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Yuan X, Hou Y, Qin N, Xiang L, Jiang Z, Bao X. Flaxseed-derived peptide, Ile-Pro-Pro-Phe (IPPF), ameliorates hepatic cholesterol metabolism to treat metabolic dysfunction-associated steatotic liver disease by promoting cholesterol conversion and excretion. Food Funct 2025; 16:2808-2823. [PMID: 40094418 DOI: 10.1039/d4fo04478a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Flaxseed-derived peptide IPPF has been reported to effectively inhibit cholesterol micellization and reduce cholesterol accumulation in vitro. However, its effects on hepatic cholesterol accumulation and related dysfunction-associated steatotic liver disease (MASLD) in vivo, along with the underlying mechanisms and specific molecular targets, remain unclear. This study investigated the impact of IPPF on hepatic cholesterol accumulation to ameliorate MASLD and its potential mechanisms in vivo. Six-week-old male C57BL/6J mice were fed a high-cholesterol, high-fat diet and treated with different doses of IPPF via oral gavage for six weeks. IPPF intervention significantly reduced hepatic cholesterol levels and oxidative stress damage while increasing fecal cholesterol and bile acid excretion. Non-targeted metabolomics analysis revealed that IPPF primarily affected pathways related to ABC transporters and bile acid metabolism. IPPF intake upregulated the mRNA expression of Abcg5/8 and Cyp7a1 in the liver. Molecular docking, dynamics and Surface plasmon resonance (SPR) simulations demonstrated that IPPF binds strongly to ABCG5/8 and CYP7A1, forming stable complexes. Furthermore, cholesterol accumulation and MASLD in HepG2 cells induced by palmitic acid (PA) was alleviated by IPPF, but this effect was partly stopped when CYP7A1 or ABCG5/8 was inhibited. In conclusion, flaxseed-derived peptide IPPF targets CYP7A1 and ABCG5/8, promoting cholesterol conversion and excretion, thereby reducing hepatic cholesterol accumulation and offering a potential nutritional treatment for MASLD. IPPF can be used as a novel dietary cholesterol-lowering functional ingredient. This study provides a scientific basis and new perspective for the development of cholesterol-lowering functional foods and dietary supplements.
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MESH Headings
- Animals
- Male
- Mice, Inbred C57BL
- Mice
- Flax/chemistry
- Liver/metabolism
- Liver/drug effects
- Cholesterol/metabolism
- Cholesterol 7-alpha-Hydroxylase/metabolism
- Cholesterol 7-alpha-Hydroxylase/genetics
- ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics
- Humans
- ATP Binding Cassette Transporter, Subfamily G, Member 8/metabolism
- ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics
- Diet, High-Fat/adverse effects
- Bile Acids and Salts/metabolism
- Hep G2 Cells
- Molecular Docking Simulation
- Peptides/pharmacology
- Peptides/chemistry
- Oxidative Stress/drug effects
- Lipoproteins
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Affiliation(s)
- Xingyu Yuan
- Department of life science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
| | - Yifeng Hou
- Department of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongoli, P. R. China.
| | - Narisu Qin
- Department of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongoli, P. R. China.
| | - Lu Xiang
- Department of life science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
| | - Zhe Jiang
- Department of life science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P. R. China
| | - Xiaolan Bao
- Department of Food Science and Engineering, Inner Mongolia Agricultural University, Hohhot, Inner Mongoli, P. R. China.
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Xiao MY, Li S, Pei WJ, Gu YL, Piao XL. Natural Saponins on Cholesterol-Related Diseases: Treatment and Mechanism. Phytother Res 2025; 39:1292-1318. [PMID: 39754504 DOI: 10.1002/ptr.8432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 11/27/2024] [Accepted: 12/14/2024] [Indexed: 01/06/2025]
Abstract
Saponins are compounds composed of lipophilic aglycones linked to hydrophilic sugars. Natural saponins are isolated from plants and some Marine organisms. As important cholesterol-lowering drugs, natural saponins have attracted wide attention for their therapeutic potential in a variety of cholesterol-related metabolic diseases. To review the effects of natural saponins on cholesterol-related metabolic diseases, and to deepen the understanding of the cholesterol-lowering mechanism of saponins. The literature related to saponins and cholesterol-lowering diseases was collected using keywords "saponins" and "cholesterol" from PubMed, Web of Science, and Google Scholar from January 2000 to May 2024. The total number of articles related to saponins and cholesterol-lowering diseases was 240 after excluding irrelevant articles. Natural saponins can regulate cholesterol to prevent and treat a variety of diseases, such as atherosclerosis, diabetes, liver disease, hyperlipidemia, cancer, and obesity. Mechanistically, natural saponins regulate cholesterol synthesis and uptake through the AMPK/SREBP2/3-hydroxy-3-methyl-glutaryl coenzyme A reductase pathway and PCSK9/LDLR pathway, and regulate cholesterol efflux and esterification targeting Liver X receptor/ABC pathway and ACAT family. Natural saponins have broad application prospects in regulating cholesterol metabolism, for the development of more cholesterol-lowering drugs provides a new train of thought. However, it is still necessary to further explore the molecular mechanism and expand clinical trials to provide more evidence.
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Affiliation(s)
- Man-Yu Xiao
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Si Li
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Wen-Jing Pei
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Yu-Long Gu
- School of Pharmacy, Minzu University of China, Beijing, China
| | - Xiang-Lan Piao
- School of Pharmacy, Minzu University of China, Beijing, China
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Clark AT, Russo-Savage L, Ashton LA, Haghshenas N, Amselle NA, Schulman IG. A mutation in LXRα uncovers a role for cholesterol sensing in limiting metabolic dysfunction-associated steatohepatitis. Nat Commun 2025; 16:1102. [PMID: 39875396 PMCID: PMC11775210 DOI: 10.1038/s41467-025-56565-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 01/17/2025] [Indexed: 01/30/2025] Open
Abstract
Liver x receptor alpha (LXRα) functions as an intracellular cholesterol sensor that regulates lipid metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, elevated cholesterol in the liver may play a critical role in the development of MASH. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH in LXRα mutant mice suggesting that LXRα normally functions to impede the development of liver disease.
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Affiliation(s)
- Alexis T Clark
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Lillian Russo-Savage
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Neurological Sciences, University of Vermont, Burlington, VT, USA
| | - Luke A Ashton
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Niki Haghshenas
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Nicolas A Amselle
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Ira G Schulman
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA.
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4
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Le May C, Ducheix S, Cariou B, Rimbert A. From Genetic Findings to new Intestinal Molecular Targets in Lipid Metabolism. Curr Atheroscler Rep 2025; 27:26. [PMID: 39798054 DOI: 10.1007/s11883-024-01264-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 01/13/2025]
Abstract
PURPOSE OF REVIEW While lipid-lowering therapies demonstrate efficacy, many patients still contend with significant residual risk of atherosclerotic cardiovascular diseases (ASCVD). The intestine plays a pivotal role in regulating circulating lipoproteins levels, thereby exerting influence on ASCVD pathogenesis. This review underscores recent genetic findings from the last six years that delineate new biological pathways and actors in the intestine which regulate lipid-related ASCVD risk. RECENT FINDINGS Specifically, we detail the role of LIMA1 in cholesterol absorption within enterocytes, the function of PLA2G12B in the expansion and lipidation of chylomicrons, the involvement of SURF4 in lipoprotein secretion, and the discovery of a gut-derived hormone named CHOLESIN that modulates cholesterol homeostasis through GPR146 via a gut-liver crosstalk. We further discuss the potential of these newly identified genes and pathways as novel targets for pharmaceutical intervention. Newly identified genetic and intestinal molecular mechanisms offer promising opportunities for preventing and treating ASCVD, but careful evaluation and further research are needed to optimize their clinical application.
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Affiliation(s)
- Cédric Le May
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Simon Ducheix
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Bertrand Cariou
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France
| | - Antoine Rimbert
- Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, F-44000, Nantes, France.
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Wei M, LYu P, Li P, Hu J, Wu R, Ouyang Q, Guo K. Baolier Capsule's Secret Weapon: Piperine Boosts Cholesterol Excretion to Combat Atherosclerosis. Drug Des Devel Ther 2024; 18:6427-6446. [PMID: 39749187 PMCID: PMC11693944 DOI: 10.2147/dddt.s499598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/19/2024] [Indexed: 01/04/2025] Open
Abstract
Purpose The Baolier capsule (BLEC) is a proprietary Mongolian medicine administered for treating hypercholesterolemia and atherosclerosis (AS). However, the therapeutic effects, primary bioactive ingredients, and potential mechanisms underlying hypercholesterolemia and AS remain unclear. This study aimed to investigate the pharmacological effects, principal active ingredients, and mechanisms of BLEC against hypercholesterolemia and AS. Methods Adeno-associated virus tail vein injection was utilized to construct liver-specific LXRα knockout ApoE-/- mice. A high-fat diet was utilized to feed ApoE-/- mice to build hyperlipidemia and AS mouse models. The aorta or liver stained with Oil Red O was used to assess the effect of the drugs on AS or fatty liver formation after the oral administration of BLEC, piperine, statins, or ezetimibe to the mice following the experimental protocol. Biochemical assays were utilized to evaluate the effect of the drugs on serum lipid levels and cholesterol efflux indicators. Transcriptomics was employed to investigate the effect of BLEC on liver gene expression levels. HPLC-MS/MS was used to determine BLEC and its major components in the liver. Western blotting or quantitative reverse transcription polymerase chain reaction was conducted to detect LXRα, ABCA1, ABCG5, ABCG8, and CYP7A1 expression. Results Here, we revealed that BLEC decreases lipid levels in the serum and liver, as well as decelerates AS by promoting cholesterol excretion. BLEC and piperine, which are the main components exposed in the target liver tissue, activate LXRα to upregulate ABCA1, ABCG5, ABCG8, and CYP7A1, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and feces. Notably, piperines demonstrated synergistic beneficial effects with atorvastatin or ezetimibe, which are two widely used hypocholesterolemic and anti-atherosclerotic drugs. Conclusion BLEC and its main active ingredient, piperine, promote cholesterol excretion, reduce serum cholesterol levels, inhibit AS, and exhibit good clinical application value and prospects.
