. [PMID: 38317864 PMCID: PMC10839041 DOI: 10.3389/fcvm.2024.1342388] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 01/03/2024] [Indexed: 02/07/2024] Open
Abstract
Introduction Totum-070 is a combination of five plant extracts enriched in polyphenols to target hypercholesterolemia, one of the main risk factors for cardiovascular diseases. The aim of this study was to investigate the effects of Totum-070 on cholesterol levels in an animal model of diet-induced hypercholesterolemia. Methods C57BL/6JOlaHsd male mice were fed a Western diet and received Totum-070, or not, by daily gavage (1g/kg and 3g/kg body weight) for 6 weeks. Results The Western diet induced obesity, fat accumulation, hepatic steatosis and increased plasma cholesterol compared with the control group. All these metabolic perturbations were alleviated by Totum-070 supplementation in a dose-dependent manner. Lipid excretion in feces was higher in mice supplemented with Totum-070, suggesting inhibition of intestinal lipid absorption. Totum-070 also increased the fecal concentration of short chain fatty acids, demonstrating a direct effect on intestinal microbiota. Discussion The characterization of fecal microbiota by 16S amplicon sequencing showed that Totum-070 supplementation modulated the dysbiosis associated with metabolic disorders. Specifically, Totum-070 increased the relative abundance of Muribaculum (a beneficial bacterium) and reduced that of Lactococcus (a genus positively correlated with increased plasma cholesterol level). Together, these findings indicate that the cholesterol-lowering effect of Totum-070 bioactive molecules could be mediated through multiple actions on the intestine and gut microbiota.
Collapse
Affiliation(s)
| | | | - Auriane Bron
- UMR 454 Microbiologie Environnement DIgestif et Santé (MEDIS), Université Clermont Auvergne, Clermont-Ferrand, France
| | | | | | | | - Niek Blomberg
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Thierry Maugard
- Equipe BCBS (Biotechnologies et Chimie des Bioressources Pour la Santé), UMR CNRS 7266 LIENSs, La Rochelle Université, La Rochelle, France
| | - Benoit Chassaing
- Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cité, Paris, France
| | | | - Stéphanie Blanquet-Diot
- UMR 454 Microbiologie Environnement DIgestif et Santé (MEDIS), Université Clermont Auvergne, Clermont-Ferrand, France
| | - Jean-Marie Bard
- Laboratoire de Biochimie Générale et Appliquée, UFR de Pharmacie, ISOMer-UE 2160, IUML-Institut Universitaire Mer et Littoral-FR3473 CNRS, Université de Nantes, Nantes, France
| | | |
Collapse
|
|
5
|
Langhi C, Vallier M, Otero YF, Maura M, Le Joubioux F, Groult H, Achour O, Pebriana RB, Giera M, Guigas B, Maugard T, Chassaing B, Peltier S, Bard JM, Sirvent P. Totum-070, a Polyphenol-Rich Plant Extract, Prevents Hypercholesterolemia in High-Fat Diet-Fed Hamsters by Inhibiting Intestinal Cholesterol Absorption. Nutrients 2023; 15:5056. [PMID: 38140315 PMCID: PMC10746001 DOI: 10.3390/nu15245056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide, and hypercholesterolemia is a central risk factor for atherosclerosis. This study evaluated the effects of Totum-070, a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia. The molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced the total cholesterol (-41%), non-HDL cholesterol (-47%), and triglycerides (-46%) in a dose-dependent manner, compared with HFD. HFD-induced hepatic steatosis was also significantly decreased by Totum-070, an effect associated with the reduction in various lipid and inflammatory gene expression. Upon challenging with olive oil gavage, the post-prandial triglyceride levels were strongly reduced. The sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group and associated with reduction of intestinal cholesterol absorption. These effects were confirmed in the Caco2 cells, where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, a microbiota composition analysis revealed a strong effect of Totum-070 on the alpha and beta diversity of bacterial species and a significant decrease in the Firmicutes to Bacteroidetes ratio. Altogether, our findings indicate that Totum-070 lowers hypercholesterolemia by reducing intestinal cholesterol absorption, suggesting that its use as dietary supplement may be explored as a new preventive strategy for cardiovascular diseases.
Collapse
Affiliation(s)
- Cédric Langhi
- R&D Riom Center, Valbiotis, 20-22 rue Henri et Gilberte Goudier, 63200 Riom, France
| | - Marie Vallier
- R&D Riom Center, Valbiotis, 20-22 rue Henri et Gilberte Goudier, 63200 Riom, France
| | - Yolanda F. Otero
- R&D Riom Center, Valbiotis, 20-22 rue Henri et Gilberte Goudier, 63200 Riom, France
| | - Maheva Maura
- R&D Center, Valbiotis, 23 Avenue Albert Einstein, 17000 La Rochelle, France
| | | | - Hugo Groult
- Equipe BCBS (Biotechnologies et Chimie des Bioressources pour la Santé), UMR (Unité Mixte de Recherche) CNRS (Centre National de la Recherche Scientifique) 7266 LIENSs (LIttoral ENvironnement Et Sociétés), La Rochelle Université, 17042 La Rochelle, France
| | - Oussama Achour
- BioAqtiv, Equipe BCBS (Biotechnologies et Chimie des Bioressources pour la Santé), LIENSs (LIttoral ENvironnement Et Sociétés), UMR (Unité Mixte de Recherche) 7266 CNRS (Centre National de la Recherche Scientifique), La Rochelle Université, 17042 La Rochelle, France
| | - Ratna Budhi Pebriana
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albi-nusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albi-nusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Thierry Maugard
- Equipe BCBS (Biotechnologies et Chimie des Bioressources pour la Santé), UMR (Unité Mixte de Recherche) CNRS (Centre National de la Recherche Scientifique) 7266 LIENSs (LIttoral ENvironnement Et Sociétés), La Rochelle Université, 17042 La Rochelle, France
| | - Benoit Chassaing
- Team “Mucosal Microbiota in Chronic Inflammatory Diseases”, Institut Cochin, INSERM (Institut National de la Santé et de la Recherche Médicale) U1016, CNRS UMR 8104, Université Paris Cité, 75014 Paris, France
| | - Sébastien Peltier
- R&D Périgny Center, Valbiotis, 12F rue Paul Vatine, 17180 Périgny, France
| | - Jean-Marie Bard
- Laboratoire de Biochimie Générale et Appliquée, UFR (Unité de Formation et de Recherche) de Pharmacie, ISOMer-UE 2160, IUML-Institut Universitaire Mer et Littoral-FR3473 CNRS, Université de Nantes, 44035 Nantes, France
| | - Pascal Sirvent
- R&D Riom Center, Valbiotis, 20-22 rue Henri et Gilberte Goudier, 63200 Riom, France
| |
Collapse
|
|
6
|
Piccinin E, Arconzo M, Matrella ML, Cariello M, Polizzi A, Lippi Y, Bertrand-Michel J, Guillou H, Loiseau N, Villani G, Moschetta A. Intestinal Pgc1α ablation protects from liver steatosis and fibrosis. JHEP Rep 2023; 5:100853. [PMID: 37886435 PMCID: PMC10597770 DOI: 10.1016/j.jhepr.2023.100853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 10/28/2023] Open
Abstract
Background & Aims The gut-liver axis modulates the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of conditions characterised by hepatic steatosis and a progressive increase of inflammation and fibrosis, culminating in metabolic dysfunction-associated steatohepatitis. Peroxisome proliferator-activated receptor-gamma coactivator 1α (Pgc1α) is a transcriptional co-regulator of mitochondrial activity and lipid metabolism. Here, the intestinal-specific role of Pgc1α was analysed in liver steatosis and fibrosis. Methods We used a mouse model in which Pgc1α was selectively deleted from the intestinal epithelium. We fed these mice and their wild-type littermates a Western diet to recapitulate the major features of liver steatosis (after 2 months of diet) and metabolic dysfunction-associated steatohepatitis (after 4 months of diet). The chow diet was administered as a control diet. Results In humans and mice, low expression of intestinal Pgc1α is inversely associated with liver steatosis, inflammation, and fibrosis. Intestinal disruption of Pgc1α impairs the transcription of a wide number of genes, including the cholesterol transporter Niemann-Pick C1-like 1 (Npc1l1), thus limiting the uptake of cholesterol from the gut. This results in a lower cholesterol accretion in the liver and a decreased production of new fatty acids, which protect the liver from lipotoxic lipid species accumulation, inflammation, and related fibrotic processes. Conclusions In humans and mice, intestinal Pgc1α induction during Western diet may be another culprit driving hepatic steatosis and fibrosis. Here, we show that enterocyte-specific Pgc1α ablation protects the liver from steatosis and fibrosis by reducing intestinal cholesterol absorption, with subsequent decrease of cholesterol and de novo fatty acid accumulation in the liver. Impact and implications Liver diseases result from several insults, including signals from the gut. Although the incidence of liver diseases is continuously increasing worldwide, effective drug therapy is still lacking. Here, we showed that the modulation of an intestinal coactivator regulates the liver response to a Western diet, by limiting the uptake of dietary cholesterol. This results in a lower accumulation of hepatic lipids together with decreased inflammation and fibrosis, thus limiting the progression of liver steatosis and fibrosis towards severe end-stage diseases.
Collapse
Affiliation(s)
- Elena Piccinin
- Department of Interdisciplinary Medicine, University of Bari ‘Aldo Moro’, Bari, Italy
- Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari ‘Aldo Moro’, Bari, Italy
| | - Maria Arconzo
- Department of Interdisciplinary Medicine, University of Bari ‘Aldo Moro’, Bari, Italy
| | - Maria Laura Matrella
- Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari ‘Aldo Moro’, Bari, Italy
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari ‘Aldo Moro’, Bari, Italy
| | - Arnaud Polizzi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Yannick Lippi
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | | | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Nicolas Loiseau
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Gaetano Villani
- Department of Translational Biomedicine and Neuroscience (DiBraiN), University of Bari ‘Aldo Moro’, Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari ‘Aldo Moro’, Bari, Italy
- INBB, National Institute for Biostructures and Biosystems, Rome, Italy
| |
Collapse
|
|
7
|
Guo J, Wang Y, Li P, Wu W, Xu F, Zhou K, Xu B. The modulatory effects on enterohepatic cholesterol metabolism of novel cholesterol-lowering peptides from gastrointestinal digestion of Xuanwei ham. Food Res Int 2023; 173:113391. [PMID: 37803728 DOI: 10.1016/j.foodres.2023.113391] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/13/2023] [Accepted: 08/16/2023] [Indexed: 10/08/2023]
Abstract
The aim of this study was to investigate the effects and mechanism of in vitro protein digestive products of Xuanwei ham with different ripening periods on cholesterol metabolism and hypercholesterolemia. The results showed that compared with other gastrointestinal digestion (GID) groups, the GID group of Xuanwei ham with 3-year ripening period (XWH3-GID) inhibited the expression of Niemann-Pick C1-like 1 (NPC1L1) and acetyl-CoA acetyltransferase 2 (ACAT2) through hepatocyte nuclear factor 1-alpha (HNF-1α), which in turn effectively inhibited cholesterol absorption in Caco-2 cell monolayers. Following absorption by Caco-2 cell monolayers, the XWH3-GID group suppressed the expression and secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) via HNF-1α, which enhanced the protein expression and fluorescence intensity of low density lipoprotein receptor (LDLR) on the HepG2 cell membrane, and thus promoted the uptake of low density lipoprotein (LDL). Importantly, three novel peptides (LFP, PKF and VPFP) derived from titin were identified after intestinal epithelial transport in the XWH3-GID group, which could exert cholesterol-lowering effects through inhibiting intestinal cholesterol absorption and promoting peripheral hepatic LDL uptake, and effectively ameliorate western diet-induced hypercholesterolemia in ApoE-/- mice. These results suggest that Xuanwei ham with 3-year ripening period can be used as a source of cholesterol-lowering peptides and has potential to intervene in hypercholesterolemia.
