|
1
|
Comeglio P, Guarnieri G, Filippi S, Cellai I, Acciai G, Holyer I, Zetterberg F, Leffler H, Kahl-Knutson B, Sarchielli E, Morelli A, Maggi M, Slack RJ, Vignozzi L. The galectin-3 inhibitor selvigaltin reduces liver inflammation and fibrosis in a high fat diet rabbit model of metabolic-associated steatohepatitis. Front Pharmacol 2024; 15:1430109. [PMID: 39144627 PMCID: PMC11322497 DOI: 10.3389/fphar.2024.1430109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
Introduction Galectin-3 is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. Selvigaltin (previously known as GB1211) is a novel orally active galectin-3 small molecule inhibitor that has high affinity for galectin-3 (human KD = 25 nM; rabbit KD = 12 nM) and high oral bioavailability in rabbits and man. In this study the efficacy of selvigaltin was investigated in a high fat diet (HFD) rabbit model of metabolic-associated steatohepatitis (MASH). Methods Male New Zealand White rabbits were individually caged under standard conditions in a temperature and humidity-controlled room on a 12 h light/darkness cycle. After 1 week of regular diet (RD), rabbits were randomly assigned for 8 or 12 weeks to different groups: RD/vehicle, RD/selvigaltin, HFD (8 weeks), HFD/vehicle and HFD/selvigaltin (0.3, 1.0, 5.0 or 30 mg/kg selvigaltin with vehicle/selvigaltin p.o. dosed therapeutically q.d. 5 days per week from week 9 or 12). Liver inflammation, steatosis, ballooning, and fibrosis was measured via blood metabolic markers, histomorphological evaluation [Oil Red O, Giemsa, Masson's trichome, picrosirius red (PSR) and second harmonic generation (SHG)], and mRNA and protein expression. Results Steatosis, inflammation, ballooning, and fibrosis were all increased from RD to HFD/vehicle groups. Selvigaltin demonstrated target engagement by significantly decreasing galectin-3 levels in the liver as measured via immunohistochemistry and mRNA analysis. Selvigaltin dose-dependently reduced biomarkers of liver function (AST, ALT, bilirubin), inflammation (cells foci), and fibrosis (PSR, SHG), as well as decreasing the mRNA and protein expression of several key inflammation and fibrosis biomarkers (e.g., IL6, TGFβ3, SNAI2, collagen). Doses of 1.0 or 5.0 mg/kg demonstrated consistent efficacy across most biological endpoints supporting the current clinical doses of selvigaltin being investigated in liver disease. Discussion Selvigaltin significantly reduced hepatic inflammation and fibrosis in an HFD rabbit model of MASH following therapeutic dosing for 4 weeks in a dose-dependent manner. These data support the human selvigaltin dose of 100 mg b.i.d. that has been shown to reduce key liver biomarkers during a clinical study in liver cirrhosis.
Collapse
Affiliation(s)
- Paolo Comeglio
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Giulia Guarnieri
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Sandra Filippi
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Ilaria Cellai
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Gabriele Acciai
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | | | | | | | | | - Erica Sarchielli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Annamaria Morelli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Mario Maggi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Rome, Italy
| | | | - Linda Vignozzi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
- Interuniversity Consortium “Istituto Nazionale Biostrutture e Biosistemi” (INBB), Rome, Italy
| |
Collapse
|
|
2
|
Chen S, Jiao Y, Han Y, Zhang J, Deng Y, Yu Z, Wang J, He S, Cai W, Xu J. Edible traditional Chinese medicines improve type 2 diabetes by modulating gut microbiotal metabolites. Acta Diabetol 2024; 61:393-411. [PMID: 38227209 DOI: 10.1007/s00592-023-02217-6] [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: 09/02/2023] [Accepted: 11/17/2023] [Indexed: 01/17/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder with intricate pathogenic mechanisms. Despite the availability of various oral medications for controlling the condition, reports of poor glycemic control in type 2 diabetes persist, possibly involving unknown pathogenic mechanisms. In recent years, the gut microbiota have emerged as a highly promising target for T2DM treatment, with the metabolites produced by gut microbiota serving as crucial intermediaries connecting gut microbiota and strongly related to T2DM. Increasingly, traditional Chinese medicine is being considered to target the gut microbiota for T2DM treatment, and many of them are edible. In studies conducted on animal models, edible traditional Chinese medicine have been shown to primarily alter three significant gut microbiotal metabolites: short-chain fatty acids, bile acids, and branched-chain amino acids. These metabolites play crucial roles in alleviating T2DM by improving glucose metabolism and reducing inflammation. This review primarily summarizes twelve edible traditional Chinese medicines that improve T2DM by modulating the aforementioned three gut microbiotal metabolites, along with potential underlying molecular mechanisms, and also incorporation of edible traditional Chinese medicines into the diets of T2DM patients and combined use with probiotics for treating T2DM are discussed.