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Affiliation(s)
- Mengqiu Wei
- Intensive Care Unit, Zhongshan City People’s Hospital, Zhongshan, 528400, People’s Republic of China
| | - Ping LYu
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
| | - Peng Li
- Department of Geriatrics, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, People’s Republic of China
| | - Jing Hu
- Department of Cardiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, People’s Republic of China
| | - Ruozhuo Wu
- School of Biological and Pharmaceutical Engineering, Wuhan Huaxia Institute of Technology, Wuhan, 430223, People’s Republic of China
| | - Qingqing Ouyang
- Department of Rheumatology and Immunology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China
| | - Kai Guo
- Department of Cardiology, The Seventh Affiliated Hospital of Southern Medical University, Southern Medical University, Foshan, 528244, People’s Republic of China
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6
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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7
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Gonzalez E, Lee MD, Tierney BT, Lipieta N, Flores P, Mishra M, Beckett L, Finkelstein A, Mo A, Walton P, Karouia F, Barker R, Jansen RJ, Green SJ, Weging S, Kelliher J, Singh NK, Bezdan D, Galazska J, Brereton NJB. Spaceflight alters host-gut microbiota interactions. NPJ Biofilms Microbiomes 2024; 10:71. [PMID: 39209868 PMCID: PMC11362537 DOI: 10.1038/s41522-024-00545-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
The ISS rodent habitat has provided crucial insights into the impact of spaceflight on mammals, inducing symptoms characteristic of liver disease, insulin resistance, osteopenia, and myopathy. Although these physiological responses can involve the microbiome on Earth, host-microbiota interactions during spaceflight are still being elucidated. We explore murine gut microbiota and host gene expression in the colon and liver after 29 and 56 days of spaceflight using multiomics. Metagenomics revealed significant changes in 44 microbiome species, including relative reductions in bile acid and butyrate metabolising bacteria like Extibacter muris and Dysosmobacter welbionis. Functional prediction indicate over-representation of fatty acid and bile acid metabolism, extracellular matrix interactions, and antibiotic resistance genes. Host gene expression described corresponding changes to bile acid and energy metabolism, and immune suppression. These changes imply that interactions at the host-gut microbiome interface contribute to spaceflight pathology and that these interactions might critically influence human health and long-duration spaceflight feasibility.
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Affiliation(s)
- E Gonzalez
- Microbiome Unit, Canadian Centre for Computational Genomics, Department of Human Genetics, McGill University, Montréal, Canada
- Centre for Microbiome Research, McGill University, Montréal, Canada
| | - M D Lee
- Exobiology Branch, NASA Ames Research Centre, Moffett Field, CA, USA
- Blue Marble Space Institute of Science, Seattle, WA, USA
| | - B T Tierney
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - N Lipieta
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA
| | - P Flores
- BioServe Space Technologies, University of Colorado Boulder, Boulder, CO, USA
| | - M Mishra
- Grossman School of Medicine, New York University, New York, USA
| | - L Beckett
- University of Nottingham, Nottingham, NG7 2RD, UK
| | - A Finkelstein
- NASA GeneLab for High Schools (GL4HS) program, NASA Ames Research Centre, Moffett Field, CA, USA
| | - A Mo
- NASA GeneLab for High Schools (GL4HS) program, NASA Ames Research Centre, Moffett Field, CA, USA
| | - P Walton
- NASA GeneLab for High Schools (GL4HS) program, NASA Ames Research Centre, Moffett Field, CA, USA
| | - F Karouia
- Exobiology Branch, NASA Ames Research Centre, Moffett Field, CA, USA
- Blue Marble Space Institute of Science, Seattle, WA, USA
- Centre for Space Medicine, Baylor College of Medicine, Houston, TX, USA
| | - R Barker
- Blue Marble Space Institute of Science, Seattle, WA, USA
- Yuri GmbH, Wiesentalstr. 40, 88074, Meckenbeuren, Germany
- University of Wisconsin-Madison, Madison, WI, USA
| | - R J Jansen
- Department of Public Health, North Dakota State University, Fargo, ND, USA
- Genomics, Phenomics, and Bioinformatics Program, North Dakota State University, Fargo, ND, USA
| | - S J Green
- Genomics and Microbiome Core Facility, Rush University Medical Centre, 1653 W. Congress Parkway, Chicago, IL, 60612, USA
| | - S Weging
- Institute of Computer Science, Martin-Luther University Halle-Wittenberg, Halle, Germany
| | - J Kelliher
- Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - N K Singh
- Department of Industrial Relations, Division of Occupational Safety and Health, Oakland, USA
| | - D Bezdan
- University of Wisconsin-Madison, Madison, WI, USA
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- NGS Competence Centre Tübingen (NCCT), University of Tübingen, Tübingen, Germany
| | - J Galazska
- Space Biosciences Research Branch, NASA Ames Research Centre, Moffett Field, CA, USA
| | - N J B Brereton
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland.
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8
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Li X, Li M. Unlocking Cholesterol Metabolism in Metabolic-Associated Steatotic Liver Disease: Molecular Targets and Natural Product Interventions. Pharmaceuticals (Basel) 2024; 17:1073. [PMID: 39204178 PMCID: PMC11358954 DOI: 10.3390/ph17081073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 09/03/2024] Open
Abstract
Metabolic-associated steatotic liver disease (MASLD), the hepatic manifestation of metabolic syndrome, represents a growing global health concern. The intricate pathogenesis of MASLD, driven by genetic, metabolic, epigenetic, and environmental factors, leads to considerable clinical variability. Dysregulation of hepatic lipid metabolism, particularly cholesterol homeostasis, is a critical factor in the progression of MASLD and its more severe form, metabolic dysfunction-associated steatohepatitis (MASH). This review elucidates the multifaceted roles of cholesterol metabolism in MASLD, focusing on its absorption, transportation, biosynthesis, efflux, and conversion. We highlight recent advancements in understanding these processes and explore the therapeutic potential of natural products such as curcumin, berberine, and resveratrol in modulating cholesterol metabolism. By targeting key molecular pathways, these natural products offer promising strategies for MASLD management. Finally, this review also covers the clinical studies of natural products in MASLD, providing new insights for future research and clinical applications.
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Affiliation(s)
| | - Meng Li
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China;
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9
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Cheng X, Baki VB, Moran M, Liu B, Yu J, Zhao M, Li Q, Riethoven JJ, Gurumurth CB, Harris EN, Sun X. Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor. Mol Metab 2024; 86:101977. [PMID: 38936659 PMCID: PMC11267048 DOI: 10.1016/j.molmet.2024.101977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 06/29/2024] Open
Abstract
OBJECTIVE The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a thyroid hormone receptor-beta is the only Food and Drug Administration approved therapy. As such, there is a critical need to improve our understanding of gene expression regulation and signaling transduction in MASLD to develop new therapies. Matrin-3 is a DNA- and RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor (CAR). METHODS Matrin-3 floxed and liver-specific knockout mice were fed either a chow diet or 60 kcal% high-fat diet (HFD) for up to 16 weeks. The mice were euthanized for different analysis including liver histology, lipid levels, and gene expression. Bulk RNA-seq, bulk ATAC-seq, and single-nucleus Multiome were used to examine changes of transcriptome and chromatin accessibility in the liver. Integrative bioinformatics analysis of our data and publicly available datasets and different biochemical assays were performed to identify underlying the molecular mechanisms mediating matrin-3's effects. Liver-tropic adeno-associated virus was used to restore the expression of CAR for lipid, acute phase genes, and histological analysis. RESULTS Matrin-3 expression is induced in the steatotic livers of mice. Liver-specific matrin-3 deletion exacerbated HFD-induced steatosis, acute phase response, and inflammation in the liver of female mice. The transcriptome and chromatin accessibility were re-programmed in the liver of these mice with signatures indicating that CAR signaling is dysregulated. Mechanistically, matrin-3 interacts with CAR mRNA, and matrin-3 deficiency promotes CAR mRNA degradation. Consequently, matrin-3 deletion impaired CAR signaling by reducing CAR expression. Matrin-3 levels positively correlate with CAR expression in human livers. Ces2a and Il1r1 were identified as new target genes of CAR. Interestingly, we found that CAR discords with the expression of its target genes including Cyp2b10 and Ces2a in response to HFD, indicating CAR signaling is dysregulated by HFD despite increased CAR expression. Dysregulated CAR signaling upon matrin-3 deficiency reduced Ces2a and de-repressed Il1r1 expression. CAR restoration partially abrogated the dysregulated gene expression, exacerbated hepatic steatosis, acute phase response, and inflammation in liver-specific matrin-3 knockout mice fed a HFD. CONCLUSIONS Our findings demonstrate that matrin-3 is a key upstream regulator maintaining CAR signaling upon metabolic stress, and the matrin-3-CAR axis limits hepatic steatosis and stress response signaling that may give insights for therapeutic intervention.
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Affiliation(s)
- Xiao Cheng
- Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Vijaya Bhaskar Baki
- Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Matthew Moran
- Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
| | - Baolong Liu
- Department of Nutrition and Health Sciences, University of Nebraska - Lincoln, 230 Filley Hall, Lincoln, NE 68583-0922, USA
| | - Jiujiu Yu
- Department of Nutrition and Health Sciences, University of Nebraska - Lincoln, 230 Filley Hall, Lincoln, NE 68583-0922, USA
| | - Miaoyun Zhao
- Nebraska Center for Virology, School of Biological Sciences, University of Nebraska - Lincoln, Lincoln, NE, USA
| | - Qingsheng Li
- Nebraska Center for Virology, School of Biological Sciences, University of Nebraska - Lincoln, Lincoln, NE, USA
| | - Jean-Jack Riethoven
- Nebraska Center for Biotechnology, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA; Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska - Lincoln, Lincoln, NE 68588, USA
| | | | - Edward N Harris
- Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA; Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska - Lincoln, Lincoln, NE 68588, USA; Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska - Lincoln, USA
| | - Xinghui Sun
- Department of Biochemistry, University of Nebraska - Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA; Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska - Lincoln, Lincoln, NE 68588, USA; Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska - Lincoln, USA.
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10
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Wang Q, Shen W, Shao W, Hu H. Berberine alleviates cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice. Biochem Biophys Res Commun 2024; 719:150088. [PMID: 38740003 DOI: 10.1016/j.bbrc.2024.150088] [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: 04/11/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024]
Abstract
Berberine (BBR) is a traditional Chinese herb with broad antimicrobial activity. Gut microbiota plays an important role in the metabolism of bile acids and cholesterol. Our study investigated the effects of BBR on alleviating cholesterol and bile acid metabolism disorders induced by high cholesterol diet in mice. Adult male C57BL/6J mice fed with high cholesterol diet (HC) containing 1.25 % cholesterol (HC group) or fed with chow diet containing 0.02 % cholesterol (Chow group) served as controls. BBR50 and BBR100 group mice were fed with HC, and oral BBR daily at doses of 50 or 100 mg/kg respectively for 8 weeks. The results showed that BBR could reshape the homeostasis and composition of gut microbiota. The abundance of Clostridium genera was significantly inhibited by BBR, which resulted in a significant reduction of secondary bile acids within the enterohepatic circulation and a significant lower hydrophobic index of bile acids. The absorption of cholesterol in intestine, the deposition of cholesterol in liver and the excretion of cholesterol in biliary tract were significantly inhibited by BBR, which promoted the unsaturation of cholesterol in bile. These findings suggest the potential utility of BBR as a functional food to alleviate the negative effects of high cholesterol diet.