Collapse
Affiliation(s)
- Jie Guo
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China
| | - Ying Wang
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China
| | - Peijun Li
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China
| | - Wenda Wu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China
| | - Feiran Xu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China
| | - Kai Zhou
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China
| | - Baocai Xu
- School of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China; Engineering Research Center of Bio-process, Ministry of Education, Hefei University of Technology, Hefei 230601, China.
| |
Collapse
|
|
8
|
Van Lommel J, Holtof M, Tilleman L, Cools D, Vansteenkiste S, Polgun D, Verdonck R, Van Nieuwerburgh F, Vanden Broeck J. Post-feeding transcriptomics reveals essential genes expressed in the midgut of the desert locust. Front Physiol 2023; 14:1232545. [PMID: 37692997 PMCID: PMC10484617 DOI: 10.3389/fphys.2023.1232545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 07/26/2023] [Indexed: 09/12/2023] Open
Abstract
The digestive tract constitutes an important interface between an animal's internal and external environment. In insects, available gut transcriptome studies are mostly exploratory or look at changes upon infection or upon exposure to xenobiotics, mainly performed in species belonging to holometabolan orders, such as Diptera, Lepidoptera or Coleoptera. By contrast, studies focusing on gene expression changes after food uptake and during digestion are underrepresented. We have therefore compared the gene expression profiles in the midgut of the desert locust, Schistocerca gregaria, between three different time points after feeding, i.e., 24 h (no active digestion), 10 min (the initial stage of feeding), and 2 h (active food digestion). The observed gene expression profiles were consistent with the polyphagous herbivorous lifestyle of this hemimetabolan (orthopteran) species. Our study reveals the upregulation of 576 genes 2 h post-feeding. These are mostly predicted to be associated with digestive physiology, such as genes encoding putative digestive enzymes or nutrient transporters, as well as genes putatively involved in immunity or in xenobiotic metabolism. The 10 min time point represented an intermediate condition, suggesting that the S. gregaria midgut can react rapidly at the transcriptional level to the presence of food. Additionally, our study demonstrated the critical importance of two transcripts that exhibited a significant upregulation 2 h post-feeding: the vacuolar-type H(+)-ATPase and the sterol transporter Niemann-Pick 1b protein, which upon RNAi-induced knockdown resulted in a marked increase in mortality. Their vital role and accessibility via the midgut lumen may make the encoded proteins promising insecticidal target candidates, considering that the desert locust is infamous for its huge migrating swarms that can devastate the agricultural production in large areas of Northern Africa, the Middle East, and South Asia. In conclusion, the transcriptome datasets presented here will provide a useful and promising resource for studying the midgut physiology of S. gregaria, a socio-economically important pest species.
Collapse
Affiliation(s)
- Joachim Van Lommel
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
| | - Michiel Holtof
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
| | | | - Dorien Cools
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
| | - Seppe Vansteenkiste
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
| | - Daria Polgun
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
| | - Rik Verdonck
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
- Environmental Biology, Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | | | - Jozef Vanden Broeck
- Molecular Developmental Physiology and Signal Transduction Lab, Department of Biology, University of Leuven, Leuven, Belgium
| |
Collapse
|
|
9
|
Wu X, Ma XH, Lin J, Yang X, Shi JH, Xie Z, Chen YX, Zhang WJ. Fluorescent visualization and evaluation of NPC1L1-mediated vesicular endocytosis during intestinal cholesterol absorption in mice. LIFE METABOLISM 2023; 2:load011. [PMID: 39872735 PMCID: PMC11749127 DOI: 10.1093/lifemeta/load011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 01/30/2025]
Abstract
Excessive cholesterol absorption from intestinal lumen contributes to the pathogenesis of hypercholesterolemia, which is an independent risk factor for atherosclerotic cardiovascular disease. Niemann-Pick C1-like 1 (NPC1L1) is a major membrane protein responsible for cholesterol absorption, in which the physiological role of vesicular endocytosis is still controversial, and it lacks a feasible tool to visualize and evaluate the endocytosis of NPC1L1 vesicles in vivo. Here, we genetically labeled endogenous NPC1L1 protein with EGFP in a knock-in mouse model, and demonstrated fluorescent visualization and evaluation of the endocytic vesicles of NPC1L1-cago during intestinal cholesterol absorption. The homozygous NPC1L1-EGFP mice have normal NPC1L1 expression pattern as well as cholesterol homeostasis on chow or high-cholesterol diets. The fluorescence of NPC1L1-EGFP fusion protein localizes at the brush border membrane of small intestine, and EGFP-positive vesicles is visualized beneath the membrane as early as 5 min post oral gavage of cholesterol. Of note, the vesicles colocalize with the early endosomal marker early endosome antigen 1 (EEA1) and the filipin-stained free cholesterol. Pretreatment with NPC1L1 inhibitor ezetimibe inhibits the formation of these cholesterol-induced endocytic vesicles. Our data support the notion that NPC1L1-mediated cholesterol absorption is a vesicular endocytic process. NPC1L1-EGFP mice are a useful model for visualizing cellular NPC1L1-cargo vesicle itineraries and for evaluating NPC1L1 activity in vivo in response to diverse pharmacological agents and nutrients.
Collapse
Affiliation(s)
- Xiaojing Wu
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Xian-Hua Ma
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Jie Lin
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Xiaohang Yang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Jian-Hui Shi
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Zhifang Xie
- Ministry of Education Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yu-Xia Chen
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Weiping J Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| |
Collapse
|
|
10
|
Zeng J, Liu W, Liang B, Shi L, Yang S, Meng J, Chang J, Hu X, Zhang R, Xing D. Inhibitory Effect of Isoliquiritigenin in Niemann-Pick C1-Like 1-Mediated Cholesterol Uptake. Molecules 2022; 27:7494. [PMID: 36364321 PMCID: PMC9654431 DOI: 10.3390/molecules27217494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 10/28/2022] [Accepted: 10/31/2022] [Indexed: 07/21/2023] Open
Abstract
Isoliquiritigenin (ISL) is a flavonoid with a chalcone structure extracted from the natural herb Glycyrrhiza glabra. Its anti-inflammatory, antibacterial, antioxidant, and anticancer activities have been extensively studied. Moreover, ISL also possess hypolipidemic and atherosclerosis-reducing effects. However, its cholesterol-lowering mechanisms have not been reported yet. Niemann Pick C1 Like 1 (NPC1L1) is a specific transporter of cholesterol uptake. In this study, we found for the first time that ISL downregulates NPC1L1 expression and competitively inhibits cellular cholesterol uptake by binding to NPC1L1 in a concentration-dependent manner in vitro. This study provides a theoretical basis for further investigation of the molecular mechanisms of its cholesterol-lowering effect in vivo and inspired emerging drug research for cholesterol-lowering purposes through NPC1L1 inhibition.
Collapse
Affiliation(s)
- Jun Zeng
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Wenjing Liu
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Bing Liang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Lingyu Shi
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Shanbo Yang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Jingsen Meng
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Jing Chang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266000, China
- Qingdao Cancer Institute, Qingdao 266000, China
| | - Xiaokun Hu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | | | - Dongming Xing
- Qingdao Cancer Institute, Qingdao 266000, China
- School of Life Sciences, Tsinghua University, Beijing 100010, China
| |
Collapse
|
|
11
|
Liu W, Liang B, Zeng J, Meng J, Shi L, Yang S, Chang J, Wang C, Hu X, Wang X, Han N, Lu C, Li J, Wang C, Li H, Zhang R, Xing D. First Discovery of Cholesterol-Lowering Activity of Parthenolide as NPC1L1 Inhibitor. Molecules 2022; 27:molecules27196270. [PMID: 36234807 PMCID: PMC9572688 DOI: 10.3390/molecules27196270] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 12/05/2022] Open
Abstract
Elevated cholesterol significantly increases the risk of developing atherosclerosis and coronary heart disease. The key to treating hypercholesterolemia is lowering plasma cholesterol levels. There have been no studies on the cholesterol-lowering potential of parthenolide (PTL), a naturally occurring small molecule from Tanacetum parthenium. Here, we first put forth PTL’s cholesterol-lowering ability to inhibit cellular uptake of cholesterol in a dose-dependent manner. Its performance was on par with the positive control drug, ezetimibe. Niemann–Pick C1 Like-1 (NPC1L1) has been identified as a potential therapeutic target for hypercholesterolemia. The interaction of PTL with NPC1L1 could be explained by the results of molecular docking and filipin staining further reinforces this hypothesis. Furthermore, PTL reduced the expression of NPC1L1 in HepG2 cells in a concentration-dependent manner, which suggests that PTL functions as a potential NPC1L1 inhibitor with therapeutic potential for hypercholesterolemia.
Collapse
Affiliation(s)
- Wenjing Liu
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Qingdao Cancer Institute, Qingdao 266071, China
| | - Bing Liang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
| | - Jun Zeng
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Qingdao Cancer Institute, Qingdao 266071, China
| | - Jingsen Meng
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Qingdao Cancer Institute, Qingdao 266071, China
| | - Lingyu Shi
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Qingdao Cancer Institute, Qingdao 266071, China
| | - Shanbo Yang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Qingdao Cancer Institute, Qingdao 266071, China
| | - Jing Chang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Qingdao Cancer Institute, Qingdao 266071, China
| | - Chao Wang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
| | - Xiaokun Hu
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Xufu Wang
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Na Han
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Chenghui Lu
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Jiao Li
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Congcong Wang
- Department of Nuclear Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Huanting Li
- Interventional Medicine Center, The Affiliated Hospital of Qingdao University, Qingdao 266071, China
| | - Renshuai Zhang
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- Correspondence: (R.Z.); (D.X.)
| | - Dongming Xing
- Cancer Institute, The Affiliated Hospital of Qingdao University, School of Basic Medicine of Qingdao University, Qingdao 266071, China
- School of Life Sciences, Tsinghua University, Beijing 100190, China
- Correspondence: (R.Z.); (D.X.)
| |
Collapse
|
|
12
|
Ontawong A, Duangjai A, Sukpondma Y, Tadpetch K, Muanprasat C, Rukachaisirikul V, Inchai J, Vaddhanaphuti CS. Cholesterol-Lowering Effects of Asperidine B, a Pyrrolidine Derivative from the Soil-Derived Fungus Aspergillus sclerotiorum PSU-RSPG178: A Potential Cholesterol Absorption Inhibitor. Pharmaceuticals (Basel) 2022; 15:ph15080955. [PMID: 36015103 PMCID: PMC9414821 DOI: 10.3390/ph15080955] [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: 06/07/2022] [Revised: 07/21/2022] [Accepted: 07/29/2022] [Indexed: 11/30/2022] Open
Abstract
Isolated secondary metabolites asperidine B (preussin) and asperidine C, produced by the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, were found to exhibit inhibitory effects against 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and oxidative stress in an in vitro assay. Whether or not the known pyrrolidine asperidine B and the recently isolated piperidine asperidine C have lipid-lowering effects remains unknown. Thus, this study aimed to investigate the hypocholesterolemic effects of asperidines B and C and identify the mechanisms involved in using in vitro, ex vivo, and in vivo models. The results show that both compounds interfered with cholesterol micelle formation by increasing bile acid binding capacity, similar to the action of the bile acid sequestrant drug cholestyramine. However, only asperidine B, but not asperidine C, was found to inhibit cholesterol uptake in Caco-2 cells by up-regulating LXRα without changing cholesterol transporter NPC1L1 protein expression. Likewise, reduced cholesterol absorption via asperidine-B-mediated activation of LXRα was also observed in isolated rat jejunal loops. Asperidine B consistently decreases plasma cholesterol absorption, similar to the effect of ezetimibe in rats. Therefore, asperidine B, the pyrrolidine derivative, has therapeutic potential to be developed into a type of cholesterol absorption inhibitor for the treatment of hypercholesterolemia.