Collapse
Affiliation(s)
- Shen Chen
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Queen Mary School, Medical College, Nanchang University, Nanchang, 330006, China
| | - Yiqiao Jiao
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Queen Mary School, Medical College, Nanchang University, Nanchang, 330006, China
| | - Yiyang Han
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Queen Mary School, Medical College, Nanchang University, Nanchang, 330006, China
| | - Jie Zhang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Yuanyuan Deng
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Zilu Yu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
- Queen Mary School, Medical College, Nanchang University, Nanchang, 330006, China
| | - Jiao Wang
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Shasha He
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Wei Cai
- Department of Medical Genetics and Cell Biology, Medical College of Nanchang University, Nanchang, 330006, People's Republic of China.
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People's Republic of China.
- Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, Nanchang, Jiangxi, 330006, People's Republic of China.
- Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, Jiangxi, 330006, People's Republic of China.
| |
Collapse
|
|
3
|
Wang Y, Zou Z, Wang S, Ren A, Ding Z, Li Y, Wang Y, Qian Z, Bian B, Huang B, Xu G, Cui G. Golden bile powder prevents drunkenness and alcohol-induced liver injury in mice via the gut microbiota and metabolic modulation. Chin Med 2024; 19:39. [PMID: 38431607 PMCID: PMC10908100 DOI: 10.1186/s13020-024-00912-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/23/2024] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND Drunkenness and alcoholic liver disease (ALD) are critical public health issues associated with significant morbidity and mortality due to chronic overconsumption of alcohol. Traditional remedies, such as bear bile powder, have been historically acclaimed for their hepatoprotective properties. This study assessed the efficacy of a biotransformed bear bile powder known as golden bile powder (GBP) in alleviating alcohol-induced drunkenness and ALD. METHODS A murine model was engineered to simulate alcohol drunkenness and acute hepatic injury through the administration of a 50% ethanol solution. Intervention with GBP and its effects on alcohol-related symptoms were scrutinized, by employing an integrative approach that encompasses serum metabolomics, network medicine, and gut microbiota profiling to elucidate the protective mechanisms of GBP. RESULTS GBP administration significantly delayed the onset of drunkenness and decreased the duration of ethanol-induced inebriation in mice. Enhanced liver cell recovery was indicated by increased hepatic aldehyde dehydrogenase levels and superoxide dismutase activity, along with significant decreases in the serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, triglyceride, and total cholesterol levels (P < 0.05). These biochemical alterations suggest diminished hepatic damage and enhanced lipid homeostasis. Microbiota analysis via 16S rDNA sequencing revealed significant changes in gut microbial diversity and composition following alcohol exposure, and these changes were effectively reversed by GBP treatment. Metabolomic analyses demonstrated that GBP normalized the alcohol-induced perturbations in phospholipids, fatty acids, and bile acids. Correlation assessments linked distinct microbial genera to serum bile acid profiles, indicating that the protective efficacy of GBP may be attributable to modulatory effects on metabolism and the gut microbiota composition. Network medicine insights suggest the prominence of two active agents in GBP as critical for addressing drunkenness and ALD. CONCLUSION GBP is a potent intervention for alcohol-induced pathology and offers hepatoprotective benefits, at least in part, through the modulation of the gut microbiota and related metabolic cascades.
Collapse
Affiliation(s)
- Yarong Wang
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Zhenzhuang Zou
- Department of Pediatrics, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Sihua Wang
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Airong Ren
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Zhaolin Ding
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Yingying Li
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Yifang Wang
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Zhengming Qian
- College of Medical Imaging Laboratory and Rehabilitation, Xiangnan University, Chenzhou, 423000, Hunan, China
| | - Baolin Bian
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Bo Huang
- Department of Pediatrics, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Guiwei Xu
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China
| | - Guozhen Cui
- School of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai, 519000, Guangdong, China.