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Affiliation(s)
- Qihan Wang
- Center of Gallstone Disease, Shanghai East Hospital, Tongji University School of Medicine, and Institution of Gallstone Disease, Tongji University School of Medicine, Shanghai, China
| | - Weiyi Shen
- Center of Gallstone Disease, Shanghai East Hospital, Tongji University School of Medicine, and Institution of Gallstone Disease, Tongji University School of Medicine, Shanghai, China
| | - Wentao Shao
- Center of Gallstone Disease, Shanghai East Hospital, Tongji University School of Medicine, and Institution of Gallstone Disease, Tongji University School of Medicine, Shanghai, China; State Key Laboratory of Reproductive Medicine, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hai Hu
- Center of Gallstone Disease, Shanghai East Hospital, Tongji University School of Medicine, and Institution of Gallstone Disease, Tongji University School of Medicine, Shanghai, China.
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11
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Piccinin E, Arconzo M, Pasculli E, Tricase AF, Cultrera S, Bertrand-Michel J, Loiseau N, Villani G, Guillou H, Moschetta A. Pivotal role of intestinal cholesterol and nuclear receptor LXR in metabolic liver steatohepatitis and hepatocarcinoma. Cell Biosci 2024; 14:69. [PMID: 38824560 PMCID: PMC11144344 DOI: 10.1186/s13578-024-01248-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024] Open
Abstract
Hepatocellular carcinoma (HCC) incidence is continuously increasing worldwide, due to the rise of metabolic dysfunction-associated steatohepatitis (MASH) cases. Cholesterol is an essential driver of the metabolic dysregulations that promote HCC progression. Liver X Receptor (LXR) is a nuclear receptor best known for the regulation of lipid and cholesterol homeostasis, with a prominent function in the liver and in the intestine. Here, we aimed to explore whether modifications in intestinal lipid metabolism may contribute to the onset of HCC, particularly taking into account cholesterol metabolism and LXRs. To study the progression of MASH to HCC, we induced metabolic HCC in wild-type male mice and mice carrying an intestinal chronic activation of LXRα. Also, we analysed human hepatic transcriptome datasets. The increased consumption of fat and carbohydrates drives the intestinal activation of LXRα and accelerates the onset of the hepatic tumours. Chronic intestinal-specific activation of LXRα enhances HCC progression only in the presence of a high cholesterol intake. In HCC, despite the increased hepatic cholesterol content, LXR is not active, thus driving liver cancer development. Intriguingly, in line with these results in the mouse model, LXR transcriptome is also downregulated in human hepatocarcinoma and its expression level in liver tumours directly correlates with a decreased survival rate in patients. Overall, our findings establish the relevance of the intestine in influencing the susceptibility to MASH-HCC and point to intestinal LXRα activation as a driver of metabolic liver cancer in the presence of dietary cholesterol.
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Affiliation(s)
- Elena Piccinin
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari, 70124, 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", Piazza Giulio Cesare 11, Bari, 70124, Italy
| | - Emanuela Pasculli
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari, 70124, Italy
| | - Angela Fulvia Tricase
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari, 70124, Italy
| | - Silvia Cultrera
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari, 70124, Italy
| | | | - 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
| | - Hervé Guillou
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, Toulouse, France
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, Bari, 70124, Italy.
- INBB, National Institute for Biostructures and Biosystems, Rome, Italy.
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12
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Clark AT, Russo-Savage L, Ashton LA, Haghshenas N, Schulman IG. A Novel Mutation in LXRα Uncovers a Role for Cholesterol Sensing in Limiting Metabolic Dysfunction-Associated Steatohepatitis (MASH). BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593869. [PMID: 38798597 PMCID: PMC11118525 DOI: 10.1101/2024.05.13.593869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease.
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Affiliation(s)
- Alexis T. Clark
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
- These authors contributed equally to the work
| | - Lillian Russo-Savage
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
- These authors contributed equally to the work
- Current address: Department of Neurological Sciences, University of Vermont, Burlington, Vermont
| | - Luke A. Ashton
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Niki Haghshenas
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Ira G. Schulman
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
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13
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Hoekstra M, de Jong LM, van der Geest R, de Leeuw LR, Krisnamurthi R, Geerling JJ, Van Eck M. LXR Agonist T0901317's Hepatic Impact Overrules Its Atheroprotective Action in Macrophages, Driving Early Atherogenesis in Chow-Diet-Fed Male Apolipoprotein E Knockout Mice. Biomolecules 2024; 14:429. [PMID: 38672446 PMCID: PMC11047872 DOI: 10.3390/biom14040429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism remains anti-atherogenic under dietary conditions with a low basal hepatic lipogenesis rate. Hereto, atherosclerosis-susceptible male apolipoprotein E knockout mice were fed a low-fat diet with or without 10 mg/kg/day LXR agonist T0901317 supplementation for 8 weeks. Importantly, T0901317 significantly stimulated atherosclerosis susceptibility, despite an associated increase in the macrophage gene expression levels of cholesterol efflux transporters ABCA1 and ABCG1. The pro-atherogenic effect of T0901317 coincided with exacerbated hypercholesterolemia, hypertriglyceridemia, and a significant rise in hepatic triglyceride stores and macrophage numbers. Furthermore, T0901317-treated mice exhibited elevated plasma MCP-1 levels and monocytosis. In conclusion, these findings highlight that the pro-atherogenic hepatic effects of LXR agonism are dominant over the anti-atherogenic effects in macrophages in determining the overall atherosclerosis outcome under low-fat diet feeding conditions. A low-fat diet experimental setting, as compared to the commonly used high-fat-diet-based preclinical setup, thus appears more sensitive in uncovering the potential relevance of the off-target liver effects of novel anti-atherogenic therapeutic approaches that target macrophage LXR.
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Affiliation(s)
- Menno Hoekstra
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
| | - Laura M. de Jong
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Rick van der Geest
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Lidewij R. de Leeuw
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Rani Krisnamurthi
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Janine J. Geerling
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
| | - Miranda Van Eck
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, 2333 CC Leiden, The Netherlands; (L.M.d.J.); (M.V.E.)
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
- Pharmacy Leiden, Leiden, The Netherlands
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14
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Huang D, Shen S, Zhuang Q, Ye X, Qian Y, Dong Z, Wan X. Ganoderma lucidum polysaccharide ameliorates cholesterol gallstone formation by modulating cholesterol and bile acid metabolism in an FXR-dependent manner. Chin Med 2024; 19:16. [PMID: 38268006 PMCID: PMC10809463 DOI: 10.1186/s13020-024-00889-y] [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: 08/21/2023] [Accepted: 01/18/2024] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Cholesterol gallstone (CG) disease is a worldwide common disease characterized by cholesterol supersaturation in gallbladder bile. Ganoderma lucidum polysaccharide (GLP) has been shown to possess various beneficial effects against metabolic disorders. However, the role and underlying mechanism of GLP in CG formation are still unknown. This study aimed to determine the role of GLP in ameliorating lithogenic diet (LD)-induced CG formation. METHODS Mice were fed either a normal chow diet, a LD, or LD supplemented with GLP. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression of genes involved in cholesterol and bile acid (BA) metabolism. The BA concentrations in the ileum were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The microbiota in cecal contents were characterized using 16S ribosomal RNA (16S rRNA) gene sequencing. RESULTS GLP effectively alleviated CG formation induced by LD. Specifically, GLP reduced the total cholesterol (TC) levels, increased the total BA levels, and decreased the cholesterol saturation index (CSI) in gallbladder bile. The protective effect of GLP was attributed to the inhibition of farnesoid X receptor (FXR) signaling, increased hepatic BA synthesis and decreased hepatic cholesterol synthesis and secretion. GLP also altered the BA composition in the ileum, reducing FXR-agonistic BAs and increasing FXR-antagonistic BAs, which may contribute to the inhibition of intestinal FXR signaling. Additionally, GLP improved dysbiosis of the intestinal flora and reduced the serum levels of hydrogen sulfide (H2S), a bacterial metabolite that can induce hepatic FXR, thereby inhibiting hepatic FXR signaling. Moreover, the protective effect of GLP against CG formation could be reversed by both the global and gut-restricted FXR agonists. CONCLUSIONS Taken together, GLP ameliorates CG formation by regulating cholesterol and BA metabolism in an FXR-dependent manner. Our study demonstrates that GLP may be a potential strategy for the prevention against CG disease.
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Affiliation(s)
- Dan Huang
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Shuang Shen
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Qian Zhuang
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Xin Ye
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Yueqin Qian
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China
| | - Zhixia Dong
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China.
| | - Xinjian Wan
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai, 200233, China.
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15
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Olkkonen VM, Gylling H. Oxy- and Phytosterols as Biomarkers: Current Status and Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:353-375. [PMID: 38036889 DOI: 10.1007/978-3-031-43883-7_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Oxysterols and phytosterols are sterol compounds present at markedly low levels in tissues and serum of healthy individuals. A wealth of evidence suggests that they could be employed as biomarkers for human diseases or for cholesterol absorption.An increasing number of reports suggest circulating or tissue oxysterols as putative biomarkers for cardiovascular and neurodegenerative diseases or cancers. Thus far most of the studies have been carried out on small study populations. To achieve routine biomarker use, large prospective cohort studies are absolutely required. This, again, would necessitate thorough standardization of the oxysterol analytical methodology across the different laboratories, which now employ different technologies resulting in inconsistencies in the measured oxysterol levels. Routine use of oxysterol biomarkers would also necessitate the development of a new targeted analytical methodology suitable for high-throughput platforms.The most important use of phytosterols as biomarkers involves their use as markers for cholesterol absorption. For this to be achieved, (1) their quantitative analyses should be available in routine lipid laboratories, (2) it should be generally acknowledgment that the profile of cholesterol metabolism can reveal the risk of the development of atherosclerotic cardiovascular diseases (ASCVD), and (3) screening of the profile of cholesterol metabolism should be included in the ASCVD risk surveys. This should be done e.g. in families with a history of early onset or frequent ASCVD and in young adults aged 18-20 years, to exclude the presence of high cholesterol absorption. Individuals in high cholesterol absorption families need preventive measures from young adulthood to inhibit the possible development and progression of atherosclerosis.
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Affiliation(s)
- Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland.
- Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
| | - Helena Gylling
- Heart and Lung Center, Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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16
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Li Z, Zheng D, Zhang T, Ruan S, Li N, Yu Y, Peng Y, Wang D. The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease. Hepatol Commun 2024; 8:e0343. [PMID: 38099854 PMCID: PMC10727660 DOI: 10.1097/hc9.0000000000000343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/28/2023] [Indexed: 12/18/2023] Open
Abstract
As the most prevalent chronic liver disease globally, NAFLD encompasses a pathological process that ranges from simple steatosis to NASH, fibrosis, cirrhosis, and HCC, closely associated with numerous extrahepatic diseases. While the initial etiology was believed to be hepatocyte injury caused by lipid toxicity from accumulated triglycerides, recent studies suggest that an imbalance of cholesterol homeostasis is of greater significance. The role of nuclear receptors in regulating liver cholesterol homeostasis has been demonstrated to be crucial. This review summarizes the roles and regulatory mechanisms of nuclear receptors in the 3 main aspects of cholesterol production, excretion, and storage in the liver, as well as their cross talk in reverse cholesterol transport. It is hoped that this review will offer new insights and theoretical foundations for the study of the pathogenesis and progression of NAFLD and provide new research directions for extrahepatic diseases associated with NAFLD.