Collapse
Affiliation(s)
- Atcharaporn Ontawong
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (A.O.); (A.D.)
| | - Acharaporn Duangjai
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao 56000, Thailand; (A.O.); (A.D.)
| | - Yaowapa Sukpondma
- Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Songkhla 90112, Thailand; (Y.S.); (K.T.); (V.R.)
| | - Kwanruthai Tadpetch
- Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Songkhla 90112, Thailand; (Y.S.); (K.T.); (V.R.)
| | - Chatchai Muanprasat
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10540, Thailand;
| | - Vatcharin Rukachaisirikul
- Division of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Songkhla 90112, Thailand; (Y.S.); (K.T.); (V.R.)
| | - Jakkapong Inchai
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Chutima S. Vaddhanaphuti
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
- Correspondence: ; Tel.:+66-533-935-362
| |
Collapse
|
|
13
|
Gu J, Zhu N, Li HF, Zhang CJ, Gong YZ, Liao DF, Qin L. Ezetimibe and Cancer: Is There a Connection? Front Pharmacol 2022; 13:831657. [PMID: 35924044 PMCID: PMC9340271 DOI: 10.3389/fphar.2022.831657] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 06/23/2022] [Indexed: 11/29/2022] Open
Abstract
The high level of serum cholesterol caused by the excessive absorption of cholesterol can lead to hypercholesteremia, thus promoting the occurrence and development of cancer. Ezetimibe is a drug that reduces cholesterol absorption and has been widely used for the treatment of patients with high circulating cholesterol levels for many years. Mechanistically, ezetimibe works by binding to NPC1L1, which is a key mediator of cholesterol absorption. Accumulating data from preclinical models have shown that ezetimibe alone could inhibit the development and progression of cancer through a variety of mechanisms, including anti-angiogenesis, stem cell suppression, anti-inflammation, immune enhancement and anti-proliferation. In the past decade, there has been heated discussion on whether ezetimibe combined with statins will increase the risk of cancer. At present, more and more evidence shows that ezetimibe does not increase the risk of cancers, which supports the role of ezetimibe in anti-cancer. In this review, we discussed the latest progress in the anti-cancer properties of ezetimibe and elucidated its underlying molecular mechanisms. Finally, we highlighted the potential of ezetimibe as a therapeutic agent in future cancer treatment and prevention.
Collapse
Affiliation(s)
- Jia Gu
- Laboratory of Stem Cell Regulation With Chinese Medicine and its Application, HunanUniversity of Chinese Medicine, Changsha, China
| | - Neng Zhu
- Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Hong-Fang Li
- Laboratory of Stem Cell Regulation With Chinese Medicine and its Application, HunanUniversity of Chinese Medicine, Changsha, China
| | - Chan-Juan Zhang
- Laboratory of Stem Cell Regulation With Chinese Medicine and its Application, HunanUniversity of Chinese Medicine, Changsha, China
| | - Yong-Zhen Gong
- Laboratory of Stem Cell Regulation With Chinese Medicine and its Application, HunanUniversity of Chinese Medicine, Changsha, China
| | - Duan-Fang Liao
- Laboratory of Stem Cell Regulation With Chinese Medicine and its Application, HunanUniversity of Chinese Medicine, Changsha, China
| | - Li Qin
- Laboratory of Stem Cell Regulation With Chinese Medicine and its Application, HunanUniversity of Chinese Medicine, Changsha, China
- Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Changsha, China
- Hunan Province Engineering Research Center of Bioactive Substance Discovery of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- *Correspondence: Li Qin,
| |
Collapse
|
|
14
|
Cho Y, Rhee H, Kim YE, Lee M, Lee BW, Kang ES, Cha BS, Choi JY, Lee YH. Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study). BMC Med 2022; 20:93. [PMID: 35307033 PMCID: PMC8935785 DOI: 10.1186/s12916-022-02288-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/08/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The effect of ezetimibe, Niemann-Pick C1-like 1 inhibitor, on liver fat is not clearly elucidated. Our primary objective was to evaluate the efficacy of ezetimibe plus rosuvastatin versus rosuvastatin monotherapy to reduce liver fat using magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) in patients with non-alcoholic fatty liver disease (NAFLD). METHODS A randomized controlled, open-label trial of 70 participants with NAFLD confirmed by ultrasound who were assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks. The liver fat change was measured as average values in each of nine liver segments by MRI-PDFF. Magnetic resonance elastography (MRE) was used to measure liver fibrosis change. RESULTS Combination therapy significantly reduced liver fat compared with monotherapy by MRI-PDFF (mean difference: 3.2%; p = 0.020). There were significant reductions from baseline to study completion by MRI-PDFF for both the combination and monotherapy groups, respectively (18.1 to 12.3%; p < 0.001 and 15.0 to 12.4%; p = 0.003). Individuals with higher body mass index, type 2 diabetes, insulin resistance, and severe liver fibrosis were likely to be good responders to treatment with ezetimibe. MRE-derived change in liver fibrosis was not significantly different (both groups, p > 0.05). Controlled attenuation parameter (CAP) by transient elastography was significantly reduced in the combination group (321 to 287 dB/m; p = 0.018), but not in the monotherapy group (323 to 311 dB/m; p = 0.104). CONCLUSIONS Ezetimibe and rosuvastatin were found to be safe to treat participants with NAFLD. Furthermore, ezetimibe combined with rosuvastatin significantly reduced liver fat in this population. TRIAL REGISTRATION The trial was registered at ClinicalTrials.gov (registration number: NCT03434613 ).
Collapse
Affiliation(s)
- Yongin Cho
- Department of Endocrinology and Metabolism, Inha University School of Medicine, Incheon, Republic of Korea.,Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young-Eun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin-Young Choi
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea. .,Department of Systems Biology, Glycosylation Network Research Center, Yonsei University, Seoul, Republic of Korea.
| |
Collapse
|
|
15
|
Control of Cholesterol Metabolism Using a Systems Approach. BIOLOGY 2022; 11:biology11030430. [PMID: 35336806 PMCID: PMC8945167 DOI: 10.3390/biology11030430] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 11/25/2022]
Abstract
Simple Summary Cholesterol is the main sterol in mammals that is essential for healthy cell functionining. It plays a key role in metabolic regulation and signaling, it is a precursor molecule of bile acids, oxysterols, and all steroid hormones. It also contributes to the structural makeup of the membranes. Its homeostasis is tightly controlled since it can harm the body if it is allowed to reach abnormal blood concentrations. One of the diseases associated with elevated cholesterol levels being the major cause of morbidities and mortalities worldwide, is atherosclerosis. In this study, we have developed a model of the cholesterol metabolism taking into account local inflammation and oxidative stress. The aim was to investigate the impact of the interplay of those processes and cholesterol metabolism disturbances on the atherosclerosis development and progression. We have also analyzed the effect of combining different classes of drugs targeting selected components of cholesterol metabolism. Abstract Cholesterol is an essential component of mammalian cells and is involved in many fundamental physiological processes; hence, its homeostasis in the body is tightly controlled, and any disturbance has serious consequences. Disruption of the cellular metabolism of cholesterol, accompanied by inflammation and oxidative stress, promotes the formation of atherosclerotic plaques and, consequently, is one of the leading causes of death in the Western world. Therefore, new drugs to regulate disturbed cholesterol metabolism are used and developed, which help to control cholesterol homeostasis but still do not entirely cure atherosclerosis. In this study, a Petri net-based model of human cholesterol metabolism affected by a local inflammation and oxidative stress, has been created and analyzed. The use of knockout of selected pathways allowed us to observe and study the effect of various combinations of commonly used drugs on atherosclerosis. The analysis results led to the conclusion that combination therapy, targeting multiple pathways, may be a fundamental concept in the development of more effective strategies for the treatment and prevention of atherosclerosis.
Collapse
|
|
16
|
Hoshino Y, Sugihara T, Ikeda S, Tarumoto R, Matsuki Y, Kanda T, Iyama T, Takata T, Matono T, Nagahara T, Okano JI, Ueki M, Koda M, Osaki M, Okada F, Isomoto H. Newly Invented Micellized Vitamin K2 Recovered Prolonged Prothrombin Time under Obstructive Jaundice in Rats with Bile Duct Ligation. J Nutr Sci Vitaminol (Tokyo) 2022; 67:397-403. [PMID: 34980718 DOI: 10.3177/jnsv.67.397] [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: 11/27/2022]
Abstract
In cholestatic liver diseases, coagulopathy is induced by malabsorption of vitamin K. Supplementation of vitamin K has previously been shown to prevent coagulopathy. In this study, we tested the efficacy of a newly invented micellized vitamin K2 (m-vitK2) in treating coagulopathy, using a rat bile duct ligation (BDL) model. Experiment 1: m-vitK2 (0.3 mg/kg) or m-vitK2 (0.3 mg/kg) mixed with taurocholic acid (TA) (10 mg/body) was orally administrated every day for 7 d from the fourth day after BDL (n=6 for each). Experiment 2: To evaluate absorption, m-vitK2 (0.3 mg/kg) with or without TA (10 mg/body) was orally administered on the fourth day after BDL and compared with the untreated control BDL (n=2 for each). These data were compared with sham-operated (n=6) and untreated control BDL rats (n=6). The m-vitK2 recovered prothrombin time (PT) in Experiment 1 (control 42.7±5.7 s vs. m-vitK2 24.0±9.3 s, p<0.05). Experiment 2 demonstrated that the mixture of m-vitK2 and TA enhanced absorption compared to m-vitK2 alone. Moreover, in Experiment 1, m-vitK2 mixed with TA completely recovered PT (control 42.7±5.7 s vs. m-vitK2+TA 14.9±1.2 s, p<0.01). Micelle sizes decreased with the m-vitK2 and TA treatment (m-vitK2 86.3±5.6 nm vs. m-vitK2+TA 71.9±4.7 nm, p<0.05). Orally administered, newly invented m-vitK2 recovered coagulopathy even under obstructive jaundice. TA decreased the mean micelle size and improved m-vitK2 absorption.
Collapse
Affiliation(s)
- Yoshiki Hoshino
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Takaaki Sugihara
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Suguru Ikeda
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Ryohei Tarumoto
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Yukako Matsuki
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Tsutomu Kanda
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Takuji Iyama
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Tomoaki Takata
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Tomomitsu Matono
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Takakazu Nagahara
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Jun-Ichi Okano
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| | - Masaru Ueki
- Division of Medical Education, School of Medicine, Tottori University
| | | | - Mitsuhiko Osaki
- Division of Experimental Pathology, School of Medicine, Tottori University
| | - Futoshi Okada
- Division of Experimental Pathology, School of Medicine, Tottori University
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University
| |
Collapse
|
|
17
|
Xu C, Li H, Tang CK. Sterol Carrier Protein 2: A promising target in the pathogenesis of atherosclerosis. Genes Dis 2022; 10:457-467. [DOI: 10.1016/j.gendis.2021.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/21/2021] [Accepted: 12/01/2021] [Indexed: 10/19/2022] Open
|
|
18
|
Jia L, Ma Y, Haywood J, Jiang L, Xue B, Shi H, Dawson PA, Yu L. NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice. Cells 2021; 10:3468. [PMID: 34943976 PMCID: PMC8700447 DOI: 10.3390/cells10123468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 02/04/2023] Open
Abstract
Niemann-Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.
Collapse
Affiliation(s)
- Lin Jia
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Department of Biological Sciences, The University of Texas at Dallas, 800 W, Campbell Road, Richardson, TX 75080, USA
| | - Yinyan Ma
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jamie Haywood
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
| | - Long Jiang
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Bingzhong Xue
- Department of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
| | - Hang Shi
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
- Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Paul A. Dawson
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, USA
| | - Liqing Yu
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| |
Collapse
|
|
19
|
Molecular cloning and characterization of NPC1L1 in the Chinese tree shrew (Tupaia belangeri chinensis). Mol Biol Rep 2021; 48:7975-7984. [PMID: 34716864 DOI: 10.1007/s11033-021-06829-5] [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: 02/23/2021] [Accepted: 10/11/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND The Niemann-Pick C1-Like 1 protein, a multi-transmembrane domain molecule, is critical for intestinal cholesterol absorption, and is the entry factor for hepatitis C virus (HCV). The Chinese tree shrew (Tupaia belangeri chinensis) is closer to primates in terms of genetic evolution than rodents. Previous studies indicated that the tree shrew was suitable for HCV research; however, little is known about tree shrew NPC1L1. METHODS AND RESULTS TsNPC1L1 cDNA was amplified by rapid amplification of cDNA ends (RACE) technology. The cDNA sequence, its encoded protein structure, and expression profile were analyzed. Results indicated that the tsNPC1L1 mRNA is 4948 bp in length and encodes a 1326 amino acid protein. TsNPC1L1 possesses 84.97% identity in homology to human NPC1L1 which is higher than both mouse (80.37%) and rat (81.80%). The protein structure was also similar to human with 13 conserved transmembrane helices, and a sterol-sensing domain (SSD). Like human NPC1L1, the tsNPC1L1 mRNA transcript is highly expressed in small intestine, but it was also well-expressed in the lung and pancreas of the tree shrew. CONCLUSION The homology of tree shrew NPC1L1 was closer to human than that of rodent NPC1L1. The expression of tsNPC1L1 was the highest in small intestine, and was detectable in lung and pancreas. These results may be useful in the study of tsNPC1L1 function in cholesterol absorption and HCV infection.