| |
Collapse
|
|
4
|
Hasan IH, Shaheen SY, Alhusaini AM, Mahmoud AM. Simvastatin mitigates diabetic nephropathy by upregulating farnesoid X receptor and Nrf2/HO-1 signaling and attenuating oxidative stress and inflammation in rats. Life Sci 2024; 340:122445. [PMID: 38278349 DOI: 10.1016/j.lfs.2024.122445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/03/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Diabetic nephropathy is one of the complications of diabetes that affects the kidney and can result in renal failure. The cholesterol-lowering drug simvastatin (SIM) has shown promising effects against diabetic nephropathy (DN). This study evaluated the protective role of SIM on DN, pointing to the involvement of farnesoid X receptor (FXR) and Nrf2/HO-1 signaling in attenuating inflammatory response, oxidative injury, and tissue damage in streptozotocin-induced diabetic rats. SIM was supplemented orally for 8 weeks, and samples were collected for analysis. SIM effectively ameliorated hyperglycemia, kidney hypertrophy, body weight loss, and tissue injury and fibrosis in diabetic animals. SIM mitigated oxidative stress (OS), inflammatory response, and cell death, as evidenced by the suppressed malondialdehyde, nitric oxide, myeloperoxidase, NF-kB, TNF-α, IL-1β, CD68, Bax, and caspase-3 in the diabetic kidney. These effects were linked to suppressed Keap1, upregulated FXR, Nrf2, and HO-1, and enhanced antioxidant defenses and Bcl-2. The in silico findings revealed the binding affinity of SIM with NF-kB, caspase-3, Keap1, HO-1, and FXR. In conclusion, SIM protects against DN by attenuating hyperglycemia, kidney injury, fibrosis, inflammation, and OS, and upregulating antioxidants, FXR, and Nrf2/HO-1 signaling.
Collapse
Affiliation(s)
- Iman H Hasan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11459, Saudi Arabia..
| | - Sameerah Y Shaheen
- Department of Anatomy, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Ahlam M Alhusaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11459, Saudi Arabia
| | - Ayman M Mahmoud
- Department of Life Sciences, Faculty of Science & Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK..
| |
Collapse
|
|
5
|
Tang X, Liao Q, Li Q, Jiang L, Li W, Xu J, Xiong A, Wang R, Zhao J, Wang Z, Ding L, Yang L. Lusianthridin ameliorates high fat diet-induced metabolic dysfunction-associated fatty liver disease via activation of FXR signaling pathway. Eur J Pharmacol 2024; 965:176196. [PMID: 38006926 DOI: 10.1016/j.ejphar.2023.176196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/30/2023] [Accepted: 11/09/2023] [Indexed: 11/27/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease, but there are few specific medications for it. Lusianthridin, a major phenanthrene component that originates from Dendrobium Sonia, has various in vitro biological functions. In this study, we aimed to evaluate the therapeutic effects of lusianthridin on high-fat diet (HFD)-induced MAFLD as well as to examine the mechanism of its effects. We fed male mice high-fat-diet for 12 weeks to induce MAFLD and then continued to feed them, either with or without lusianthridin, for another six weeks. We found that lusianthridin decreased serum triacylglycerol, hepatic triacylglycerol, and serum low density lipoprotein cholesterol. It also reduced hepatic lipid accumulation based on the results of morphology analysis. Besides, it improved hepatic inflammation as well, including a decrease in serum alanine aminotransferase and a reduction in macrophage and neutrophil infiltration. Mechanistically, surface plasmon resonance, cell thermal shift assay and dual-luciferase report system results suggested that lusianthridin combined with farnesoid X receptor (FXR) ligand binding region and activated its transcriptional activity. Lusianthridin also decreased de no lipogenesis though inhibiting Srebp1c and downstream Scd-1, Lpin1 and Dgat2 expression in a FXR-dependent manner in oleic acid treated L02 cells. Correspondingly, lusianthridin inhibited Srebp1c and downstream lipogenesis in MAFLD liver tissues of mice at both of genetic and protein levels. Finally, the protective effects of lusianthridin on hepatic steaotosis were abolished in Fxr-/- mice. Taken together, our results suggested that lusianthridin attenuated high-fat-diet induced MAFLD via activation the FXR signaling pathway.
Collapse
Affiliation(s)
- Xiaowen Tang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Liao
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qinqin Li
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Linshan Jiang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Li
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jie Xu
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Aizhen Xiong
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Rufeng Wang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, 999078, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
6
|
Schmid A, Karrasch T, Schäffler A. The emerging role of bile acids in white adipose tissue. Trends Endocrinol Metab 2023; 34:718-734. [PMID: 37648561 DOI: 10.1016/j.tem.2023.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/21/2023] [Accepted: 08/02/2023] [Indexed: 09/01/2023]
Abstract
The effects of bile acids (BAs) on liver, enteroendocrine function, small intestine, and brown adipose tissue have been described extensively. Outside the liver, BAs in the peripheral circulation system represent a specific but underappreciated physiological compartment. We discuss how systemic BAs can be regarded as specific steroidal hormones that act on white adipocytes, and suggest the name 'bilokines' ('bile hormones') for the specific FXR/TGR5 receptor interaction in adipocytes. Some BAs and their agonists regulate adipocyte differentiation, lipid accumulation, hypoxia, autophagy, adipokine and cytokine secretion, insulin signaling, and glucose uptake. BA signaling could provide a new therapeutic avenue for adipoflammation and metaflammation in visceral obesity, the causal mechanisms underlying insulin resistance and type 2 diabetes mellitus (T2D).