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17
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Bydlowski SP, Levy D. Association of ABCG5 and ABCG8 Transporters with Sitosterolemia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1440:31-42. [PMID: 38036873 DOI: 10.1007/978-3-031-43883-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Sitosterolemia is a rare genetic lipid disorder, mainly characterized by the accumulation of dietary xenosterols in plasma and tissues. It is caused by inactivating mutations in either ABCG5 or ABCG8 subunits, a subfamily-G ATP-binding cassette (ABCG) transporters. ABCG5/G8 encodes a pair of ABC half transporters that form a heterodimer (G5G8). This heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the hepatobiliary and transintestinal secretion of cholesterol and dietary plant sterols to the surface of hepatocytes and enterocytes, promoting the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. In this way, ABCG5/G8 function in the reverse cholesterol transport pathway and mediate the efflux of cholesterol and xenosterols to high-density lipoprotein and bile salt micelles, respectively. Here, we review the biological characteristics and function of ABCG5/G8, and how the mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis, among other features.
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Affiliation(s)
- Sergio Paulo Bydlowski
- Lipids, Oxidation and Cell Biology Team, Laboratory of Immunology (LIM19), Heart Institute (InCor), Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil.
- National Institute of Science and Technology in Regenerative Medicine (INCT-Regenera) CNPq, Rio de Janeiro, Brazil.
| | - Debora Levy
- Lipids, Oxidation and Cell Biology Team, Laboratory of Immunology (LIM19), Heart Institute (InCor), Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil
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18
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Zhang Q, Du G, Tong L, Guo X, Wei Y. Overexpression of LOX-1 in hepatocytes protects vascular smooth muscle cells from phenotype transformation and wire injury induced carotid neoatherosclerosis through ALOX15. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166805. [PMID: 37468019 DOI: 10.1016/j.bbadis.2023.166805] [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: 10/30/2022] [Revised: 06/16/2023] [Accepted: 07/06/2023] [Indexed: 07/21/2023]
Abstract
Neoatherosclerosis (NA), the main pathological basis of late stent failure, is the main limitation of interventional therapy. However, the specific pathogenesis and treatment remain unclear. In vivo, NA model was established by carotid wire injury and high-fat feeding in ApoE-/- mice. Oxidized low-density lipoprotein receptor-1/lectin-like oxidized low-density lipoprotein receptor-1 (OLR1/LOX-1), a specific receptor for oxidized low-density lipoprotein (ox-LDL), was specifically ectopically overexpressed in hepatocytes by portal vein injection of adeno-associated serotype 8 (AAV8)-thyroid binding globulin (TBG)-Olr1 and the protective effect against NA was examined. In vitro, LOX-1 was overexpressed on HHL5 using lentivirus (LV)-OLR1 and the vascular smooth muscle cells (VSMCs)-HHL5 indirect co-culture system was established to examine its protective effect on VSMCs and the molecular mechanism. Functionally, we found that specific ectopic overexpression of LOX-1 by hepatocytes competitively engulfed and metabolized ox-LDL, alleviating its resulting phenotypic transformation of VSMCs including migration, downregulation of contractile shape markers (smooth muscle α-actin (SMαA) and smooth muscle-22α (SM22α)), and upregulation of proliferative/migratory shape markers (osteopontin (OPN) and Vimentin) as well as foaminess and apoptosis, thereby alleviating NA, which independent of low-density lipoprotein (LDL) lowering treatment (evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9)). Mechanistically, we found that overexpression of LOX-1 in hepatocytes competitively engulfed and metabolized ox-LDL through upregulation of arachidonate-15-lipoxygenase (ALOX15), which further upregulated scavenger receptor class B type I (SRBI) and ATP-binding cassette transporter A1 (ABCA1). In conclusion, the overexpression of LOX-1 in liver protects VSMCs from phenotypic transformation and wire injury induced carotid neoatherosclerosis through ALOX15.
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Affiliation(s)
- Qing Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gaohui Du
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lu Tong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaopeng Guo
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yumiao Wei
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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19
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Deng C, Pan J, Zhu H, Chen ZY. Effect of Gut Microbiota on Blood Cholesterol: A Review on Mechanisms. Foods 2023; 12:4308. [PMID: 38231771 DOI: 10.3390/foods12234308] [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: 10/13/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 01/19/2024] Open
Abstract
The gut microbiota serves as a pivotal mediator between diet and human health. Emerging evidence has shown that the gut microbiota may play an important role in cholesterol metabolism. In this review, we delve into five possible mechanisms by which the gut microbiota may influence cholesterol metabolism: (1) the gut microbiota changes the ratio of free bile acids to conjugated bile acids, with the former being eliminated into feces and the latter being reabsorbed back into the liver; (2) the gut microbiota can ferment dietary fiber to produce short-chain fatty acids (SCFAs) which are absorbed and reach the liver where SCFAs inhibit cholesterol synthesis; (3) the gut microbiota can regulate the expression of some genes related to cholesterol metabolism through their metabolites; (4) the gut microbiota can convert cholesterol to coprostanol, with the latter having a very low absorption rate; and (5) the gut microbiota could reduce blood cholesterol by inhibiting the production of lipopolysaccharides (LPS), which increases cholesterol synthesis and raises blood cholesterol. In addition, this review will explore the natural constituents in foods with potential roles in cholesterol regulation, mainly through their interactions with the gut microbiota. These include polysaccharides, polyphenolic entities, polyunsaturated fatty acids, phytosterols, and dicaffeoylquinic acid. These findings will provide a scientific foundation for targeting hypercholesterolemia and cardiovascular diseases through the modulation of the gut microbiota.
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Affiliation(s)
- Chuanling Deng
- School of Food Science and Engineering/National Technical Center (Foshan) for Quality Control of Famous and Special Agricultural Products (CAQS-GAP-KZZX043), Foshan University, Foshan 528011, China
| | - Jingjin Pan
- School of Food Science and Engineering/National Technical Center (Foshan) for Quality Control of Famous and Special Agricultural Products (CAQS-GAP-KZZX043), Foshan University, Foshan 528011, China
| | - Hanyue Zhu
- School of Food Science and Engineering/National Technical Center (Foshan) for Quality Control of Famous and Special Agricultural Products (CAQS-GAP-KZZX043), Foshan University, Foshan 528011, China
| | - Zhen-Yu Chen
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
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20
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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.
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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
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21
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Huang Z, Zhou RR. Mechanism for FXR to regulate bile acid and glycolipid metabolism to improve NAFLD. Shijie Huaren Xiaohua Zazhi 2023; 31:797-807. [DOI: 10.11569/wcjd.v31.i19.797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/16/2023] [Accepted: 09/21/2023] [Indexed: 10/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease, with liver metabolic disorders as major pathological changes, manifested as abnormal lipid accumulation, liver cell oxidative stress, etc., but its etiology is still unclear. The farnesol X receptor (FXR) is a major bile acid receptor in the "gut-liver axis", via which FXR regulates metabolism and affects the pathophysiological status of various substances through different pathways, thus contributing to the occurrence and development of NAFLD. Therefore, FXR has become a potential therapeutic target for NAFLD. This article reviews the relationship between FXR regulation of bile acid, glucose, and lipid metabolism through the "gut-liver axis" and the occurrence and development of NAFLD, to provide new insights and clues for further research about FXR-based pharmaceutical treatments.
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Affiliation(s)
- Zhi Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
| | - Rong-Rong Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, China
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22
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Wulfridge P, Davidovich A, Salvador AC, Manno GC, Tryggvadottir R, Idrizi A, Huda MN, Bennett BJ, Adams LG, Hansen KD, Threadgill DW, Feinberg AP. Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation. PLoS Genet 2023; 19:e1010997. [PMID: 37871105 PMCID: PMC10621921 DOI: 10.1371/journal.pgen.1010997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 11/02/2023] [Accepted: 09/25/2023] [Indexed: 10/25/2023] Open
Abstract
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.
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Affiliation(s)
- Phillip Wulfridge
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Adam Davidovich
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Anna C. Salvador
- Department of Cell Biology and Genetics, Texas A&M Health Science Center, College Station, Texas, United States of America
- Department of Nutrition, Texas A&M University, College Station, Texas, United States of America
| | - Gabrielle C. Manno
- Department of Cell Biology and Genetics, Texas A&M Health Science Center, College Station, Texas, United States of America
| | - Rakel Tryggvadottir
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Adrian Idrizi
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - M. Nazmul Huda
- Department of Nutrition, University of California, Davis, California, United States of America
- Obesity and Metabolism Research Unit, USDA, ARS, Western Human Nutrition Research Center, Davis, California, United States of America
| | - Brian J. Bennett
- Department of Nutrition, University of California, Davis, California, United States of America
- Obesity and Metabolism Research Unit, USDA, ARS, Western Human Nutrition Research Center, Davis, California, United States of America
| | - L. Garry Adams
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America
| | - Kasper D. Hansen
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
- Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - David W. Threadgill
- Department of Cell Biology and Genetics, Texas A&M Health Science Center, College Station, Texas, United States of America
- Department of Nutrition, Texas A&M University, College Station, Texas, United States of America
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas, United States of America
| | - Andrew P. Feinberg
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
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23
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Shen S, Huang D, Qian S, Ye X, Zhuang Q, Wan X, Dong Z. Hyodeoxycholic acid attenuates cholesterol gallstone formation via modulation of bile acid metabolism and gut microbiota. Eur J Pharmacol 2023; 955:175891. [PMID: 37429516 DOI: 10.1016/j.ejphar.2023.175891] [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: 01/31/2023] [Revised: 06/15/2023] [Accepted: 06/28/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND & AIMS Hyodeoxycholic acid (HDCA), a hydrophilic bile acid (BA), may prevent and suppress the formation of cholesterol gallstones (CGs). However, the mechanism by which HDCA prevents CGs formation remains unclear. This study aimed to investigate the underlying mechanism of HDCA in preventing CG formation. METHODS C57BL/6J mice were fed either a lithogenic diet (LD), a chow diet, or LD combined with HDCA. The concentration of BAs in the liver and ileum were determined using liquid chromatography-mass spectrometry (LC-MS/MS). Genes involved in cholesterol and BAs metabolism were detected using polymerase chain reaction (PCR). The gut microbiota in the faeces was determined using 16S rRNA. RESULTS HDCA supplementation effectively prevented LD-induced CG formation. HDCA increased the gene expression of BA synthesis enzymes, including Cyp7a1, Cyp7b1, and Cyp8b1, and decreased the expression of the cholesterol transporter Abcg5/g8 gene in the liver. HDCA inhibited LD-induced Nuclear farnesoid X receptor (Fxr) activation and reduced the gene expression of Fgf15 and Shp in the ileum. These data indicate that HDCA could prevent CGs formation partly by promoting BA synthesis in the liver and reduced the cholesterol efflux. In addition, HDCA administration reversed the LD-induced decrease in the abundance of norank_f_Muribaculaceae, which was inversely proportional to cholesterol levels. CONCLUSIONS HDCA attenuated CG formation by modulating BA synthesis and gut microbiota. This study provides new insights into the mechanism by which HDCA prevents CG formation. LAY SUMMARY In this study, we found that HDCA supplementation suppressed LD-induced CGs in mice by inhibiting Fxr in the ileum, enhancing BA synthesis, and increasing the abundance of norank_f_Muribaculaceae in the gut microbiota. HDCA can also downregulate the level of total cholesterol in the serum, liver, and bile.