Collapse
|
|
20
|
Schade DS, Gonzales K, Kaminsky N, Adolphe A, Shey L, Eaton RP. Resolving the Egg and Cholesterol Intake Controversy: New Clinical Insights Into Cholesterol Regulation by the Liver and Intestine. Endocr Pract 2021; 28:102-109. [PMID: 34547473 DOI: 10.1016/j.eprac.2021.09.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/19/2021] [Accepted: 09/09/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Cardiovascular disease is the number one cause of death. Achieving American Heart Association low-density lipoprotein (LDL) cholesterol treatment goals is very difficult for many patients. The importance of a low cholesterol diet is controversial and not emphasized by most physicians. Of critical importance is determining whether each individual is a "hyper- or hypo-absorber" of dietary cholesterol. Furthermore, the quantity of each individual's baseline daily dietary cholesterol and saturated fat intake is important in assessing the effect of added egg yolk cholesterol and saturated fat on blood LDL cholesterol. METHODS Gut cholesterol is absorbed via a specific enteric receptor (the Niemann- Pick-like receptor). Dietary cholesterol contributes one fourth of the absorbed cholesterol, while the remaining gut cholesterol is derived from secreted bile cholesterol. This dietary quantity of cholesterol is significant when other determinants are constant. For some individuals, dietary cholesterol has no adverse effects and in others, a significant elevation in blood LDL cholesterol may occur. RESULTS There are no readily available blood tests to determine the effect of egg yolk cholesterol and saturated fat on an individual's plasma LDL cholesterol. However, a one month trial of a low cholesterol and saturated fat diet will provide the needed information to make clinical decisions. CONCLUSION This article delineates the mechanisms that are altered by genetic and environmental factors that determine the net effects of dietary cholesterol and saturated fat on circulating LDL cholesterol. It then makes a practical clinical recommendation based on these mechanisms.
Collapse
Affiliation(s)
- David S Schade
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
| | - Kristen Gonzales
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Neil Kaminsky
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Allen Adolphe
- Division of Internal Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Lynda Shey
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Diabetes Comprehensive Care Center, Albuquerque, New Mexico
| | - Robert Philip Eaton
- Division of Endocrinology, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
| |
Collapse
|
|
21
|
Ge H, Liu G, Yamawaki TM, Tao C, Alexander ST, Ly K, Fordstrom P, Shkumatov AA, Li CM, Rajamani S, Zhou M, Ason B. Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice. Sci Rep 2021; 11:17449. [PMID: 34465831 PMCID: PMC8408133 DOI: 10.1038/s41598-021-96936-x] [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: 04/28/2021] [Accepted: 08/06/2021] [Indexed: 11/13/2022] Open
Abstract
Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.
Collapse
Affiliation(s)
- Hongfei Ge
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Gongxin Liu
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Tracy M Yamawaki
- Genomic Analysis Unit, Amgen Research, South San Francisco, CA, USA
| | - Caroline Tao
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Shawn T Alexander
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Kimberly Ly
- Translational Safety and Bioanalytical Sciences, Amgen Research, South San Francisco, CA, USA
| | - Preston Fordstrom
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Artem A Shkumatov
- Translational Safety and Bioanalytical Sciences, Amgen Research, South San Francisco, CA, USA
| | - Chi-Ming Li
- Genomic Analysis Unit, Amgen Research, South San Francisco, CA, USA
| | - Sridharan Rajamani
- Translational Safety and Bioanalytical Sciences, Amgen Research, South San Francisco, CA, USA
| | - Mingyue Zhou
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Brandon Ason
- Cardiometabolic Disorders Therapeutic Area, Amgen Research, Amgen, Inc, 1120 Veterans Blvd, South San Francisco, CA, 94080, USA.
| |
Collapse
|
|
22
|
Yoon H, Lee Y, Kang HJ, Ju J, Ji Y, Park H, Park H, Lee H, Holzapfel WH. Two putative probiotic strains improve diet-induced hypercholesterolemia through modulating intestinal cholesterol uptake and hepatic cholesterol efflux. J Appl Microbiol 2021; 132:562-570. [PMID: 34133840 DOI: 10.1111/jam.15181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 11/30/2022]
Abstract
AIMS Two putative probiotic strains, Lacticaseibacillus (Lc.) rhamnosus BFE5264 and Lactiplantibacillus (Lp.) plantarum NR74, have been shown to suppress cholesterol uptake and promote cholesterol efflux in Caco-2 cells. However, an in vivo beneficial effect of these strains on plasma cholesterol levels has not been verified yet; neither have the underlying mechanisms of regulating cholesterol metabolism clarified thus far. This study has focused on these two aspects. METHODS AND RESULTS A murine model has been used, and the animals receiving a high-fat/high-cholesterol diet showed elevated plasma cholesterol levels. However, supplementation of Lc. rhamnosus BFE5264 and Lp. plantarum NR74 resulted in the down regulation of Niemann-Pick C1-like 1 (NPC1L1) in the intestine in addition to counteracting the diet-induced suppression of low-density lipoprotein receptor expression in the liver. ATP Binding Cassette Subfamily A Member 1 (ABCA1) was only significantly increased upon administration of Lc. rhamnosus BFE5264. CONCLUSIONS The present findings demonstrate that supplementation with Lc. rhamnosus BFE5264 and Lp. plantarum NR74 may improve diet-induced hypercholesterolemia by suppression of cholesterol absorption in the small intestine and by supporting the regulation of cholesterol metabolism in the liver. SIGNIFICANCE AND IMPACT OF THE STUDY This work contributes to understanding the beneficial effects of probiotics on host cholesterol metabolism and underlying mechanisms related to hypercholesterolemia.
Collapse
Affiliation(s)
- Hongsup Yoon
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Yuri Lee
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Hye-Ji Kang
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Jaehyun Ju
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Yosep Ji
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Hyunjoon Park
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Haryung Park
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Heejae Lee
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| | - Wilhelm H Holzapfel
- Department of Advanced Convergence, Handong Global University, Pohang, Republic of Korea
| |
Collapse
|
|
23
|
Piccinin E, Cariello M, Moschetta A. Lipid metabolism in colon cancer: Role of Liver X Receptor (LXR) and Stearoyl-CoA Desaturase 1 (SCD1). Mol Aspects Med 2020; 78:100933. [PMID: 33218679 DOI: 10.1016/j.mam.2020.100933] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/01/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most commonly occurring cancers worldwide. Although several genetic alterations have been associated with CRC onset and progression, nowadays the reprogramming of cellular metabolism has been recognized as a fundamental step of the carcinogenic process. Intestinal tumor cells frequently display an aberrant activation of lipid metabolism. Indeed, to satisfy the growing needs of a continuous proliferation, cancer cells can either increase the uptake of exogenous lipids or upregulate the endogenous lipogenesis and cholesterol synthesis. Therefore, strategies aimed at limiting lipid accumulation are now under development in order to counteract malignancies. Two major players of lipids metabolism have been so far identified for their contribution to CRC development: the nuclear receptor Liver X Receptor (LXRs) and the enzyme Stearoyl-CoA Desaturase 1 (SCD1). Whereas LXR is mainly recognized for its role as a cholesterol sensor, finally promoting the loss of cellular cholesterol and whole-body homeostasis, SCD1 acts as the major regulator of new fatty acids, finely tuning the monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA) ratio. Intriguingly, SCD1 is directly regulated by LXRs. Despite LXRs agonists have elicited great interest as a promising therapeutic target for cancer, LXR's ability to induce SCD1 and new fatty acids synthesis represent a major obstacle in the development of new effective treatments. Thus, further investigations are required to fully dissect the concomitant modulation of both players, to develop specific therapies aimed at blocking intestinal cancer cells proliferation, eventually counteracting CRC progression.
Collapse
Affiliation(s)
- Elena Piccinin
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; INBB, National Institute for Biostructures and Biosystems, Rome, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy; INBB, National Institute for Biostructures and Biosystems, Rome, Italy; National Cancer Center, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy.
| |
Collapse
|
|
24
|
Kasbi Chadli F, Treguier M, Briand F, Sulpice T, Ouguerram K. Ezetimibe Enhances Macrophage-to-Feces Reverse Cholesterol Transport in Golden Syrian Hamsters Fed a High-Cholesterol Diet. J Pharmacol Exp Ther 2020; 375:349-356. [PMID: 32873624 DOI: 10.1124/jpet.120.000062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 08/04/2020] [Indexed: 11/22/2022] Open
Abstract
The aim of this work was to evaluate reverse cholesterol transport (RCT) in hamster, animal model expressing CETP under a high cholesterol diet (HF) supplemented with Ezetimibe using primary labelled macrophages. We studied three groups of hamsters (n=8/group) for 4 weeks: 1) chow diet group: Chow, 2) High cholesterol diet group: HF and 3) HF group supplemented with 0.01% of ezetimibe: HF+0.01%Ezet. Following intraperitoneal injection of 3H-cholesterol-labelled hamster primary macrophages, we measured the in vivo macrophage-to-feces RCT. .HF group exhibited an increase of triglycerides (TG), cholesterol, glucose in plasma and higher TG and cholesterol content in liver (p<0.01) compared to Chow group. Ezetimibe induced a significant decrease in plasma cholesterol with a lower LDL and VLDL cholesterol (p<0.001) and in liver cholesterol (p<0.001) and TG (p<0.01) content compared to HF. In vivo RCT essay showed an increase of tracer level in plasma and liver (p<0.05) but not in feces in HF compared to Chow group. The amount of labelled total sterol and cholesterol in liver and feces was significantly reduced (p<0.05) and increased (p=0.05) respectively with Ezetimibe treatment. No significant increase was obtained for labelled feces bile acids in HF+0.01%Ezet compared to HF. Ezetimibe decreased SCD1 gene expression and increased SR-B1 (p<0.05) in liver but did not affect NPC1L1 nor ABCG5 and ABCG8 expression in jejunum. In conclusion, ezetimibe exhibited an atheroprotective effect by enhancing RCT in hamster and decreasing LDL cholesterol. Ours findings showed also a hepatoprotective effect of ezetimibe by decreasing hepatic fat content. Significance Statement This work was assessed to determine the effect of ezetimibe treatment on high cholesterol diet induced disturbances and especially the effect on reverse cholesterol transport in animal model with CETP activity and using labelled primary hamster macrophages. We were able to demonstrate that ezetimibe exhibited an atheroprotective effect by enhancing RCT and by decreasing LDL cholesterol in hamster. We showed also a hepatoprotective effect of ezetimibe by decreasing hepatic fat content.
Collapse
Affiliation(s)
| | - Morgan Treguier
- 1 INRAe, UMR 1280, Physiopathologie des Adaptations Nutritionnelles, CHU Hotel-Dieu, F-44 000 Nantes, France;, France
| | | | | | | |
Collapse
|
|
25
|
Yamanashi Y, Takada T, Yamamoto H, Suzuki H. NPC1L1 Facilitates Sphingomyelin Absorption and Regulates Diet-Induced Production of VLDL/LDL-associated S1P. Nutrients 2020; 12:nu12092641. [PMID: 32872588 PMCID: PMC7551898 DOI: 10.3390/nu12092641] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/27/2020] [Accepted: 08/28/2020] [Indexed: 01/22/2023] Open
Abstract
Niemann-Pick C1-Like 1 (NPC1L1) is a cholesterol importer and target of ezetimibe, a cholesterol absorption inhibitor used clinically for dyslipidemia. Recent studies demonstrated that NPC1L1 regulates the intestinal absorption of several fat-soluble nutrients, in addition to cholesterol. The study was conducted to reveal new physiological roles of NPC1L1 by identifying novel dietary substrate(s). Very low-density lipoprotein and low-density lipoprotein (VLDL/LDL) are increased in Western diet (WD)-fed mice in an NPC1L1-dependent manner, so we comprehensively analyzed the NPC1L1-dependent VLDL/LDL components. Apolipoprotein M (apoM), a binding protein of sphingosine-1-phosphate (S1P: a lipid mediator), and S1P were NPC1L1-dependently increased in VLDL/LDL by WD feeding. S1P is metabolized from sphingomyelin (SM) and SM is abundant in WD, so we focused on intestinal SM absorption. In vivo studies with Npc1l1 knockout mice and in vitro studies with NPC1L1-overexpressing cells revealed that SM is a physiological substrate of NPC1L1. These results suggest a scenario in which dietary SM is absorbed by NPC1L1 in the intestine, followed by SM conversion to S1P and, after several steps, S1P is exported into the blood as the apoM-bound form in VLDL/LDL. Our findings provide insight into the functions of NPC1L1 for a better understanding of sphingolipids and S1P homeostasis.