Collapse
Affiliation(s)
- Andreas Schmid
- Basic Research Laboratory for Molecular Endocrinology, Adipocyte Biology, and Biochemistry, University of Giessen, D 35392 Giessen, Germany
| | - Thomas Karrasch
- Department of Internal Medicine III - Endocrinology, Diabetology, and Metabolism, University of Giessen, D 35392 Giessen, Germany
| | - Andreas Schäffler
- Department of Internal Medicine III - Endocrinology, Diabetology, and Metabolism, University of Giessen, D 35392 Giessen, Germany.
| |
Collapse
|
|
7
|
Carrasco AG, Izquierdo-Lahuerta A, Valverde ÁM, Ni L, Flores-Salguero E, Coward RJ, Medina-Gómez G. The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2023; 1868:159329. [PMID: 37156296 DOI: 10.1016/j.bbalip.2023.159329] [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: 12/26/2022] [Revised: 03/16/2023] [Accepted: 04/20/2023] [Indexed: 05/10/2023]
Abstract
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
Collapse
Affiliation(s)
- Almudena G Carrasco
- Universidad Rey Juan Carlos, Dpto. de Ciencias Básicas de la Salud, Avda. de Atenas s/n. 28922, Alcorcón, Madrid, Spain
| | - Adriana Izquierdo-Lahuerta
- Universidad Rey Juan Carlos, Dpto. de Ciencias Básicas de la Salud, Avda. de Atenas s/n. 28922, Alcorcón, Madrid, Spain.
| | - Ángela M Valverde
- Institute of Biomedical Research "Alberto Sols" (CSIC-UAM), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBER-dem), ISCIII, 28029 Madrid, Spain; MEMORISM Research Unit of University Rey Juan Carlos-Institute of Biomedical Research "Alberto Sols" (CSIC), Madrid, Spain
| | - Lan Ni
- Bristol Renal, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Elena Flores-Salguero
- Universidad Rey Juan Carlos, Dpto. de Ciencias Básicas de la Salud, Avda. de Atenas s/n. 28922, Alcorcón, Madrid, Spain
| | - Richard J Coward
- Bristol Renal, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Gema Medina-Gómez
- Universidad Rey Juan Carlos, Dpto. de Ciencias Básicas de la Salud, Avda. de Atenas s/n. 28922, Alcorcón, Madrid, Spain; MEMORISM Research Unit of University Rey Juan Carlos-Institute of Biomedical Research "Alberto Sols" (CSIC), Madrid, Spain.
| |
Collapse
|
|
8
|
Dehondt H, Marino A, Butruille L, Mogilenko DA, Nzoussi Loubota AC, Chávez-Talavera O, Dorchies E, Vallez E, Haas J, Derudas B, Bongiovanni A, Tardivel M, Kuipers F, Lefebvre P, Lestavel S, Tailleux A, Dombrowicz D, Caron S, Staels B. Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis. Mol Metab 2023; 69:101686. [PMID: 36746333 PMCID: PMC9958065 DOI: 10.1016/j.molmet.2023.101686] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. METHODS We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR-/-) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR-/-) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR-/- mice. RESULTS eWAT from HFD-fed whole-body FXR-/- and Ad-FXR-/- mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR-/- mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR-/- mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. CONCLUSIONS These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.