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Affiliation(s)
- Shuang Shen
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Central Lab, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Huang
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shengnan Qian
- Central Lab, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin Ye
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Zhuang
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinjian Wan
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Zhixia Dong
- Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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24
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Ravi PC, Thugu TR, Singh J, Dasireddy RR, Kumar SA, Isaac NV, Oladimeji A, DeTrolio V, Abdalla R, Mohan V, Iqbal J. Gallstone Disease and Its Correlation With Thyroid Disorders: A Narrative Review. Cureus 2023; 15:e45116. [PMID: 37842424 PMCID: PMC10568238 DOI: 10.7759/cureus.45116] [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: 07/08/2023] [Accepted: 09/12/2023] [Indexed: 10/17/2023] Open
Abstract
Over the years, several studies have revealed an important link between thyroid disorders and gallstone disease. According to these studies, hypothyroidism and hyperthyroidism are associated with cholesterol gallstone disease. This association between thyroid hormone disorders and cholesterol gallstone disease is due to the importance of thyroid hormones on cholesterol synthesis, bile functioning and content, and gallbladder motility. Several genes and receptors have been found on the thyroid gland, liver, and gallbladder to verify this association. These genes affect thyroid hormone secretion, lipid metabolism, and bile secretion. Defects in these various gene expression and protein functions lead to bile duct diseases. Other causes that lead to cholesterol gallstone disease are supersaturation of the bile with cholesterol and impaired gallbladder motility, which leads to bile stasis. This article has discussed these factors in detail while highlighting the association between thyroid hormones and cholesterol gallstone disease.
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Affiliation(s)
| | - Thanmai Reddy Thugu
- Internal Medicine, Sri Padmavathi Medical College for Women, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati, IND
| | - Jugraj Singh
- Internal Medicine, Punjab Institute of Medical Sciences, Jalandhar, IND
| | | | - Sharanya Anil Kumar
- Medicine and Surgery, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, IND
| | - Natasha Varghese Isaac
- Medicine, St. John's Medical College Hospital, Rajiv Gandhi University of Health Sciences (RGUHS), Bengaluru, IND
| | | | | | - Rasha Abdalla
- Medicine and Surgery, Shendi University, Shendi, SDN
| | - Vineetha Mohan
- Medicine and Surgery, Government Medical College Kottayam, Kottayam, IND
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25
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Simonen P, Öörni K, Sinisalo J, Strandberg TE, Wester I, Gylling H. High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases? Atherosclerosis 2023; 376:53-62. [PMID: 37290267 DOI: 10.1016/j.atherosclerosis.2023.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 06/01/2023] [Accepted: 06/01/2023] [Indexed: 06/10/2023]
Abstract
Lowering elevated low-density lipoprotein cholesterol (LDL-C) concentrations reduces the risk of atherosclerotic cardiovascular diseases (ASCVDs). However, increasing evidence suggests that cholesterol metabolism may also be involved in the risk reduction of ASCVD events. In this review, we discuss if the different profiles of cholesterol metabolism, with a focus on high cholesterol absorption, are atherogenic, and what could be the possible mechanisms. The potential associations of cholesterol metabolism and the risk of ASCVDs are evaluated from genetic, metabolic, and population-based studies and lipid-lowering interventions. According to these studies, loss-of-function genetic variations in the small intestinal sterol transporters ABCG5 and ABCG8 result in high cholesterol absorption associated with low cholesterol synthesis, low cholesterol elimination from the body, and a high risk of ASCVDs. In contrast, loss-of-function genetic variations in another intestinal sterol transporter, NPC1L1 result in low cholesterol absorption associated with high cholesterol synthesis, elevated cholesterol elimination from the body, and low risk of ASCVDs. Statin monotherapy is not sufficient to reduce the ASCVD risk in cases of high cholesterol absorption, and these individuals need combination therapy of statin with cholesterol absorption inhibition. High cholesterol absorption, i.e., >60%, is estimated to occur in approximately one third of a population, so taking it into consideration is important to optimise lipid-lowering therapy to prevent atherosclerosis and reduce the risk of ASCVD events.
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Affiliation(s)
- Piia Simonen
- Heart and Lung Center, Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Katariina Öörni
- Wihuri Research Institute, Helsinki, Finland; Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Juha Sinisalo
- Heart and Lung Center, Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Timo E Strandberg
- Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Center for Life-Course Health Research, University of Oulu, Oulu, Finland
| | | | - Helena Gylling
- Heart and Lung Center, Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
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26
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Kim MH, Lee EJ, Kim SJ, Jung YJ, Park WJ, Park I. Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression. PLoS One 2023; 18:e0287146. [PMID: 37310967 DOI: 10.1371/journal.pone.0287146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 05/30/2023] [Indexed: 06/15/2023] Open
Abstract
Macrophage inhibitory cytokine 1 (MIC-1), which is overproduced in various human cancers and associated with cachexia, acts on the hypothalamus to suppress appetite and reduce body weight. We investigated the mechanisms through which MIC-1 affects bile acid metabolism and gallstone formation, which are poorly understood. Over 6 weeks, male C57BL/6 mice fed either standard chow or a lithogenic diet were intraperitoneally injected with phosphate-buffered saline (PBS) or MIC-1 (200 μg/kg/week). Among lithogenic diet-fed mice, MIC-1 treatment resulted in increased gallstone formation compared with PBS treatment. Compared with PBS treatment, MIC-1 treatment decreased hepatic cholesterol and bile acid levels and reduced expression of HMG-CoA reductase (HMGCR), the master cholesterol metabolism regulator sterol regulatory element-binding protein 2, cholesterol 7α-hydroxylase (CYP7A1), mitochondrial sterol 27-hydroxylase, and oxysterol 7α-hydroxylase. Compared with PBS treatment, MIC-1 treatment had no effect on small heterodimer partner, farnesoid X receptor, or pregnane X receptor expression, and extracellular signal-related kinase and c-Jun N-terminal kinase phosphorylation decreased, suggesting that these factors do not contribute to the MIC-1-induced reduction in CYP7A1 expression. Compared with PBS treatment, MIC-1 treatment increased AMP-activated protein kinase (AMPK) phosphorylation. Treatment with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced CYP7A1 and HMGCR expression, whereas the AMPK inhibitor Compound C reversed MIC-1-induced reductions in CYP7A1 and HMGCR expression. Furthermore, in MIC-1-treated mice, total biliary cholesterol levels increased together with increased ATP-binding cassette subfamily G (ABCG)5 and ABCG8 expression. Compared with PBS treatment, MIC-1 treatment did not affect expression of liver X receptors α and β, liver receptor homolog 1, hepatocyte nuclear factor 4α, or NR1I3 (also known as constitutive androstane receptor), which are upstream of ABCG5/8; however, MIC-1 treatment increased ABCG5/8 expression and promoter activities. Our study indicates that MIC-1 influences gallstone formation by increasing AMPK phosphorylation, reducing CYP7A1 and HMGCR expression, and increasing ABCG5 and ABCG8 expression.
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Affiliation(s)
- Min Hee Kim
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Eun-Ji Lee
- Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Su-Jeong Kim
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Yun-Jae Jung
- Department of Microbiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon, Republic of Korea
- Department of Health Science and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, Republic of Korea
| | - Woo-Jae Park
- Department of Biochemistry, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Inkeun Park
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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27
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Song Z, Xiong H, Meng X, Ma Q, Wei Y, Li Y, Liu J, Liang M, Xu H. Dietary Cholesterol Supplementation Inhibits the Steroid Biosynthesis but Does Not Affect the Cholesterol Transport in Two Marine Teleosts: A Hepatic Transcriptome Study. AQUACULTURE NUTRITION 2023; 2023:2308669. [PMID: 37312679 PMCID: PMC10260315 DOI: 10.1155/2023/2308669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/09/2023] [Accepted: 05/26/2023] [Indexed: 06/15/2023]
Abstract
Cholesterol has been used as additive in fish feeds due to the reduced use of fish meal and fish oil. In order to evaluate the effects of dietary cholesterol supplementation (D-CHO-S) on fish physiology, a liver transcriptome analysis was performed following a feeding experiment on turbot and tiger puffer with different levels of dietary cholesterol. The control diet contained 30% fish meal (0% fish oil) without cholesterol supplementation, while the treatment diet was supplemented with 1.0% cholesterol (CHO-1.0). A total of 722 and 581 differentially expressed genes (DEG) between the dietary groups were observed in turbot and tiger puffer, respectively. These DEG were primarily enriched in signaling pathways related to steroid synthesis and lipid metabolism. In general, D-CHO-S downregulated the steroid synthesis in both turbot and tiger puffer. Msmo1, lss, dhcr24, and nsdhl might play key roles in the steroid synthesis in these two fish species. Gene expressions related to cholesterol transport (npc1l1, abca1, abcg1, abcg2, abcg5, abcg8, abcb11a, and abcb11b) in the liver and intestine were also extensively investigated by qRT-PCR. However, the results suggest that D-CHO-S rarely affected the cholesterol transport in both species. The protein-protein interaction (PPI) network constructed on steroid biosynthesis-related DEG showed that in turbot, Msmo1, Lss, Nsdhl, Ebp, Hsd17b7, Fdft1, and Dhcr7 had high intermediary centrality in the dietary regulation of steroid synthesis. In conclusion, in both turbot and tiger puffer, the supplementation of dietary cholesterol inhibits the steroid metabolism but does not affect the cholesterol transport.
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Affiliation(s)
- Ziling Song
- College of Fisheries and Life Sciences, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai 201306, China
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Haiyan Xiong
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Xiaoxue Meng
- College of Fisheries and Life Sciences, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai 201306, China
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Qiang Ma
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Yuliang Wei
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Yanlu Li
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Jian Liu
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Mengqing Liang
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
| | - Houguo Xu
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao 266071, China
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28
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Kim H, Park C, Kim TH. Targeting Liver X Receptors for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2023; 12:cells12091292. [PMID: 37174692 PMCID: PMC10177243 DOI: 10.3390/cells12091292] [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: 04/08/2023] [Revised: 04/29/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, no medication has been approved for the treatment of NAFLD yet. Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that serve as master regulators of lipid homeostasis and play pivotal roles in controlling various metabolic processes, including lipid metabolism, inflammation and immune response. Of note, NAFLD progression is characterized by increased accumulation of triglycerides and cholesterol, hepatic de novo lipogenesis, mitochondrial dysfunction and augmented inflammation, all of which are highly attributed to dysregulated LXR signaling. Thus, targeting LXRs may provide promising strategies for the treatment of NAFLD. However, emerging evidence has revealed that modulating the activity of LXRs has various metabolic consequences, as the main functions of LXRs can distinctively vary in a cell type-dependent manner. Therefore, understanding how LXRs in the liver integrate various signaling pathways and regulate metabolic homeostasis from a cellular perspective using recent advances in research may provide new insights into therapeutic strategies for NAFLD and associated metabolic diseases.