Collapse
Affiliation(s)
| | - Tappei Takada
- Correspondence: ; Tel.: +81-3-3815-5411 (ext. 37514)
| | | | | |
Collapse
|
|
26
|
Ke XX, Chao H, Abbas MN, Kausar S, Gul I, Ji H, Yang L, Cui H. Niemann-Pick type C1 regulates cholesterol transport and metamorphosis in silkworm, Bombyx mori (Dazao). Int J Biol Macromol 2020; 152:525-534. [DOI: 10.1016/j.ijbiomac.2020.02.296] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/07/2020] [Accepted: 02/25/2020] [Indexed: 01/29/2023]
|
|
27
|
Zheng JC, Yue XR, Kuang WQ, Li SL, Tang R, Zhang ZF, Kurban A, Zhao C, Liu TX, Jing X. NPC1b as a novel target in controlling the cotton bollworm, Helicoverpa armigera. PEST MANAGEMENT SCIENCE 2020; 76:2233-2242. [PMID: 31976620 DOI: 10.1002/ps.5761] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 01/06/2020] [Accepted: 01/24/2020] [Indexed: 06/10/2023]
Abstract
BACKGROUND Insects cannot synthesize sterols and must acquire them from food. The mechanisms underlying how insects uptake dietary sterols are largely unknown except that NPC1b, an integral membrane protein, has been shown to be responsible for dietary cholesterol uptake in Drosophila melanogaster. However, whether NPC1b orthologs in other insect species, particularly the economically important pests, function similarly remains to be determined. RESULTS In this study, we characterized the function of NPC1b in Helicoverpa armigera, a global pest that causes severe yield losses to many important crops. Limiting dietary cholesterol uptake to insects significantly inhibited food ingestion and weight gain. Compared to the wild-type H. armigera, the CRISPR/Cas9-edited NPC1b mutant larvae were incapable of getting adequate cholesterol and died in their early life stage. Gene expression profile and in situ hybridization analyses indicated that NPC1b was mainly expressed in the midgut where dietary cholesterol was absorbed. Expression of NPC1b was also correlated with the feeding life stages and was especially upregulated during early larval instars. Protein-ligand docking and sequence similarity analyses further demonstrated that NPC1b proteins of lepidopteran insects shared a relatively conserved cholesterol binding region, NPC1b_NTD, which, however, was highly divergent from bees-derived sequences. CONCLUSION NPC1b was crucial for dietary cholesterol uptake and growth of H. armigera, and therefore could serve as an insecticide target for the development of a novel pest-management approach to control this economically significant insect pest with little off-target effect on bees and sterol-autotrophic animals. © 2020 Society of Chemical Industry.
Collapse
Affiliation(s)
- Jin-Cheng Zheng
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Basic Medical School, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China
| | - Xiao-Rong Yue
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| | - Wen-Qing Kuang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| | - Sa-Li Li
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| | - Rui Tang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| | - Zhan-Feng Zhang
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| | - Anwar Kurban
- College of Agronomy, Xinjiang Agricultural University, Urumqi, Xinjiang, China
| | - Chaoyang Zhao
- College of Natural and Agricultural Sciences, University of California, Riverside, CA, USA
| | - Tong-Xian Liu
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiangfeng Jing
- State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
- Key Laboratory of Integrated Pest Management on the Loess Plateau of Ministry of Agriculture, College of Plant Protection, Northwest A&F University, Yangling, Shaanxi, China
| |
Collapse
|
|
28
|
Kiourtzidis M, Kühn J, Schutkowski A, Baur AC, Hirche F, Stangl GI. Inhibition of Niemann-Pick C1-like protein 1 by ezetimibe reduces uptake of deuterium-labeled vitamin D in mice. J Steroid Biochem Mol Biol 2020; 197:105504. [PMID: 31682937 DOI: 10.1016/j.jsbmb.2019.105504] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/22/2019] [Accepted: 10/22/2019] [Indexed: 12/17/2022]
Abstract
For a long time, orally ingested vitamin D was assumed to enter the body exclusively via simple passive diffusion. Recent data from in vitro experiments have described Niemann-Pick C1-like protein 1 (Npc1l1) as an important sterol transporter for vitamin D absorption. However, short-term applications of ezetimibe, which inhibits Npc1l1, were not associated with reduced vitamin D uptake in animals and humans. The current study aimed to elucidate the effect of long-term inhibition of Npc1l1 by ezetimibe on the uptake and storage of orally administered triple deuterated vitamin D3 (vitamin D3-d3). Therefore, 30 male wild-type mice were randomly assigned into three groups and received diets with 25 μg/kg of vitamin D3-d3 that contained 0 (control group), 50 or 100 mg/kg ezetimibe for six weeks. Mice fed diets with 50 or 100 mg/kg ezetimibe had lower circulating levels of cholesterol than control mice (-12 %, -15 %, P < 0.01). In contrast, the concentrations of 7-dehydrocholesterol in serum (P < 0.001) and liver (P < 0.05) were higher in mice treated with ezetimibe than in control mice, indicating an increased sterol synthesis to compensate for cholesterol reduction. Long-term application of ezetimibe significantly reduced the concentrations of vitamin D3-d3 in the serum and tissues of mice. The magnitude of vitamin D3 reduction was comparable between the two ezetimibe groups. In comparison to the control group, mice treated with ezetimibe had lower concentrations of deuterated vitamin D3 compared with the control group in serum (62 %, P < 0.001), liver (79 %, P < 0.001), kidney (54 %, P < 0.001), adipose tissues (55 %, P < 0.001) and muscle (41 %, P < 0.001). Surprisingly, the serum concentration of deuterated 25-hydroxyvitamin D3 was higher in the group fed 100 mg/kg ezetimibe than in the control group (P < 0.05). The protein expression of the vitamin D hydroxylases Cyp2r1, Cyp27a1, Cyp3a11, Cyp24a1 and Cyp2j3 in liver and Cyp27b1 and Cyp24a1 in kidney remained largely unaffected by ezetimibe. To conclude, Npc1l1 appears to be crucial for the uptake of orally ingested vitamin D because long-term inhibition of Npc1l1 by ezetimibe strongly reduced the levels of deuterium-labeled vitamin D in the body; the observed rise in deuterated 25-hydroxyvitamin D3 in serum of these mice can not be explained by the expression levels of the key enzymes involved in vitamin D hydroxylation.
Collapse
Affiliation(s)
- Mikis Kiourtzidis
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany.
| | - Julia Kühn
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany.
| | - Alexandra Schutkowski
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany.
| | - Anja C Baur
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany; Competence Cluster of Cardiovascular Health and Nutrition (nutriCARD), Halle-Jena-Leipzig, Germany.
| | - Frank Hirche
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany.
| | - Gabriele I Stangl
- Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany; Competence Cluster of Cardiovascular Health and Nutrition (nutriCARD), Halle-Jena-Leipzig, Germany.
| |
Collapse
|
|
29
|
Transcriptomic Responses in the Livers and Jejunal Mucosa of Pigs under Different Feeding Frequencies. Animals (Basel) 2019; 9:ani9090675. [PMID: 31547261 PMCID: PMC6769473 DOI: 10.3390/ani9090675] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 09/06/2019] [Accepted: 09/10/2019] [Indexed: 12/02/2022] Open
Abstract
Simple Summary Nutrition management strategies are closely related to body development and health, and feeding frequency affects pig feed intake, feed efficiency, body composition, and growth performance. However, the effect of feeding one time daily and two times daily on the intestine has been given less attention. In this study, we investigated the transcriptomic responses induced in the livers and jejunal mucosa of growing pigs by daily feeding schedules. We found that when compared with feeding once daily, two times feeding had no significant effect on the growth performance of growing pigs with the same average daily feed intake. A two meals regimen reduced the concentration of triglycerides in serum and liver, affected the body metabolism by promoting lipid transport, lipogenesis, fatty acid oxidation, chylomicron formation and transport, gluconeogenesis, and inhibiting adipocyte differentiation. These findings support the idea that different feeding regimens could affect lipid metabolism and can be effective in nutritional strategies against metabolic dysfunction. Abstract Feeding frequency in one day is thought to be associated with nutrient metabolism and the physical development of the body in both experimental animals and humans. The present study was conducted to investigate transcriptomic responses in the liver and jejunal mucosa of pigs to evaluate the effects of different feeding frequencies on the body’s metabolism. Twelve Duroc × Landrance × Yorkshire growing pigs with an average initial weight (IW) of 14.86 ± 0.20 kg were randomly assigned to two groups: feeding one time per day (M1) and feeding two times per day (M2); each group consisted of six replicates (pens), with one pig per pen. During the one-month experimental period, pigs in the M1 group were fed on an ad libitum basis at 8:00 am; and the M2 group was fed half of the standard feeding requirement at 8:00 am and adequate feed at 16:00 pm. The results showed that average daily feed intake, average daily gain, feed:gain, and the organ indices were not significantly different between the two groups (p > 0.05). The total cholesterol (T-CHO), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) concentrations in the serum, and the TG concentration in the liver in the M2 groups were significant lower than those in the M1 group, while the T-CHO concentration in the liver were significant higher in the M2 group (p < 0.05). Jejunal mucosa transcriptomic analysis showed the gene of Niemann-Pick C1-Like 1 (NPC1L1), Solute carrier family 27 member 4 (SLC27A4), Retinol binding protein 2 (RBP2), Lecithin retinol acyltransferase (LRAT), Apolipoprotein A (APOA 1, APOA 4, APOB, and APOC 3) were upregulated in the M2 group, indicating that fat digestion was enhanced in the small intestine, whereas Perilipin (PLIN1 and PLIN2) were downregulated, indicating that body fat was not deposited. Fatty acid binding proteins (FABPs) and Acetyl-CoA acyltransferase 1 (ACAA1) were upregulated in the M2 group, indicating that two times feeding daily could promote the oxidative decomposition of fatty acids. In conclusion, under the conditions in this study, the feeding frequency had no significant effect on the growth performance of pigs, but affected the body’s lipid metabolism, and the increase of feeding frequency promoted the fat digestion in the small intestine and the oxidative decomposition of fatty acids in the liver.
Collapse
|
|
30
|
Malhotra P, Soni V, Yamanashi Y, Takada T, Suzuki H, Gill RK, Saksena S, Dudeja PK, Alrefai WA. Mechanisms of Niemann-Pick type C1 Like 1 protein degradation in intestinal epithelial cells. Am J Physiol Cell Physiol 2019; 316:C559-C566. [PMID: 30789754 PMCID: PMC6482670 DOI: 10.1152/ajpcell.00465.2018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/24/2018] [Accepted: 02/12/2019] [Indexed: 01/06/2023]
Abstract
Intestinal Niemann-Pick C1 Like 1 (NPC1L1) protein plays a key role in cholesterol absorption. A decrease in NPC1L1 expression has been implicated in lowering plasma cholesterol and mitigating the risk for coronary heart disease. Little is known about the mechanisms responsible for NPC1L1 protein degradation that upon activation may lead to a reduction in NPC1L1 protein levels in intestinal epithelial cells (IECs). In current studies, the human intestinal Caco-2 and HuTu-80 cell lines expressing NPC1L1-hemagglutinin fusion protein were used to investigate the mechanisms of NPC1L1 protein degradation. Incubation with the proteasome inhibitors MG-132 and lactacystin (10 μM, 24 h) significantly increased NPC1L1 protein levels in IECs. Also, the inhibition of the lysosomal pathway with bafilomycin A1 (80 nM, 24 h) resulted in a significant increase in NPC1L1 protein levels. Immunoprecipitation studies showed that NPC1L1 protein is both a poly- and monoubiquinated polypeptide and that the inhibition of the proteasomal pathway remarkably increased the level of the polyubiquinated NPC1L1. The surface expression of NPC1L1 was increased by the inhibition of both proteasomal and lysosomal pathways. Furthermore, the pharmacological inhibition of mitogen-activated protein kinase pathway (PD-98059, 15 μM, 24 h) and siRNA silencing of ERK1/2 resulted in a significant decrease in NPC1L1 protein levels in IECs. In conclusion, our results showed that basal level of intestinal cholesterol transporter NPC1L1 protein is modulated by both ubiquitin proteasome- and lysosome-dependent degradation as well as by ERK1/2-dependent pathway. The modulation of these pathways may provide novel clues for therapeutic intervention to inhibit cholesterol absorption and lower plasma cholesterol.