Collapse
Affiliation(s)
- Hélène Dehondt
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Arianna Marino
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Laura Butruille
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Denis A Mogilenko
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | | | - Oscar Chávez-Talavera
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Emilie Dorchies
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Emmanuelle Vallez
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Joel Haas
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bruno Derudas
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Antonino Bongiovanni
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France
| | - Meryem Tardivel
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France
| | - Folkert Kuipers
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Sophie Lestavel
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Anne Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - David Dombrowicz
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Sandrine Caron
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| |
Collapse
|
|
9
|
Li H, Xi Y, Liu H, Xin X. Gypenosides ameliorate high-fat diet-induced non-alcoholic steatohepatitis via farnesoid X receptor activation. Front Nutr 2022; 9:914079. [PMID: 36091227 PMCID: PMC9449333 DOI: 10.3389/fnut.2022.914079] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Background Gypenosides (Gyps), the major botanical component of Gynostemma pentaphyllum, was found to up-regulate the farnesoid X receptor (FXR) in a mouse model of non-alcoholic steatohepatitis (NASH). However, the exact role of FXR and underlying mechanisms in Gyps-mediated effects on NASH remain to be elucidated. Purpose This study investigated whether Gyps attenuates NASH through directly activating FXR in high-fat diet (HFD)-induced NASH, and delineated the molecular pathways involved. Study design A mouse model of HFD-induced NSAH was used to examine effects of Gyps on NASH with obeticholic acid (OCA) as a positive control, and the role of FXR in its mechanism of action was investigated in wild-type (WT) and FXR knockout (KO) mice. Methods WT or FXR KO mice were randomly assigned into four groups: normal diet (ND) group as negative control, HFD group, HFD + Gyps group, or HFD + OCA group. Results Treatment with Gyps and OCA significantly improved liver histopathological abnormalities in HFD-induced NASH, reduced the non-alcoholic fatty liver disease (NAFLD) activity score (NAS), and lowered hepatic triglyceride (TG) content compared with the HFD group. In agreement with these liver tissue changes, biochemical tests of blood samples revealed that alanine aminotransferase (ALT), aspartate aminotransferase (AST), TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), and fasting insulin (FINS) levels were significantly lower in the HFD + Gyps vs. HFD group. Furthermore, Gyps and OCA treatment significantly up-regulated hepatic FXR, small heterodimer partner (SHP), carnitine palmitoyltransferase 1A (CPT1A), and lipoprotein lipase (LPL) expression, and significantly down-regulated sterol-regulatory element binding protein 1 (SREBP1), fatty acid synthetase (FASN), and stearoyl-CoA desaturase 1 (SCD1) protein levels compared with the HFD group in WT mice but not in FXR KO mice. Notably, Gyps- and OCA-mediated pharmacological effects were significantly abrogated by depletion of the FXR gene in FXR KO mice. Conclusion Gyps ameliorated HFD-induced NASH through the direct activation of FXR and FXR-dependent signaling pathways.
Collapse
Affiliation(s)
- Hongshan Li
- Liver Disease Department of Integrative Medicine, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo, China
- *Correspondence: Hongshan Li,
| | - Yingfei Xi
- Liver Disease Department of Integrative Medicine, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Hongliang Liu
- Liver Disease Department of Integrative Medicine, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Xin Xin
- Shuguang Hospital, Institute of Liver Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
10
|
Zhou W, Anakk S. Enterohepatic and non-canonical roles of farnesoid X receptor in controlling lipid and glucose metabolism. Mol Cell Endocrinol 2022; 549:111616. [PMID: 35304191 PMCID: PMC9245558 DOI: 10.1016/j.mce.2022.111616] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022]
Abstract
Farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates bile acid homeostasis along with nutrient metabolism. In addition to the gastrointestinal (GI) tract, FXR expression has been widely noted in kidney, adrenal gland, pancreas, adipose, skeletal muscle, heart, and brain. Except for the liver and gut, the relevance of FXR signaling in metabolism in other tissues remains poorly understood. This review examines the classical and non-canonical tissue-specific roles of FXR in regulating, lipids, and glucose homeostasis under normal and diseased states. FXR activation has been reported to be protective against cholestasis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), type 2 diabetes, cardiovascular and kidney diseases. Several ongoing clinical trials are investigating FXR ligands as a therapeutic target for primary biliary cholangitis (PBC) and NASH, which substantiate the significance of FXR signaling in modulating metabolic processes. This review highlights that FXR ligands, albeit an attractive therapeutic target for treating metabolic diseases, tissue-specific modulation of FXR may be the key to overcoming some of the adverse clinical effects.
Collapse
Affiliation(s)
- Weinan Zhou
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
| |
Collapse
|
|
11
|
Lustig RH, Collier D, Kassotis C, Roepke TA, Ji Kim M, Blanc E, Barouki R, Bansal A, Cave MC, Chatterjee S, Choudhury M, Gilbertson M, Lagadic-Gossmann D, Howard S, Lind L, Tomlinson CR, Vondracek J, Heindel JJ. Obesity I: Overview and molecular and biochemical mechanisms. Biochem Pharmacol 2022; 199:115012. [PMID: 35393120 PMCID: PMC9050949 DOI: 10.1016/j.bcp.2022.115012] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/12/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023]
Abstract
Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY3-36) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the "obesogen hypothesis" (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.