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Affiliation(s)
- Hyejin Kim
- College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Chaewon Park
- College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Tae Hyun Kim
- College of Pharmacy, Sookmyung Women's University, Seoul 04310, Republic of Korea
- Drug Information Research Institute, Sookmyung Women's University, Seoul 04310, Republic of Korea
- Muscle Physiome Research Center, Sookmyung Women's University, Seoul 04310, Republic of Korea
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29
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Wulfridge P, Davidovich A, Salvador AC, Manno GC, Tryggvadottir R, Idrizi A, Huda MN, Bennett BJ, Adams LG, Hansen KD, Threadgill DW, Feinberg AP. Precision pharmacological reversal of genotype-specific diet-induced metabolic syndrome in mice informed by transcriptional regulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.25.538156. [PMID: 37163127 PMCID: PMC10168252 DOI: 10.1101/2023.04.25.538156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genomic DNA methylation analyses and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects reveals a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts genotype-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis, as well as increased inflammatory-related gene expression changes in NOD. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention, and a mouse platform for guiding this approach.
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30
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Okamoto N, Fujinaga D, Yamanaka N. Steroid hormone signaling: What we can learn from insect models. VITAMINS AND HORMONES 2023; 123:525-554. [PMID: 37717997 DOI: 10.1016/bs.vh.2022.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Ecdysteroids are a group of steroid hormones in arthropods with pleiotropic functions throughout their life history. Ecdysteroid research in insects has made a significant contribution to our current understanding of steroid hormone signaling in metazoans, but how far can we extrapolate our findings in insects to other systems, such as mammals? In this chapter, we compare steroid hormone signaling in insects and mammals from multiple perspectives and discuss similarities and differences between the two lineages. We also highlight a few understudied areas and remaining questions of steroid hormone biology in metazoans and propose potential future research directions.
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Affiliation(s)
- Naoki Okamoto
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Daiki Fujinaga
- Department of Entomology, University of California, Riverside, CA, United States
| | - Naoki Yamanaka
- Department of Entomology, University of California, Riverside, CA, United States.
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31
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Adigun TO, Danazumi AU, Umar HI, Na'Allah A, Alabi MA, Joel WO, Aberuagba A, Alejolowo OO, Bamidele JO, Omotayo OS, Medayedupin OA. In silico molecular modeling and simulations of black tea theaflavins revealed theaflavin-3'-gallate as putative liver X receptor-beta agonist. J Biomol Struct Dyn 2023; 41:13015-13028. [PMID: 36729100 DOI: 10.1080/07391102.2023.2175264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/11/2023] [Indexed: 02/03/2023]
Abstract
The low constitutive activation of Liver X receptor, an endogenous nuclear receptor with two subtypes (α and β), is a condition lying at the crossroad of cancer and cardiovascular disease. Both natural and synthetic Liver X receptor agonists have reportedly shown remarkable antiproliferative and atheroprotective effects but the repeated doses of its synthetic ones are also paradoxically associated with hyperlipidaemic effects and neurotoxicity, though attributed to the alpha subtype. This highlights the need for novel, safe, and potent LXR-beta-selective agonists. Hypocholesterolaemic effects of black theaflavins have been widely reported, but data on the exact theaflavin compound (s) responsible for these effects is currently lacking. Neither is information on the possible modulatory effects of the compound (s) on LXR-beta nor its possible implications in the context of drug development for cardiovascular diseases and cancers is explored. On this account, we investigated the potential interaction of four main theaflavin monomers (TF1, TF2A, TF2B & TF3) with human LXR-beta through robust computational modelling that entails molecular docking, free energy calculations and molecular dynamics simulations. The ligands were further profiled (in silico) for absorption, distribution, metabolism, excretion, and toxicological properties. Our result revealed theaflavin TF2B as a putative LXR-beta agonist, possibly responsible for the widely observed hypocholesterolaemic effect in black tea. This finding, while encouraging, needs to be experimentally verified in wet studies.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Temidayo O Adigun
- Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Ilorin, Nigeria
| | - Ammar U Danazumi
- Faculty of Chemistry, Warsaw, University of Technology, Warsaw, Poland
- Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Haruna I Umar
- Molecular Biology and Bioinformatics Lab, Department of Biochemistry, Federal University of Technology Akure, Akure, Nigeria
- Computer-aided Therapeutic Discovery and Design Group, Federal University of Technology Akure, Akure, Nigeria
| | - Asiat Na'Allah
- Department of Biochemistry, Faculty of Pure and Applied Sciences, Kwara State University, Malete, Nigeria
| | - Mutiu A Alabi
- Department of Biochemistry, Faculty of Pure and Applied Sciences, Kwara State University, Malete, Nigeria
| | - Wisdom O Joel
- Department of Biochemistry, College of Science and Technology, Covenant University, Ota, Nigeria
| | - Adepeju Aberuagba
- Department of Biochemistry, McPherson University, Seriki Sotayo, Nigeria
| | | | - Joy O Bamidele
- Science Laboratory Technology, The Federal Polytechnic Ilaro, Ilaro, Nigeria
| | - Olakunle S Omotayo
- Science Laboratory Technology, The Federal Polytechnic Ilaro, Ilaro, Nigeria
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Griffett K, Burris TP. Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases. Front Med (Lausanne) 2023; 10:1102469. [PMID: 36817797 PMCID: PMC9932051 DOI: 10.3389/fmed.2023.1102469] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/16/2023] [Indexed: 02/04/2023] Open
Abstract
Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, we review the development of LXR inverse agonists that were originally optimized for their ability to enable recruitment of corepressors leading to silencing of genes that drive de novo lipogenesis. Such compounds have efficacy in animal models of MAFLD, dyslipidemia, and cancer. Several classes of LXR inverse agonists have been identified and one is now in clinical trials for treatment of severe dyslipidemia.
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Affiliation(s)
- Kristine Griffett
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States
| | - Thomas P. Burris
- The University of Florida Genetics Institute, Gainesville, FL, United States,*Correspondence: Thomas P. Burris,
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Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD. Int J Mol Sci 2023; 24:ijms24032142. [PMID: 36768465 PMCID: PMC9916810 DOI: 10.3390/ijms24032142] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
O-linked b-N-acetyl-glucosaminylation (O-GlcNAcylation) is one of the most common post-translational modifications of proteins, and is established by modifying the serine or threonine residues of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc signaling is considered a critical nutrient sensor, and affects numerous proteins involved in cellular metabolic processes. O-GlcNAcylation modulates protein functions in different patterns, including protein stabilization, enzymatic activity, transcriptional activity, and protein interactions. Disrupted O-GlcNAcylation is associated with an abnormal metabolic state, and may result in metabolic disorders. As the liver is the center of nutrient metabolism, this review provides a brief description of the features of the O-GlcNAc signaling pathway, and summarizes the regulatory functions and underlying molecular mechanisms of O-GlcNAcylation in liver metabolism. Finally, this review highlights the role of O-GlcNAcylation in liver-associated diseases, such as diabetes and nonalcoholic fatty liver disease (NAFLD). We hope this review not only benefits the understanding of O-GlcNAc biology, but also provides new insights for treatments against liver-associated metabolic disorders.
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Liang YH, Luo YH, Chen IS, Lin HR. Engelheptanoxides behave as liver X receptor α agonists. Med Chem Res 2023. [DOI: 10.1007/s00044-023-03016-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Bideyan L, López Rodríguez M, Priest C, Kennelly JP, Gao Y, Ferrari A, Rajbhandari P, Feng AC, Tevosian SG, Smale ST, Tontonoz P. Hepatic GATA4 regulates cholesterol and triglyceride homeostasis in collaboration with LXRs. Genes Dev 2022; 36:1129-1144. [PMID: 36522129 PMCID: PMC9851399 DOI: 10.1101/gad.350145.122] [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: 10/01/2022] [Accepted: 12/02/2022] [Indexed: 12/16/2022]
Abstract
GATA4 is a transcription factor known for its crucial role in the development of many tissues, including the liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, we identified GATA4 as a transcriptional regulator of metabolism in the liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in the adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites, especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of GATA4 binding genes involved in hepatic cholesterol export and triglyceride hydrolysis was down-regulated in Gata4LKO mice. We further demonstrate that GATA4 collaborates with LXR nuclear receptors in the liver. GATA4 and LXRs share a number of binding sites, and GATA4 was required for the full transcriptional response to LXR activation. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.
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Affiliation(s)
- Lara Bideyan
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - Maykel López Rodríguez
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - Christina Priest
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - John P Kennelly
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - Yajing Gao
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - Alessandra Ferrari
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - Prashant Rajbhandari
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
| | - An-Chieh Feng
- Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, USA
| | - Sergei G Tevosian
- Department of Physiological Sciences, University of Florida, Gainesville, Florida 32610, USA
| | - Stephen T Smale
- Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, USA
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, USA
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Ducheix S, Piccinin E, Peres C, Garcia‐Irigoyen O, Bertrand‐Michel J, Fouache A, Cariello M, Lobaccaro J, Guillou H, Sabbà C, Ntambi JM, Moschetta A. Reduction in gut-derived MUFAs via intestinal stearoyl-CoA desaturase 1 deletion drives susceptibility to NAFLD and hepatocarcinoma. Hepatol Commun 2022; 6:2937-2949. [PMID: 35903850 PMCID: PMC9512486 DOI: 10.1002/hep4.2053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/21/2022] [Accepted: 07/06/2022] [Indexed: 11/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is defined by a set of hepatic conditions ranging from steatosis to steatohepatitis (NASH), characterized by inflammation and fibrosis, eventually predisposing to hepatocellular carcinoma (HCC). Together with fatty acids (FAs) originated from adipose lipolysis and hepatic lipogenesis, intestinal-derived FAs are major contributors of steatosis. However, the role of mono-unsaturated FAs (MUFAs) in NAFLD development is still debated. We previously established the intestinal capacity to produce MUFAs, but its consequences in hepatic functions are still unknown. Here, we aimed to determine the role of the intestinal MUFA-synthetizing enzyme stearoyl-CoA desaturase 1 (SCD1) in NAFLD. We used intestinal-specific Scd1-KO (iScd1-/- ) mice and studied hepatic dysfunction in different models of steatosis, NASH, and HCC. Intestinal-specific Scd1 deletion decreased hepatic MUFA proportion. Compared with controls, iScd1-/- mice displayed increased hepatic triglyceride accumulation and derangement in cholesterol homeostasis when fed a MUFA-deprived diet. Then, on Western diet feeding, iScd1-/- mice triggered inflammation and fibrosis compared with their wild-type littermates. Finally, intestinal-Scd1 deletion predisposed mice to liver cancer. Conclusions: Collectively, these results highlight the major importance of intestinal MUFA metabolism in maintaining hepatic functions and show that gut-derived MUFAs are protective from NASH and HCC.