Collapse
Affiliation(s)
- Pooja Malhotra
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois
| | - Vinay Soni
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois
| | - Yoshihide Yamanashi
- Department of Pharmacy, The University of Tokyo Hospital , Tokyo , Japan
- Faculty of Medicine, The University of Tokyo , Tokyo , Japan
| | - Tappei Takada
- Department of Pharmacy, The University of Tokyo Hospital , Tokyo , Japan
- Faculty of Medicine, The University of Tokyo , Tokyo , Japan
| | - Hiroshi Suzuki
- Department of Pharmacy, The University of Tokyo Hospital , Tokyo , Japan
- Faculty of Medicine, The University of Tokyo , Tokyo , Japan
| | - Ravinder K Gill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois
| | - Seema Saksena
- Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois
| | - Pradeep K Dudeja
- Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois
| | - Waddah A Alrefai
- Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois
| |
Collapse
|
|
31
|
Ontawong A, Duangjai A, Muanprasat C, Pasachan T, Pongchaidecha A, Amornlerdpison D, Srimaroeng C. Lipid-lowering effects of Coffea arabica pulp aqueous extract in Caco-2 cells and hypercholesterolemic rats. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 52:187-197. [PMID: 30599898 DOI: 10.1016/j.phymed.2018.06.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 05/17/2018] [Accepted: 06/18/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Coffea arabica pulp (CP) is the first by-product obtained from coffee berries during coffee processing. The major constituents of CP, including chlorogenic acid, caffeine, and epicatechin exhibit anti-hyperlipidemic effects in in vitro and in vivo models. Whether Coffea arabica pulp aqueous extract (CPE) has a lipid-lowering effect remains unknown. PURPOSE This study examined the effect of CPE on cholesterol absorption, and identified the mechanisms involved in lowered cholesterol in in vitro and in vivo models. METHODS Uptake of [3H]-cholesterol micelles and the mode of CPE inhibition were determined using human intestinal Caco-2 cells, and subsequently, confirmed using isolated rat jejunal loops. In addition, the 12-week high-fat diet-induced hypercholesterolemic rats (HF) received either CPE (1000 mg/kg BW), a sole and high dose which was selected because it contained approximately 12 mg of CGA that was previously shown to have lipid-lowering effects, or ezetimibe (10 mg/kg BW), a cholesterol inhibitor. The rats were divided into HF, HF ++ CPE, and HF ++ ezetimibe groups for the next 12 weeks. Normal rats received a normal diet (ND) and CPE (ND + CPE). Body weights and lipid profiles were evaluated. Cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), protein expression and liver X receptor alpha (LXRα) mRNA expression were determined. In vitro micellar complex properties were also investigated. RESULTS CPE inhibited [3H]-cholesterol micelle transport in Caco-2 cells and rat jejunal loops in a dose-dependent, non-competitive manner partly by decreasing membrane NPC1L1 expression. Congruently, CPE and its major constituents activated LXRα which, in turn, down-regulated NPC1L1. Furthermore, CPE interfered with physicochemical characteristics of cholesterol mixed micelles. These data were consistent with decreased body weight and slowed body weight gain and improved lipid profiles by CPE in hypercholesterolemic rats while no change occurred in these parameters in normal rats. Down-regulated intestinal NPC1L1 expression mediated by increased LXRα mRNA were also observed in HF ++ CPE and ND + CPE rats. CONCLUSION CPE has a cholesterol-lowering effect in in vitro and in vivo via inhibition of intestinal cholesterol absorption by down-regulating NPC1L1 mediated LXRα activation and interfering with micellar complex formation. Accordingly, CPE could be developed as nutraceutical product to prevent dyslipidemia-induced obesity and insulin resistance.
Collapse
Affiliation(s)
- Atcharaporn Ontawong
- Department of Physiology, Faculty of Medicine, Chiang Mai University, 110 Intavaroros Rd., Sri-phum District, Muang, Chiang Mai 50200, Thailand; Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Acharaporn Duangjai
- Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand
| | - Chatchai Muanprasat
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tipthida Pasachan
- Department of Physiology, Faculty of Medicine, Chiang Mai University, 110 Intavaroros Rd., Sri-phum District, Muang, Chiang Mai 50200, Thailand
| | - Anchalee Pongchaidecha
- Department of Physiology, Faculty of Medicine, Chiang Mai University, 110 Intavaroros Rd., Sri-phum District, Muang, Chiang Mai 50200, Thailand
| | | | - Chutima Srimaroeng
- Department of Physiology, Faculty of Medicine, Chiang Mai University, 110 Intavaroros Rd., Sri-phum District, Muang, Chiang Mai 50200, Thailand.
| |
Collapse
|
|
32
|
Yamanashi Y, Takada T, Suzuki H. Associations between Lifestyle-Related Diseases and Transporters Involved in Intestinal Absorption and Biliary Excretion of Cholesterol. Biol Pharm Bull 2018; 41:1-10. [PMID: 29311470 DOI: 10.1248/bpb.b17-00690] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Westernization of dietary habits leads to an increase in lipid intake and is thought to be responsible for an increase in patients with dyslipidemia. It is a well-known fact that the impaired cholesterol homeostasis is closely related to the development of various lifestyle-related diseases such as fatty liver, diabetes, and gallstone as well as dyslipidemia leading to atherosclerosis and cardiovascular diseases such as heart attack and stroke. Therefore, appropriate management of cholesterol levels in the body is considered important in prevention and treatments of these lifestyle-related diseases and in addition, molecular mechanisms controlling plasma (and/or hepatic) cholesterol levels have been intensively studied. Due to its hydrophobicity, cholesterol was long believed to pass through cell membranes by passive diffusion. However, recent studies have identified a number of plasma membrane transporters that are responsible for the cellular uptake or efflux of cholesterol and involved in developments of lifestyle-related diseases. In this review, we focus on Niemann-Pick C1 Like 1 (NPC1L1) and a heterodimer of ATP-binding cassette transporter G5 and G8 (ABCG5/G8), both of which are responsible for intestinal cholesterol absorption and biliary cholesterol secretion, and discuss the relationship between these cholesterol transporters and lifestyle-related diseases. In addition, we also discuss the related uncertainties that need to be explored in future studies.
Collapse
Affiliation(s)
- Yoshihide Yamanashi
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
| | - Tappei Takada
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
| | - Hiroshi Suzuki
- Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo
| |
Collapse
|
|
33
|
Abstract
Vitamin K (VK) is an essential cofactor for the post-translational conversion of peptide-bound glutamate to γ-carboxyglutamate. The resultant vitamin K-dependent proteins are known or postulated to possess a variety of biological functions, chiefly in the maintenance of hemostasis. The vitamin K cycle is a cellular pathway that drives γ-carboxylation and recycling of VK via γ-carboxyglutamyl carboxylase (GGCX) and vitamin K epoxide reductase (VKOR), respectively. In this review, we show how novel molecular biological approaches are providing new insights into the pathophysiological mechanisms caused by rare mutations of both GGCX and VKOR. We also discuss how other protein regulators influence the intermediary metabolism of VK, first through intestinal absorption and second through a pathway that converts some dietary phylloquinone to menadione, which is prenylated to menaquinone-4 (MK-4) in target tissues by UBIAD1. The contribution of MK-4 synthesis to VK functions is yet to be revealed.
Collapse
Affiliation(s)
- Martin J Shearer
- Centre for Haemostasis and Thrombosis, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, United Kingdom;
| | - Toshio Okano
- Department of Hygienic Sciences, Kobe Pharmaceutical University, Kobe 658-8558 Japan;
| |
Collapse
|
|
34
|
Zou J, Zhang S, Li P, Zheng X, Feng D. Supplementation with curcumin inhibits intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice. Nutr Res 2018; 56:32-40. [PMID: 30055772 DOI: 10.1016/j.nutres.2018.04.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 10/17/2022]
Abstract
Atherosclerosis is a major cause of cardiovascular disease caused by high cholesterol. Reduced intestinal cholesterol absorption has been shown to exert strong cholesterol-lowering and antiatherogenic effects. Previously, we reported that curcumin reduced cholesterol absorption in high-fat diet-fed hamster by downregulating the intestinal expression of Niemann-Pick C1-like 1. Here, we tested the hypothesis that supplementation with curcumin can also reduce intestinal cholesterol absorption in high-fat diet-fed apolipoprotein E knockout (ApoE-/-) mice and prevent atherosclerosis development. ApoE-/- mice were fed a high-fat diet supplemented with or without curcumin (0.1% w/w) for 16 weeks. Aortic sinus sections revealed that curcumin supplementation reduced the extent of atherosclerotic lesions by 45%. Curcumin treatment also reduced cholesterol accumulation in the aortas by 56% and lowered plasma total cholesterol and low-density lipoprotein cholesterol levels. Moreover, the antiatherogenic and cholesterol-lowering effects of curcumin coincided with a significant decrease in intestinal cholesterol absorption. It was reduced by nearly 51%, and the decreased cholesterol absorption was modulated by inhibiting the intestinal expression of Niemann-Pick C1-like 1, predominantly in the duodenal and jejunal segments of the small intestine. These findings support the hypothesis that curcumin supplementation reduces intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet-fed ApoE-/- mice. Curcumin affords a potent antiatherogenic action by inhibiting intestinal cholesterol absorption in the mouse.
Collapse
Affiliation(s)
- Jun Zou
- Department of Cardiology, Affiliated NanHai Hospital of Southern Medical University, 528200, China
| | - Shanshan Zhang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, 510080, China
| | - Peiyang Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, 510080, China
| | - Xiumei Zheng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, 510080, China
| | - Dan Feng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University, 510080, China.
| |
Collapse
|
|
35
|
de Boer JF, Kuipers F, Groen AK. Cholesterol Transport Revisited: A New Turbo Mechanism to Drive Cholesterol Excretion. Trends Endocrinol Metab 2018; 29:123-133. [PMID: 29276134 DOI: 10.1016/j.tem.2017.11.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Revised: 11/26/2017] [Accepted: 11/29/2017] [Indexed: 12/31/2022]
Abstract
A fine-tuned balance between cholesterol uptake and excretion by the body is pivotal to maintain health and to remain free from the deleterious consequences of cholesterol accumulation such as cardiovascular disease. The pathways involved in intracellular and extracellular cholesterol transport are a subject of intense investigation and are being unraveled in increasing detail. In addition, insight into the complex interactions between cholesterol and bile acid metabolism has increased considerably in the last couple of years. This review provides an overview of the mechanisms involved in cholesterol uptake and excretion, with a particular emphasis on the most recent progress in this field. Special attention is given to the transintestinal cholesterol excretion (TICE) pathway, which was recently demonstrated to have a remarkably high transport capacity and to be sensitive to pharmacological modulation.
Collapse
Affiliation(s)
- Jan Freark de Boer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Albert K Groen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Vascular Medicine, University of Amsterdam Academic Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
|
36
|
Chen KJ, Jin RM, Shi CC, Ge RL, Hu L, Zou QF, Cai QY, Jin GZ, Wang K. The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma. J Cancer 2018; 9:556-563. [PMID: 29483961 PMCID: PMC5820923 DOI: 10.7150/jca.19996] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 08/15/2017] [Indexed: 12/31/2022] Open
Abstract
Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.