Collapse
Affiliation(s)
- Robert H Lustig
- Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, CA 94143, United States
| | - David Collier
- Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Christopher Kassotis
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, United States
| | - Troy A Roepke
- School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901, United States
| | - Min Ji Kim
- Department of Biochemistry and Toxicology, University of Paris, INSERM U1224 (T3S), 75006 Paris, France
| | - Etienne Blanc
- Department of Biochemistry and Toxicology, University of Paris, INSERM U1224 (T3S), 75006 Paris, France
| | - Robert Barouki
- Department of Biochemistry and Toxicology, University of Paris, INSERM U1224 (T3S), 75006 Paris, France
| | - Amita Bansal
- College of Health & Medicine, Australian National University, Canberra, Australia
| | - Matthew C Cave
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY 40402, United States
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, University of South Carolina, Columbia, SC 29208, United States
| | - Mahua Choudhury
- College of Pharmacy, Texas A&M University, College Station, TX 77843, United States
| | - Michael Gilbertson
- Occupational and Environmental Health Research Group, University of Stirling, Stirling, Scotland, United Kingdom
| | - Dominique Lagadic-Gossmann
- Research Institute for Environmental and Occupational Health, University of Rennes, INSERM, EHESP, Rennes, France
| | - Sarah Howard
- Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, United States
| | - Lars Lind
- Department of Medical Sciences, University of Uppsala, Uppsala, Sweden
| | - Craig R Tomlinson
- Norris Cotton Cancer Center, Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States
| | - Jan Vondracek
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
| | - Jerrold J Heindel
- Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, United States.
| |
Collapse
|
|
12
|
Tao J, Yu XL, Yuan YJ, Shen X, Liu J, Gu PP, Wang Z, Ma YT, Li GQ. DMRT2 Interacts With FXR and Improves Insulin Resistance in Adipocytes and a Mouse Model. Front Endocrinol (Lausanne) 2022; 12:723623. [PMID: 35250844 PMCID: PMC8891600 DOI: 10.3389/fendo.2021.723623] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
Insulin resistance (IR) plays a critical role in cardiovascular diseases and metabolic diseases. In this study, we identified the downregulation of DMRT2 in adipose tissues from insulin-resistant subjects through bioinformatics analysis and in an insulin-resistant mouse model through experimental analysis. DMRT2 overexpression significantly attenuated HDF-induced insulin resistance and inflammation in mice. Moreover, in control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, DMRT2 overexpression attenuated but DMRT2 knockdown enhanced the insulin resistance of 3T3-L1 adipocytes. DMRT2 interacted with FXR and positively regulated FXR level and transcription activity. In both control and insulin-resistant differentiated mouse 3T3-L1 adipocytes, FXR knockdown enhanced the insulin resistance and attenuated the effects of DMRT2 overexpression upon 3T3-L1 adipocyte insulin resistance. In conclusion, we identify the downregulation of DMRT2 in the insulin-resistant mouse model and cell model. DMRT2 interacts with FXR and improves insulin resistance in adipocytes.
Collapse
Affiliation(s)
- Jing Tao
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xiao-Lin Yu
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Graduate School of Xinjiang Medical University, Urumqi, China
| | - Yu-Juan Yuan
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Graduate School of Xinjiang Medical University, Urumqi, China
| | - Xin Shen
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jun Liu
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Pei-Pei Gu
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Zhao Wang
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yi-Tong Ma
- Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Guo-Qing Li
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| |
Collapse
|
|
13
|
Comeglio P, Sarchielli E, Filippi S, Cellai I, Guarnieri G, Morelli A, Rastrelli G, Maseroli E, Cipriani S, Mello T, Galli A, Bruno BJ, Kim K, Vangara K, Papangkorn K, Chidambaram N, Patel MV, Maggi M, Vignozzi L. Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model. J Endocrinol Invest 2021; 44:2175-2193. [PMID: 33586025 PMCID: PMC8421272 DOI: 10.1007/s40618-021-01522-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/27/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. METHODS Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson's trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. RESULTS Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. CONCLUSIONS Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.
Collapse
Affiliation(s)
- P Comeglio
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - E Sarchielli
- Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - S Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - I Cellai
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - G Guarnieri
- Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - A Morelli
- Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - G Rastrelli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - E Maseroli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - S Cipriani
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - T Mello
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - A Galli
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - B J Bruno
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | - K Kim
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | - K Vangara
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | | | | | - M V Patel
- Lipocine Inc., Salt Lake City, Utah, 84088, USA
| | - M Maggi
- Endocrinology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Rome, Italy
| | - L Vignozzi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy.