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Affiliation(s)
- Simon Ducheix
- Department of Interdisciplinary MedicineUniversity of Bari “Aldo Moro”BariItaly
| | - Elena Piccinin
- Department of Basic Medical Science, Neurosciences, and Sense organsUniversity of Bari “Aldo Moro”BariItaly
| | - Claudia Peres
- INBB, National Institute for Biostructures and BiosystemsRomeItaly
| | | | - Justine Bertrand‐Michel
- MetaboHUB‐MetaToul, National Infrastructure of Metabolomics and FluxomicsToulouseFrance
- I2MC, Université de Toulouse, InsermUniversité Toulouse III–Paul SabatierToulouseFrance
| | - Allan Fouache
- INSERM U 1103, CNRS, UMR 6293Université Clermont AuvergneGReDAubièreFrance
- Centre de Recherche en Nutrition Humaine d'AuvergneClermont‐FerrandFrance
| | - Marica Cariello
- Department of Interdisciplinary MedicineUniversity of Bari “Aldo Moro”BariItaly
| | - Jean‐Marc Lobaccaro
- INSERM U 1103, CNRS, UMR 6293Université Clermont AuvergneGReDAubièreFrance
- Centre de Recherche en Nutrition Humaine d'AuvergneClermont‐FerrandFrance
| | - Hervé Guillou
- Integrative Toxicology and Metabolism TeamToxalim (Research Centre in Food Toxicology)Université de Toulouse, INRA, ENVTINP‐Purpan, UPSToulouseFrance
| | - Carlo Sabbà
- Department of Interdisciplinary MedicineUniversity of Bari “Aldo Moro”BariItaly
| | - James M. Ntambi
- Departments of Biochemistry and of Nutritional SciencesUniversity of Wisconsin MadisonMadisonWisconsinUSA
| | - Antonio Moschetta
- Department of Interdisciplinary MedicineUniversity of Bari “Aldo Moro”BariItaly
- INBB, National Institute for Biostructures and BiosystemsRomeItaly
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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Current Options and Future Perspectives in the Treatment of Dyslipidemia. J Clin Med 2022; 11:jcm11164716. [PMID: 36012957 PMCID: PMC9410330 DOI: 10.3390/jcm11164716] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/02/2022] [Accepted: 08/10/2022] [Indexed: 12/22/2022] Open
Abstract
Low-density lipoprotein cholesterol (LDL-C) plays a crucial role in the development of atherosclerosis. Statin therapy is the standard treatment for lowering LDL-C in primary and secondary prevention. However, some patients do not reach optimal LDL-C target levels or do not tolerate statins, especially when taking high doses long-term. Combining statins with different therapeutic approaches and testing other new drugs is the future key to reducing the burden of cardiovascular disease (CVD). Recently, several new cholesterol-lowering drugs have been developed and approved; others are promising results, enriching the pharmacological armamentarium beyond statins. Triglycerides also play an important role in the development of CVD; new therapeutic approaches are also very promising for their treatment. Familial hypercholesterolemia (FH) can lead to CVD early in life. These patients respond poorly to conventional therapies. Recently, however, new and promising pharmacological strategies have become available. This narrative review provides an overview of the new drugs for the treatment of dyslipidemia, their current status, ongoing clinical or preclinical trials, and their prospects. We also discuss the new alternative therapies for the treatment of dyslipidemia and their relevance to practice.
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Luo G, Xiang L, Xiao L. Acetyl-CoA Deficiency Is Involved in the Regulation of Iron Overload on Lipid Metabolism in Apolipoprotein E Knockout Mice. Molecules 2022; 27:molecules27154966. [PMID: 35956917 PMCID: PMC9370536 DOI: 10.3390/molecules27154966] [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: 06/15/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022] Open
Abstract
The role of dietary iron supplementation in the development of nonalcoholic fatty liver disease (NAFLD) remains controversial. This study aimed to investigate the effect of excess dietary iron on NAFLD development and the underlying mechanism. Apolipoprotein E knockout mice were fed a chow diet, a high-fat diet (HFD), or an HFD containing 2% carbonyl iron (HFD + Fe) for 16 weeks. The serum and liver samples were acquired for biochemical and histopathological examinations. Isobaric tags for relative and absolute quantitation were performed to identify differentially expressed proteins in different groups. Excess dietary iron alleviated HFD-induced NAFLD, as evidenced by significant decreases in serum/the hepatic accumulation of lipids and the NAFLD scores in HFD + Fe-fed mice compared with those in HFD-fed mice. The hepatic acetyl-CoA level was markedly decreased in the HFD + Fe group compared with that in the HFD group. Important enzymes involved in the source and destination of acetyl-CoA were differentially expressed between the HFD and HFD + Fe groups, including the enzymes associated with cholesterol metabolism, glycolysis, and the tricarboxylic acid cycle. Furthermore, iron overload-induced mitochondrial dysfunction and oxidative stress occurred in mouse liver, as evidenced by decreases in the mitochondrial membrane potential and antioxidant expression. Therefore, iron overload regulates lipid metabolism by leading to an acetyl-CoA shortage that reduces cholesterol biosynthesis and might play a role in NAFLD pathogenesis. Iron overload-induced oxidative stress and mitochondrial dysfunction may impair acetyl-CoA formation from pyruvate and β-oxidation. Our study provides acetyl-CoA as a novel perspective for investigating the pathogenesis of NAFLD.
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Affiliation(s)
- Gang Luo
- Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Lu Xiang
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha 410078, China
| | - Lin Xiao
- Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha 410078, China
- Correspondence: ; Tel.: +86-731-8448-7130
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Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion. Nature 2022; 608:413-420. [PMID: 35922515 DOI: 10.1038/s41586-022-05006-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 06/22/2022] [Indexed: 11/08/2022]
Abstract
High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.
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Cholesterol-lowering activity of 10-gingerol in HepG2 cells is associated with enhancing LDL cholesterol uptake, cholesterol efflux and bile acid excretion. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Namba N, Noguchi-Yachide T, Matsumoto Y, Hashimoto Y, Fujii S. Design, synthesis and structure-activity relationship of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisoprop-2-yl)phenylsilane derivatives as liver X receptor agonists. Bioorg Med Chem 2022; 66:116792. [PMID: 35576658 DOI: 10.1016/j.bmc.2022.116792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/26/2022]
Abstract
Liver X receptor (LXR) α and LXRβ are nuclear receptors playing key roles in lipid metabolism, and LXR ligands are attractive drug candidates for metabolic disorders. Here we report the structural development of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenylsilane derivatives as LXR agonists bearing silyl functionalities as the hydrophobic pharmacophore, based on the structure of the known sulfonamide LXR agonist T0901317. Most of the synthesized compounds exhibit agonistic activity toward LXRs, but the LXR subtype-selectivity differs depending upon the substituents on the silicon atom. Among them, tri(n-propyl) derivative 12 shows potent LXR-agonistic activity with moderate α subtype-selectivity, while dimethylphenylsilyl derivative 19 shows modest β-selectivity. These results indicate that silanes can serve as an alternative to the sulfonamide moiety of LXR agonists, and are promising structural options for the development of novel subtype-selective LXR agonists.
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Affiliation(s)
- Nao Namba
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
| | - Tomomi Noguchi-Yachide
- Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Yuichiro Matsumoto
- Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Yuichi Hashimoto
- Institute for Quantitative Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Shinya Fujii
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
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Ressaissi A, Serralheiro MLM. Hydroxycinnamic acid derivatives effect on hypercholesterolemia, comparison with ezetimibe: Permeability assays and FTIR spectroscopy on Caco-2 cell line. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100105. [PMID: 35591881 PMCID: PMC9111184 DOI: 10.1016/j.crphar.2022.100105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 04/08/2022] [Accepted: 04/26/2022] [Indexed: 10/31/2022] Open
Abstract
High blood cholesterol levels may increase the risk of developing atherosclerosis. Since intestinal cholesterol absorption plays a major role in maintaining total body cholesterol homeostasis, the aim of the present study was to compare the effect of ezetimibe and three hydroxycinnamic acid derivatives (rosmarinic acid, chlorogenic acid and m-coumaric acid) that are present in several medicinal plants on cholesterol absorption in the intestinal Caco-2 cells. In addition to the permeability assays, studies on alteration of the biochemical properties of Caco-2 cells under the effect of ezetimibe and hydroxycinnamic acid derivatives was evaluated using FTIR accompanied with multivariate analysis by PCA. The cholesterol permeability assays showed that these compounds could decrease cholesterol permeability with a percentage ranging from 76.98 to 96.6% with the highest inhibition for ezetimibe. whereas the FTIR studies didn't show similar changes between ezetimibe and the three hydroxycinnamic acid derivatives in protein and nucleic acids region, suggesting that these compounds have hypocholesterolemic effect. Nevertheless, each compound originated a different change on Caco-2 treated cells suggesting a different mode of action.
Hydroxycinnamic acid derivatives and ezetimibe permeated the intestinal barrier. Hydroxycinnamic acid derivatives decreased cholesterol permeability. Hydroxycinnamic acid derivatives could affect the cell components. PCA of FTIR spectra showed differences on protein and nucleic acid regions.
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Reversal of NAFLD After VSG Is Independent of Weight-Loss but RYGB Offers More Efficacy When Maintained on a High-Fat Diet. Obes Surg 2022; 32:2010-2022. [PMID: 35419698 DOI: 10.1007/s11695-022-06053-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/28/2022] [Accepted: 04/07/2022] [Indexed: 12/11/2022]
Abstract
PURPOSE Bariatric surgery is emerging as an effective treatment for obesity and the metabolic syndrome. Recently, we demonstrated that Roux-en-Y gastric bypass (RYGB), but not vertical sleeve gastrectomy (VSG), resulted in improvements to white adipose physiology and enhanced brown adipose functioning. Since beneficial alterations to liver health are also expected after bariatric surgery, comparing the post-operative effects of RYGB and VSG on liver physiology is essential to their application in the treatment of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS The effects of RYGB and VSG on liver physiology were compared using diet induced mouse model of obesity. High-fat diet (HFD) was administered for 12 weeks after surgery and alterations to liver physiology were assessed. RESULTS Both RYGB and VSG showed decreased liver weight as well as reductions to hepatic cholesterol and triglyceride levels. There were demonstrable improvements to NAFLD activity score (NAS) and fibrosis stage scoring after both surgeries. In RYGB, these beneficial changes to liver function resulted from the downregulation of pro-fibrotic and upregulation anti-fibrotic genes, as well as increased fatty acid oxidation and bile acid flux. For VSG, though similar alterations were observed, they were less potent. However, VSG did significantly downregulate pro-fibrotic genes and showed increased glycogen content paralleled by decreased glycogenolysis which may have contributed to the resolution of NAFLD. CONCLUSION RYGB and VSG improve liver physiology and function, but RYGB is more efficacious. Resolutions of NAFLD in RYGB and VSG are achieved through different processes, independent of weight loss.