Collapse
Affiliation(s)
- Ke-Ji Chen
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Ri-Ming Jin
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Chun-Chao Shi
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Rui-Liang Ge
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Lei Hu
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Qi-Fei Zou
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Quan-Yu Cai
- Quan-Yu Cai, Department of Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Guang-Zhi Jin
- Guang-Zhi Jin, Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| | - Kui Wang
- The Second Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China
| |
Collapse
|
|
37
|
Juritsch A, Tsai YT, Patel MS, Rideout TC. Transcriptional control of enterohepatic lipid regulatory targets in response to early cholesterol and phytosterol exposure in apoE -/- mice. BMC Res Notes 2017; 10:529. [PMID: 29084592 PMCID: PMC5661921 DOI: 10.1186/s13104-017-2859-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 10/23/2017] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE An excessive rise in blood lipids during pregnancy may promote metabolic dysfunction in adult progeny. We characterized how maternal phytosterol (PS) supplementation affected serum lipids and the expression of lipid-regulatory genes in the intestine and liver of newly-weaned apo-E deficient offspring from dams fed a chow diet supplemented with cholesterol (0.15%, CH) or cholesterol and PS (2%) (CH/PS) throughout pregnancy and lactation. RESULTS Serum lipid concentrations and lipoprotein particle numbers were exacerbated in offspring from cholesterol-supplemented mothers but normalized to chow-fed levels in pups exposed to PS through the maternal diet during gestation and lactation. Compared with the CH pups, pups from PS-supplemented mothers demonstrated higher (p < 0.05) expression of the primary intestinal cholesterol transport protein (Niemann-Pick C1-like 1) and the rate-limiting enzyme in hepatic cholesterol synthesis (HMG-CoAr), suggestive of a compensatory response to restore cholesterol balance. Furthermore, pups from PS-supplemented mothers exhibited a coordinated downregulation (p < 0.05) of several genes regulating fatty acid synthesis including PGC1β, SREBP1c, FAS, and ACC compared with the CH group. These results suggest that maternal PS supplementation during hypercholesterolemic pregnancies protects against aberrant lipid responses in newly-weaned offspring and results in differential regulation of cholesterol and lipid regulatory targets within the enterohepatic loop.
Collapse
Affiliation(s)
- Anthony Juritsch
- Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, 14214, USA
| | - Yi-Ting Tsai
- Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, 14214, USA
| | - Mulchand S Patel
- Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14214, USA
| | - Todd C Rideout
- Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, 14214, USA.
| |
Collapse
|
|
38
|
Lim FT, Lim SM, Ramasamy K. Cholesterol lowering by Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 in adult zebrafish is associated with improved memory and involves an interplay between npc1l1 and abca1. Food Funct 2017; 8:2817-2828. [PMID: 28725889 DOI: 10.1039/c7fo00764g] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This study assessed the cholesterol lowering effect of Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 using adult zebrafish. Animals were fed with a high cholesterol diet (HCD) with/without LAB for seven weeks. Serum and liver cholesterol was quantified using colorimetric and dye staining methods. Expressions of npc1l1 and abca1 in the liver and intestine and appa in the brain were quantified using RT-PCR. Serum and liver cholesterol was significantly lowered in LAB4- and LAB12-fed zebrafish (≤64% and ≤71%, respectively), with reduced liver cholesterol deposition. The cholesterol lowering effect was accompanied by down-regulation of npc1l1 in intestines (≤28.7%), up-regulation of abca1 in the liver (≥30.5%) and down-regulation of appa in the brain (≤24.5%). A moderately strong positive Pearson correlation (r = 0.617, p < 0.01) was found between appa and serum cholesterol. LAB-fed zebrafish exhibited improved spatial learning and memory. LAB4 and LAB12 can be potentially used in preventing hypercholesterolaemia and Alzheimer's diseases.
Collapse
Affiliation(s)
- Fei Tieng Lim
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, University Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
| | - Siong Meng Lim
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, University Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
| | - Kalavathy Ramasamy
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, University Teknologi MARA (UiTM), 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
| |
Collapse
|
|
39
|
Dietary lipid content reorganizes gut microbiota and probiotic L. rhamnosus attenuates obesity and enhances catabolic hormonal milieu in zebrafish. Sci Rep 2017; 7:5512. [PMID: 28717234 PMCID: PMC5514052 DOI: 10.1038/s41598-017-05147-w] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 05/24/2017] [Indexed: 12/25/2022] Open
Abstract
In the present study, we explored whether dietary lipid content influences the gut microbiome in adult zebrafish. Diets containing three different lipid levels (high [HFD], medium [MFD], and low [LFD]) were administered with or without the supplementation of Lactobacillus rhamnosus (P) to zebrafish in order to explore how the dietary lipid content may influence the gut microbiome. Dietary lipid content shifted the gut microbiome structure. The addition of L. rhamnosus in the diets, induced transcriptional reduction of orexigenic genes, upregulation of anorexigenic genes, and transcriptional decrease of genes involved in cholesterol and triglyceride (TAG) metabolism, concomitantly with lower content of cholesterol and TAG. Probiotic feeding also decreased nesfatin-1 peptide in HFD-P and attenuated weight gain in HFD-P and MFD-P fed zebrafish, but not in LFD-P group. Intestinal ultrastructure was not affected by dietary fat level or probiotic inclusion. In conclusion, these findings underline the role of fat content in the diet in altering gut microbiota community by shifting phylotype composition and highlight the potential of probiotics to attenuate high-fat diet-related metabolic disorder.
Collapse
|
|
40
|
Jesch ED, Carr TP. Food Ingredients That Inhibit Cholesterol Absorption. Prev Nutr Food Sci 2017; 22:67-80. [PMID: 28702423 PMCID: PMC5503415 DOI: 10.3746/pnf.2017.22.2.67] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 05/23/2017] [Indexed: 12/12/2022] Open
Abstract
Cholesterol is a vital component of the human body. It stabilizes cell membranes and is the precursor of bile acids, vitamin D and steroid hormones. However, cholesterol accumulation in the bloodstream (hypercholesterolemia) can cause atherosclerotic plaques within artery walls, leading to heart attacks and strokes. The efficiency of cholesterol absorption in the small intestine is of great interest because human and animal studies have linked cholesterol absorption with plasma concentration of total and low density lipoprotein cholesterol. Cholesterol absorption is highly regulated and influenced by particular compounds in the food supply. Therefore, it is desirable to learn more about natural food components that inhibit cholesterol absorption so that food ingredients and dietary supplements can be developed for consumers who wish to manage their plasma cholesterol levels by non-pharmacological means. Food components thus far identified as inhibitors of cholesterol absorption include phytosterols, soluble fibers, phospholipids, and stearic acid.
Collapse
Affiliation(s)
- Elliot D Jesch
- Department of Food, Nutrition and Packaging Sciences, Clemson University, Clemson, SC 29634, USA
| | - Timothy P Carr
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| |
Collapse
|
|
41
|
Abstract
Vitamin K is a cofactor for γ-glutamyl carboxylase, which catalyzes the posttranslational conversion of specific glutamyl residues to γ-carboxyglutamyl residues in a variety of vitamin K-dependent proteins (VKDPs) involved in blood coagulation, bone and cartilage metabolism, signal transduction, and cell proliferation. Despite the great advances in the genetic, structural, and functional studies of VKDPs as well as the enzymes identified as part of the vitamin K cycle which enable it to be repeatedly recycled within the cells, little is known of the identity and roles of key regulators of vitamin K metabolism in mammals and humans. This review focuses on new insights into the molecular mechanisms underlying the intestinal absorption and in vivo tissue conversion of vitamin K1 to menaquinone-4 (MK-4) with special emphasis on two major advances in the studies of intestinal vitamin K transporters in enterocytes and a tissue MK-4 biosynthetic enzyme UbiA prenyltransferase domain-containing protein 1 (UBIAD1), which participates in the in vivo conversion of a fraction of dietary vitamin K1 to MK-4 in mammals and humans, although it remains uncertain whether UBIAD1 functions as a key regulator of intracellular cholesterol metabolism, bladder and prostate tumor cell progression, vascular integrity, and protection from oxidative stress.
Collapse
|
|
42
|
Feng D, Zou J, Zhang S, Li X, Li P, Lu M. Bisphenol A promotes cholesterol absorption in Caco-2 cells by up-regulation of NPC1L1 expression. Lipids Health Dis 2017; 16:2. [PMID: 28057006 PMCID: PMC5217666 DOI: 10.1186/s12944-016-0395-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 12/15/2016] [Indexed: 02/06/2023] Open
Abstract
Background Bisphenol A (BPA), an commonly exposed environmental chemicals in humans, has been shown to have a hypercholesterolemic effect with molecular mechanism not clear. Since intestinal cholesterol absorption plays a major role in maintaining total body cholesterol homeostasis, the present study is to investigate whether BPA affects cholesterol absorption in the intestinal Caco-2 cells. Methods: The Caco-2 cells were pretreated with BPA at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and sterol regulatory element binding protein-2 (SREBP-2) was analyzed by Western blot and qPCR. Results We found that confluent Caco-2 cells expressed NPC1L1, and the absorption of cholesterol in the cells was inhibited by ezetimibe, a specific inhibitor of NPC1L1. We then pretreated the cells with 0.1–10 nM BPA for 24 h and found that BPA at 1 and 10 nM doses promoted cholesterol absorption. In addition, we found that the BPA-induced promotion of cholesterol absorption was associated with significant increase in the levels of NPC1L1 protein and NPC1L1 mRNA. Moreover, the stimulatory effects of BPA on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the SREBP-2 pathway. Conclusions This study provides the first evidence that BPA promotes cholesterol absorption in the intestinal cells and the stimulatory effect of BPA is mediated, at least in part, by SREBP-2-NPC1L1 signaling pathway.
Collapse
Affiliation(s)
- Dan Feng
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University (Northern Campus), 74 Zhongshan Road 2, Guangzhou, Guangdong Province, 510080, China.
| | - Jun Zou
- Department of Cardiology, Affiliated NanHai Hospital of Southern Medical University, Foshan, 528200, China
| | - Shanshan Zhang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University (Northern Campus), 74 Zhongshan Road 2, Guangzhou, Guangdong Province, 510080, China
| | - Xuechun Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University (Northern Campus), 74 Zhongshan Road 2, Guangzhou, Guangdong Province, 510080, China
| | - Peiyang Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University (Northern Campus), 74 Zhongshan Road 2, Guangzhou, Guangdong Province, 510080, China
| | - Minqi Lu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Preventive Medicine, School of Public Health, Sun Yat-sen University (Northern Campus), 74 Zhongshan Road 2, Guangzhou, Guangdong Province, 510080, China
| |
Collapse
|
|
43
|
Widdowson WM, McGowan A, Phelan J, Boran G, Reynolds J, Gibney J. Vascular Disease Is Associated With the Expression of Genes for Intestinal Cholesterol Transport and Metabolism. J Clin Endocrinol Metab 2017; 102:326-335. [PMID: 27841945 DOI: 10.1210/jc.2016-2728] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/07/2016] [Indexed: 01/10/2023]
Abstract
CONTEXT Intestinal cholesterol metabolism is important in influencing postprandial lipoprotein concentrations, and might be important in the development of vascular disease. OBJECTIVE This study evaluated associations between expression of intestinal cholesterol metabolism genes, postprandial lipid metabolism, and endothelial function/early vascular disease in human subjects. DESIGN/PATIENTS One hundred patients undergoing routine oesophago-gastro-duodenoscopy were recruited. mRNA levels of Nieman-Pick C1-like 1 protein (NPC1L1), ABC-G5, ABC-G8, ABC-A1, microsomal tissue transport protein (MTTP), and sterol-regulatory element-binding protein (SREBP)-2 were measured in duodenal biopsies using quantitative reverse transcription polymerase chain reaction. Postprandially, serum lipid and glycemic profiles were measured, endothelial function was assessed using fasting, and postprandial flow-mediated dilatation (FMD) and carotid intima-media thickness (IMT). Subjects were divided into those above and below the median value of relative expression of each gene, and results were compared between the groups. RESULTS There were no between-group differences in demographic variables or classical cardiovascular risks. For all genes, the postprandial triglyceride incremental area under the curve was greater (P < 0.05) in the group with greater expression. Postprandial apolipoprotein B48 (ApoB48) levels were greater (P < 0.05) in groups with greater expression of NPC1L1, ABC-G8, and SREBP-2. For all genes, postprandial but not fasting FMD was lower (P < 0.01) in the group with greater expression. Triglyceride and ApoB48 levels correlated significantly with postprandial FMD. Carotid artery IMT was greater (P < 0.05) in groups with greater expression of MTTP, ABC-A1, and SREBP-2. CONCLUSION Intestinal cholesterol metabolism gene expression is significantly associated with postprandial increment in triglycerides, intestinal ApoB48, and reduced postprandial FMD. Some genes were also associated with increased IMT. These findings suggest a role of intestinal cholesterol metabolism in development of early vascular disease.