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Rome, Italy.
| |
Collapse
|
|
14
|
Hu C, Jia W. Multi-omics profiling: the way towards precision medicine in metabolic diseases. J Mol Cell Biol 2021; 13:mjab051. [PMID: 34406397 PMCID: PMC8697344 DOI: 10.1093/jmcb/mjab051] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic diseases including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (MetS) are alarming health burdens around the world, while therapies for these diseases are far from satisfying as their etiologies are not completely clear yet. T2DM, NAFLD, and MetS are all complex and multifactorial metabolic disorders based on the interactions between genetics and environment. Omics studies such as genetics, transcriptomics, epigenetics, proteomics, and metabolomics are all promising approaches in accurately characterizing these diseases. And the most effective treatments for individuals can be achieved via omics pathways, which is the theme of precision medicine. In this review, we summarized the multi-omics studies of T2DM, NAFLD, and MetS in recent years, provided a theoretical basis for their pathogenesis and the effective prevention and treatment, and highlighted the biomarkers and future strategies for precision medicine.
Collapse
Affiliation(s)
- Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus,
Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth
People's Hospital, Shanghai 200233, China
- Institute for Metabolic Disease, Fengxian Central Hospital, The Third School of
Clinical Medicine, Southern Medical University, Shanghai 201499, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus,
Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth
People's Hospital, Shanghai 200233, China
| |
Collapse
|
|
15
|
Maseroli E, Comeglio P, Corno C, Cellai I, Filippi S, Mello T, Galli A, Rapizzi E, Presenti L, Truglia MC, Lotti F, Facchiano E, Beltrame B, Lucchese M, Saad F, Rastrelli G, Maggi M, Vignozzi L. Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men. J Endocrinol Invest 2021; 44:819-842. [PMID: 32772323 PMCID: PMC7946690 DOI: 10.1007/s40618-020-01381-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/31/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.
Collapse
Affiliation(s)
- E Maseroli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - P Comeglio
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - C Corno
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - I Cellai
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - S Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - T Mello
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - A Galli
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - E Rapizzi
- Endocrinology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - L Presenti
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - M C Truglia
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - F Lotti
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - E Facchiano
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - B Beltrame
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - M Lucchese
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - F Saad
- Medical Affairs, Bayer AG, Kaiser-Wilhelm-Allee 1, 51373, Leverkusen, Germany
| | - G Rastrelli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - M Maggi
- Endocrinology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Viale delle Medaglie d'Oro 305, 00136, Rome, Italy
| | - L Vignozzi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy.
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Viale delle Medaglie d'Oro 305, 00136, Rome, Italy.
| |
Collapse
|
|
16
|
Sardi C, Martini E, Mello T, Camelliti S, Sfondrini L, Marcucci F, Kallikourdis M, Sommariva M, Rumio C. Effect of acetylsalicylic acid on inflamed adipose tissue. Insulin resistance and hepatic steatosis in a mouse model of diet-induced obesity. Life Sci 2020; 264:118618. [PMID: 33141040 DOI: 10.1016/j.lfs.2020.118618] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 10/05/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022]
Abstract
AIMS Obesity represents a global health problem. Excessive caloric intake promotes the release of inflammatory mediators by hypertrophic adipocytes and obesity-induced inflammation is now recognized as a risk factor for the development of several diseases, such as cardiovascular diseases, insulin resistance, type-II diabetes, liver steatosis and cancer. Since obesity causes inflammation, we tested the ability of acetylsalicylic acid (ASA), a potent anti-inflammatory drug, in counteracting this inflammatory process and in mitigating obesity-associated health complications. MAIN METHODS Mice were fed with standard (SD) or high fat diet (HFD) for 3 months and then treated with acetylsalicylic acid for the subsequent two months. We then analyzed the metabolic and inflammatory status of their adipose and liver tissue by histological, molecular and biochemical analysis. KEY FINDINGS Although ASA did not exert any effect on body weight, quantification of adipocyte size revealed that the drug slightly reduced adipocyte hypertrophy, however not sufficient so as to induce weight loss. Most importantly, ASA was able to improve insulin resistance. Gene expression profiles of pro- and anti-inflammatory cytokines as well as the expression of macrophage and lymphocyte markers revealed that HFD led to a marked macrophage accumulation in the adipose tissue and an increase of several pro-inflammatory cytokines, a situation almost completely reverted after ASA administration. In addition, liver steatosis caused by HFD was completely abrogated by ASA treatment. SIGNIFICANCE ASA can efficiently ameliorate pathological conditions usually associated with obesity by inhibiting the inflammatory process occurring in the adipose tissue.