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Integrative analysis reveals multiple modes of LXR transcriptional regulation in liver. Proc Natl Acad Sci U S A 2022; 119:2122683119. [PMID: 35145035 PMCID: PMC8851562 DOI: 10.1073/pnas.2122683119] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2022] [Indexed: 02/08/2023] Open
Abstract
The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRβ from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y) motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.
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Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159121. [PMID: 35150895 DOI: 10.1016/j.bbalip.2022.159121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 02/01/2022] [Indexed: 11/24/2022]
Abstract
Enterocytes of the small intestine (SI) play an important role in maintaining systemic lipid levels by regulating dietary lipid absorption and postprandial lipoprotein secretion. An excessive amount of dietary-derived triglycerides (TGs) taken up by the apical side of enterocytes or basolaterally internalized lipoprotein remnants can be transiently stored in cytosolic lipid droplets (cLDs). As mice lacking adipose TG lipase (ATGL) in the SI display massive accumulation of cLDs but also delayed cholesterol absorption, we hypothesized that SI-specific overexpression of ATGL (Atgl iTg) might have beneficial effects on lipid homeostasis in the gut and possibly throughout the body. Here, we demonstrate that Atgl iTg mice had only modestly increased enzymatic activity despite drastically elevated Atgl mRNA levels (up to 120-fold) on chow diet, and was highly induced upon high-fat/high-cholesterol diet (HF/HCD) feeding. Atgl iTg mice showed markedly reduced intestinal TG concentrations after acute and chronic lipid challenge without affecting chylomicron TG secretion. Circulating plasma cholesterol levels were significantly lower in Atgl iTg mice under different feeding conditions, contrasting the accelerated uptake of dietary cholesterol into the circulation after HF/HCD feeding. In the fasted state, gene expression analysis revealed modulation of PPARα and liver X receptor (LXR) target genes by an increased fatty acid release, whereas the decreased plasma cholesterol concentrations in refed mice were more likely due to changes in HDL synthesis and secretion. We conclude that ATGL, in addition to its role in TG catabolism, plays a critical role in whole-body cholesterol homeostasis by modulating PPARα and LXR signaling in intestinal enterocytes.
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Nuclear Receptors in Energy Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:61-82. [DOI: 10.1007/978-3-031-11836-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Lee H, Shin E, Kang H, Youn H, Youn B. Soybean-Derived Peptides Attenuate Hyperlipidemia by Regulating Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis. Nutrients 2021; 14:95. [PMID: 35010970 PMCID: PMC8747086 DOI: 10.3390/nu14010095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 11/16/2022] Open
Abstract
Increased triglyceride, cholesterol, and low-density lipoprotein (LDL) levels cause hyperlipidemia. Despite the availability of statin-based drugs to reduce LDL levels, additional effective treatments for reducing blood lipid concentrations are required. Herein, soybean hydrolysate prepared via peptic and tryptic hydrolysis promoted trans-intestinal cholesterol excretion (TICE) by increasing ATP-binding cassette subfamily G member 5 (ABCG5) and ABCG8 expression. The peptide sequence capable of promoting TICE was determined via HPLC and LC-MS/MS. Based on this, pure artificial peptides were synthesized, and the efficacy of the selected peptides was verified using cellular and hyperlipidemic mouse models. Soybean hydrolysates, including two bioactive peptides (ALEPDHRVESEGGL and SLVNNDDRDSYRLQSGDAL), promoted TICE via the expression of ABCG5 and ABCG8 in enterocytes. They downregulated expression of hepatic cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1 via expression of fibroblast growth factor 19 (FGF19) in a liver X receptor α (LXRa)-dependent pathway. Administration of bioactive peptides to hyperlipidemic mouse models by oral gavage reduced cholesterol levels in serum via upregulation of ABCG5 and ABCG8 expression in the proximal intestine and through fecal cholesterol excretion, upregulated FGF 15/19 expression, and suppressed hepatic bile acid synthesis. Oral administration of soybean-derived bioactive peptides elicited hypolipidemic effects by increasing TICE and decreasing hepatic cholesterol synthesis.
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Affiliation(s)
- Haksoo Lee
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.L.); (E.S.); (H.K.)
| | - Eunguk Shin
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.L.); (E.S.); (H.K.)
| | - Hyunkoo Kang
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.L.); (E.S.); (H.K.)
| | - HyeSook Youn
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea
| | - BuHyun Youn
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea; (H.L.); (E.S.); (H.K.)
- Department of Biological Sciences, Pusan National University, Busan 46241, Korea
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Kajani S, Curley S, O'Reilly ME, Yin X, Dillon ET, Guo W, Nilaweera KN, Brennan L, Roche HM, McGillicuddy FC. Sodium salicylate rewires hepatic metabolic pathways in obesity and attenuates IL-1β secretion from adipose tissue - implications for obesity-impaired reverse cholesterol transport. Mol Metab 2021; 56:101425. [PMID: 34954383 PMCID: PMC8762459 DOI: 10.1016/j.molmet.2021.101425] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 11/26/2022] Open
Abstract
Introduction High-fat diet (HFD)-induced obesity impairs clearance of cholesterol through the Reverse Cholesterol Transport (RCT) pathway, with downregulation in hepatic expression of cholesterol and bile acid transporters, namely ABCG5/8 and ABCB11, and reduced high-density lipoprotein (HDL) cholesterol efflux capacity (CEC). In the current study, we hypothesized that the development of hepatosteatosis, secondary to adipose-tissue dysfunction, contributes to obesity-impaired RCT and that such effects could be mitigated using the anti-inflammatory drug sodium salicylate (NaS). Materials and methods C57BL/6J mice, fed HFD ± NaS or low-fat diet (LFD) for 24 weeks, underwent glucose and insulin tolerance testing. The 3H-cholesterol movement from macrophage-to-feces was assessed in vivo. HDL-CEC was determined ex vivo. Cytokine secretion from adipose-derived stromal vascular fraction (SVF) cells was measured ex vivo. Liver and HDL proteins were determined by mass spectrometry and analyzed using Ingenuity Pathway Analysis. Results NaS delayed HFD-induced weight gain, abrogated priming of pro-IL-1β in SVFs, attenuated insulin resistance, and prevented steatohepatitis (ectopic fat accumulation in the liver). Prevention of hepatosteatosis coincided with increased expression of PPAR-alpha/beta-oxidation proteins with NaS and reduced expression of LXR/RXR-induced proteins including apolipoproteins. The latter effects were mirrored within the HDL proteome in circulation. Despite remarkable protection shown against steatosis, HFD-induced hypercholesterolemia and repression of the liver-to-bile cholesterol transporter, ABCG5/8, could not be rescued with NaS. Discussions and conclusions The cardiometabolic health benefits of NaS may be attributed to the reprogramming of hepatic metabolic pathways to increase fatty acid utilization in the settings of nutritional overabundance. Reduced hepatic cholesterol levels, coupled with reduced LXR/RXR-induced proteins, may underlie the lack of rescue of ABCG5/8 expression with NaS. This remarkable protection against HFD-induced hepatosteatosis did not translate to improvements in cholesterol homeostasis.
Sodium salicylate (NaS) initially delays weight-gain in mice fed high-fat diet (HFD) - catch-up evident in weeks 12–24. NaS prevents HFD-induced insulin resistance, hepatosteatosis and pro-IL-1β priming in adipose tissue even upon weight-gain. Hepatic expression of proteins involved in beta oxidation, oxidative phosphorylation and TCA cycle upregulated with NaS. Hepatic expression of LXR/RXR proteins eg. apolipoproteins reduced with NaS; these effects were mirrored in HDL proteome. NaS failed to improve HFD-impaired Reverse Cholesterol Transport or hypercholesterolemia despite preventing hepatosteatosis.
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Affiliation(s)
- Sarina Kajani
- Diabetes Complications Research Centre; UCD School of Medicine; UCD Conway Institute; UCD Institute of Food and Health
| | - Sean Curley
- Diabetes Complications Research Centre; UCD School of Medicine; UCD Conway Institute; UCD Institute of Food and Health
| | - Marcella E O'Reilly
- Diabetes Complications Research Centre; UCD School of Medicine; UCD Conway Institute; UCD Institute of Food and Health
| | - Xiaofei Yin
- UCD Conway Institute; UCD Institute of Food and Health; School of Agriculture and Food Science, University College Dublin, Dublin 4, Ireland
| | | | - Weili Guo
- Diabetes Complications Research Centre; UCD School of Medicine; UCD Conway Institute; UCD Institute of Food and Health
| | - Kanishka N Nilaweera
- Teagasc Food Research Centre; VistaMilk Research Centre, Moorepark, Fermoy, Ireland
| | - Lorraine Brennan
- UCD Conway Institute; UCD Institute of Food and Health; School of Agriculture and Food Science, University College Dublin, Dublin 4, Ireland
| | - Helen M Roche
- Diabetes Complications Research Centre; UCD Conway Institute; Nutrigenomics Research Group, School of Public Health, Physiotherapy and Sports Science; UCD Institute of Food and Health
| | - Fiona C McGillicuddy
- Diabetes Complications Research Centre; UCD School of Medicine; UCD Conway Institute; UCD Institute of Food and Health.
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Cao K, Zhang K, Ma M, Ma J, Tian J, Jin Y. Lactobacillus mediates the expression of NPC1L1, CYP7A1, and ABCG5 genes to regulate cholesterol. Food Sci Nutr 2021; 9:6882-6891. [PMID: 34925816 PMCID: PMC8645708 DOI: 10.1002/fsn3.2600] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/09/2021] [Accepted: 09/11/2021] [Indexed: 01/09/2023] Open
Abstract
Hypercholesterolemia is the main cause of cardiovascular disease worldwide, and the regulation of cholesterol homeostasis is essential for human health. Lactobacillus is present in large quantities in the human intestine. As the normal flora in the gut, lactobacillus plays an important role in regulating metabolism in the human body. Lactobacillus can regulate the cholesterol content by regulating the expression of genes involved in cholesterol synthesis, metabolism, and absorption. This article reviews the biological effects and mechanisms of lactobacillus that mediate the expression of NPC1L1, CYP7A1, ABCG5, ABCG8, and other genes to inhibit cholesterol absorption, and discusses the mechanism of reducing cholesterol by lactobacillus in cells in vitro, to provide a theoretical basis for the development and utilization of lactobacillus resources.
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Affiliation(s)
- Kaihui Cao
- College of Food Science and TechnologyInner Mongolia Agricultural UniversityHohhotChina
| | - Kaiping Zhang
- Department of Cooking & Food ProcessingInner Mongolia Business and Trade Vocational CollegeHohhotChina
| | - Muran Ma
- College of Food Science and TechnologyInner Mongolia Agricultural UniversityHohhotChina
| | - Junjie Ma
- College of Food Science and TechnologyInner Mongolia Agricultural UniversityHohhotChina
| | - Jianjun Tian
- College of Food Science and TechnologyInner Mongolia Agricultural UniversityHohhotChina
| | - Ye Jin
- College of Food Science and TechnologyInner Mongolia Agricultural UniversityHohhotChina
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