Collapse
Affiliation(s)
| | - Anne McGowan
- Department of Endocrinology and Diabetes Mellitus and
| | - James Phelan
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - Gerard Boran
- Department of Chemical Pathology, Tallaght Hospital, Tallaght, Dublin 24, Ireland; and
| | - John Reynolds
- Department of Surgery, St. James's Hospital, Dublin 8, Ireland
| | - James Gibney
- Department of Endocrinology and Diabetes Mellitus and
| |
Collapse
|
|
44
|
Yan H, Fei N, Wu G, Zhang C, Zhao L, Zhang M. Regulated Inflammation and Lipid Metabolism in Colon mRNA Expressions of Obese Germfree Mice Responding to Enterobacter cloacae B29 Combined with the High Fat Diet. Front Microbiol 2016; 7:1786. [PMID: 27877172 PMCID: PMC5099522 DOI: 10.3389/fmicb.2016.01786] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 10/24/2016] [Indexed: 01/07/2023] Open
Abstract
Increased evidences have demonstrated that gut microbiota targeted diet intervention can alleviate obesity and related metabolic disorders. The underlying mechanism of interactions among diet, microbiota, and host still remains unclear. Enterobacter cloacae B29, an endotoxin-producing strain dominated in the gut of a morbidly obese volunteer (weight 174.8 kg, BMI 58.8 kg m-2) was isolated and transplanted to germfree mice (inoculated 1010 cells of B29 per day for 1 week). Using deep mRNA sequencing technology, we compared different gene expression profiles in the colon samples of the germfree mice treated with/without B29 and/or high fat diet (HFD) for 16 weeks and identified 279 differential expressed genes in total, including up-regulated genes Apoa4 (fold change, 2.77), Ido1 (2.66), Cyp4a10 (7.01), and down-regulated genes Cyp2e1 (0.11), Cyp26b1 (0.34), Akr1b7 (0.42), Adipoq (0.36), Cyp1a1 (0.11), Apoa1 (0.44), Npc1l1 (0.37), Tff2 (0.13), Apoc1 (0.30), Ctla2a (0.34), Mttp (0.49), Lpl (0.48). Fifty-nine GO biological processes and five KEGG pathways, particularly the peroxisome proliferator-activated receptors signaling pathway, were significantly enriched in response to HFD+B29, which were mainly relevant to inflammation and the metabolism of lipid, lipoprotein, and sterols. These functional changes were consistent with the developed obesity, insulin-resistance, and aggravated inflammatory conditions of the HFD+B29 mice. This work provides insight into the gene expression changes in response to HFD+B29, helping to understand the mechanism of the interactions among HFD, B29 and the germfree mice.
Collapse
Affiliation(s)
- Huiying Yan
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Na Fei
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Guojun Wu
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Chenhong Zhang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Liping Zhao
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| | - Menghui Zhang
- State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University Shanghai, China
| |
Collapse
|
|
45
|
Yuan Q, Fu Z, Wei J, Li PS, Miao HH, Qu YX, Xu J, Qin J, Li BL, Song BL, Ma Y. Identification and characterization of NPC1L1 variants in Uygur and Kazakh with extreme low-density lipoprotein cholesterol. Biochem Biophys Res Commun 2016; 479:628-635. [DOI: 10.1016/j.bbrc.2016.09.164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 09/29/2016] [Indexed: 01/20/2023]
|
|
46
|
Kikuchi T, Orihara K, Oikawa F, Han SI, Kuba M, Okuda K, Satoh A, Osaki Y, Takeuchi Y, Aita Y, Matsuzaka T, Iwasaki H, Yatoh S, Sekiya M, Yahagi N, Suzuki H, Sone H, Nakagawa Y, Yamada N, Shimano H. Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression. Mol Metab 2016; 5:1092-1102. [PMID: 27818935 PMCID: PMC5081412 DOI: 10.1016/j.molmet.2016.09.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 09/06/2016] [Accepted: 09/10/2016] [Indexed: 12/12/2022] Open
Abstract
Objective The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown. Methods To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions. Results Plasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann–Pick C1-like 1 (Npc1l1), a rate-limiting transporter mediating intestinal cholesterol absorption, was reduced in the small intestine of CREBH Tg mice. Adenosine triphosphate-binding cassette transporter A1 (Abca1), Abcg5/8, and scavenger receptor class B, member 1 (Srb1) expression levels were also reduced in CREBH Tg mice. Promoter assays revealed that CREBH directly regulates Npc1l1 expression. Conversely, CREBH null mice exhibited higher intestinal Npc1l1 expression, elevated plasma and hepatic cholesterol, and lower fecal output. Conclusion Intestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia.
Plasma cholesterol, hepatic lipid, and gallstones were lower in CREBH Tg mice. Expression of intestinal Npc1l1 was reduced in CREBH Tg mice. CREBH directly down-regulates mouse Npc1l1 promoter activity. Intestinal CREBH regulates dietary cholesterol flow from the small intestine.
Collapse
Key Words
- ABCG5/8, adenosine triphosphate-binding cassette transporter G5/G8
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Abca1, ATP-binding cassette, sub-family A1
- Apoa4, apolipoprotein A-IV
- CREBH
- CREBH, cyclic AMP-responsive element-binding protein H
- Cholesterol
- Cpt1a, carnitine palmitoyltransferase 1a, liver
- Cyp7a1, cytochrome P450, family 7, subfamily a, polypeptide 1
- ER, endoplasmic reticulum
- FGF21, fibroblast growth factor 21
- FXR, Farnesoid X receptor
- Intestine
- LD, lithogenic diet
- LPL, lipoprotein lipase
- LXR, liver X receptor
- NEFA, non-esterified fatty acids
- NPC1L1, Nieman Pick C1-like 1
- Npc1l1
- PPARα, proliferator activated receptor alpha
- RCT, reverse cholesterol transport
- SREBP, sterol regulatory element-binding protein
- Shp, small heterodimer partner
- Srb1, scavenger receptor class B, member 1
- Srebf, sterol regulatory element-binding factor
- TG, triglyceride
- WT, wild type
Collapse
Affiliation(s)
- Takuya Kikuchi
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kana Orihara
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Fusaka Oikawa
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Song-Iee Han
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Motoko Kuba
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Kanako Okuda
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Aoi Satoh
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshinori Osaki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yoshinori Takeuchi
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Yuichi Aita
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Takashi Matsuzaka
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hitoshi Iwasaki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Shigeru Yatoh
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Motohiro Sekiya
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Naoya Yahagi
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hiroaki Suzuki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hirohito Sone
- Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Niigata 951-8510, Japan
| | - Yoshimi Nakagawa
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
| | - Nobuhiro Yamada
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
| | - Hitoshi Shimano
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan.
| |
Collapse
|
|
47
|
Ijssennagger N, Janssen AWF, Milona A, Ramos Pittol JM, Hollman DAA, Mokry M, Betzel B, Berends FJ, Janssen IM, van Mil SWC, Kersten S. Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid. J Hepatol 2016; 64:1158-1166. [PMID: 26812075 DOI: 10.1016/j.jhep.2016.01.016] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 01/14/2016] [Accepted: 01/18/2016] [Indexed: 01/21/2023]
Abstract
BACKGROUND & AIMS The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA alters hepatic expression of many genes. However, no data are available on the effects of OCA in the human liver. Here we generated gene expression profiles in human precision cut liver slices (hPCLS) after treatment with OCA. METHODS hPCLS were incubated with OCA for 24 h. Wild-type or FXR(-/-) mice received OCA or vehicle by oral gavage for 7 days. RESULTS Transcriptomic analysis showed that well-known FXR target genes, including NR0B2 (SHP), ABCB11 (BSEP), SLC51A (OSTα) and SLC51B (OSTβ), and ABCB4 (MDR3) are regulated by OCA in hPCLS. Ingenuity pathway analysis confirmed that 'FXR/RXR activation' is the most significantly changed pathway upon OCA treatment. Comparison of gene expression profiles in hPCLS and mouse livers identified 18 common potential FXR targets. ChIP-sequencing in mouse liver confirmed FXR binding to IR1 sequences of Akap13, Cgnl1, Dyrk3, Pdia5, Ppp1r3b and Tbx6. CONCLUSIONS Our study shows that hPCLS respond to OCA treatment by upregulating well-known FXR target genes, demonstrating its suitability to study FXR-mediated gene regulation. We identified six novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in high or low density lipoprotein observed in NASH and primary biliary cholangitis patients treated with OCA based on the genomic expression profile in hPCLS.
Collapse
Affiliation(s)
- Noortje Ijssennagger
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands
| | - Aafke W F Janssen
- Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, 6703 HD Wageningen, The Netherlands
| | - Alexandra Milona
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands
| | - José M Ramos Pittol
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands
| | - Danielle A A Hollman
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands
| | - Michal Mokry
- Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands
| | - Bark Betzel
- Department of Surgery, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Frits J Berends
- Department of Surgery, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Ignace M Janssen
- Department of Surgery, Rijnstate Hospital, 6815 AD Arnhem, The Netherlands
| | - Saskia W C van Mil
- Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
| | - Sander Kersten
- Nutrition, Metabolism & Genomics Group, Division of Human Nutrition, Wageningen University, 6703 HD Wageningen, The Netherlands
| |
Collapse
|
|
48
|
Zhao D. Challenges associated with elucidating the mechanisms of the hypocholesterolaemic activity of saponins. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.02.023] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
|
|
49
|
Abstract
Vitamin D plays key roles in bone, infectious, inflammatory and metabolic diseases. As most people get inadequate sun exposure for sufficient vitamin D status, they need adequate intake of dietary vitamin D. Many studies see optimizing vitamin D status as a public health priority. It is thus vital to gain deeper insight into vitamin D intestinal absorption. It was long assumed that vitamin D intestinal absorption is a passive process, but new data from our laboratory showed that it is actually far more complex than previously thought. This review describes the fate of vitamin D in the human upper gastrointestinal lumen during digestion and focuses on the proteins involved in the intestinal membrane and cellular transport of vitamin D across the enterocyte. Although recent data significantly improve our understanding of vitamin D intestinal absorption, further studies are still needed to increase our knowledge of the molecular mechanisms underlying this phenomenon.
Collapse
Affiliation(s)
- Emmanuelle Reboul
- INRA, UMR 1260, "Nutrition, Obesity and Risk of Thrombosis", F-13385, Marseille, France.
| |
Collapse
|
|
50
|
Warrier M, Zhang J, Bura K, Kelley K, Wilson MD, Rudel LL, Brown JM. Sterol O-Acyltransferase 2-Driven Cholesterol Esterification Opposes Liver X Receptor-Stimulated Fecal Neutral Sterol Loss. Lipids 2016; 51:151-7. [PMID: 26729489 PMCID: PMC5221701 DOI: 10.1007/s11745-015-4116-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 12/18/2015] [Indexed: 11/28/2022]
Abstract
Statin drugs have proven a successful and relatively safe therapy for the treatment of atherosclerotic cardiovascular disease (CVD). However, even with the substantial low-density lipoprotein (LDL) cholesterol lowering achieved with statin treatment, CVD remains the top cause of death in developed countries. Selective inhibitors of the cholesterol esterifying enzyme sterol-O acyltransferase 2 (SOAT2) hold great promise as effective CVD therapeutics. In mouse models, previous work has demonstrated that either antisense oligonucleotide (ASO) or small molecule inhibitors of SOAT2 can effectively reduce CVD progression, and even promote regression of established CVD. Although it is well known that SOAT2-driven cholesterol esterification can alter both the packaging and retention of atherogenic apoB-containing lipoproteins, here we set out to determine whether SOAT2-driven cholesterol esterification can also impact basal and liver X receptor (LXR)-stimulated fecal neutral sterol loss. These studies demonstrate that SOAT2 is a negative regulator of LXR-stimulated fecal neutral sterol loss in mice.
Collapse
Affiliation(s)
- Manya Warrier
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Jun Zhang
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Kanwardeep Bura
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Kathryn Kelley
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Martha D Wilson
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Lawrence L Rudel
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - J Mark Brown
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
| |
Collapse
|