Collapse
Affiliation(s)
- Claudia Sardi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Trentacoste 2, Milan, Italy; Adaptive Immunity Laboratory, Humanitas Clinical and Research Center IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Elisa Martini
- Adaptive Immunity Laboratory, Humanitas Clinical and Research Center IRCCS, Via Manzoni 56, 20089 Rozzano, Italy
| | - Tommaso Mello
- Scienze Biomediche, Sperimentali e Cliniche 'Mario Serio', Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy
| | - Simone Camelliti
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Lucia Sfondrini
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Fabrizio Marcucci
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Trentacoste 2, Milan, Italy
| | - Marinos Kallikourdis
- Adaptive Immunity Laboratory, Humanitas Clinical and Research Center IRCCS, Via Manzoni 56, 20089 Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Italy
| | - Michele Sommariva
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milan, Italy
| | - Cristiano Rumio
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, via Trentacoste 2, Milan, Italy.
| |
Collapse
|
|
17
|
T MM, T A, P BK, Fathima A, Khanum F. In-silico therapeutic investigations of arjunic acid and arjungenin as an FXR agonist and validation in 3T3-L1 adipocytes. Comput Biol Chem 2019; 84:107163. [PMID: 31767507 DOI: 10.1016/j.compbiolchem.2019.107163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 12/31/2022]
Abstract
The present study was to illustrate the agonistic property of arjungenin and arjunic acid towards farnesoid X receptor protein (FXR).The pharmacokinetic properties like molecular interactions, absorption, distribution, metabolism, elimination and toxicity (ADMET) of the ligands were checked through in-silico studies. Protein-ligand docking was carried out using autodock software. Molecular docking analysis confirmed strong binding energy and interaction of arjungenin and arjunic acid with the target protein and the ADMET profiles identified for both compounds were promising.Further in vitro studies were performed in 3T3-L1 adipocyte to verify the agonistic property of arjungenin and arjunic acid. Oil red O staining was done to check differentiation induction. Adiponectin, leptin, triglycerides and total cholesterol levels were quantified. The mRNA expression of FXR, Cyp7a1, PPAR-γ and SREBP-1c were quantified using fluorescent real-time PCR. Cytotoxicity assay was confirmed that up to 150 μM concentration there is no significant cell death on treatment with arjunic acid and arjungenin. Treatment with arjungenin and arjunic acid confirms increased differentiation of the cells with significant (P < 0.05) increase in adiponectin (118.07% and 132.92%) and leptin (133.52% and 149.74%) protein levels compared to the negative control group. After treatment with arjungenin and arjunic acid in 3T3-L1 preadipocytes the mRNA expression of FXR, PPAR-γ and SREBP-1c were significantly (P < 0.01) increased and cyp7a1 was significantly (P < 0.01) decreased when compared with the negative control group. Overall, our results suggest that arjungenin and arjunic acid acts as an FXR agonist and may be useful for rational therapeutic strategies as a novel drug to treat cholesterol mediated metabolic syndrome and insulin resistance.
Collapse
Affiliation(s)
- Mohan Manu T
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| | - Anand T
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India.
| | - Bhuvanesh Kumar P
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| | - Asra Fathima
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| | - Farhath Khanum
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| |
Collapse
|
|
18
|
Genome-wide identification and characterization of long non-coding RNAs during differentiation of visceral preadipocytes in rabbit. Funct Integr Genomics 2019; 20:409-419. [PMID: 31745672 DOI: 10.1007/s10142-019-00729-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 11/06/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022]
Abstract
Emerging evidence suggests that long non-coding RNAs (lncRNAs) are critical regulators of diverse biological processes, including adipogenesis. Despite being considered an ideal animal model for studying adipogenesis, little is known about the roles of lncRNAs in the regulation of rabbit preadipocyte differentiation. In the present study, visceral preadipocytes isolated from newborn rabbits were cultured in vitro and induced for differentiation, and global lncRNA expression profiles of adipocytes collected at days 0, 3, and 9 of differentiation were analyzed by RNA-seq. A total of 2066 lncRNAs were identified from nine RNA-seq libraries. Compared to protein-coding transcripts, lncRNA transcripts exhibited characteristics of a longer length and lower expression level. Furthermore, 486 and 357 differentially expressed (DE) lncRNAs were identified when comparing day 3 vs. day 0 and day 9 vs. day 3, respectively. Target genes of DE lncRNAs were predicted by the cis-regulating approach. Prediction of functions revealed that DE lncRNAs when comparing day 3 vs. day 0 were involved in gene ontology (GO) terms of developmental growth, growth, developmental cell growth, and stem cell proliferation, and involved in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of PI3K-Akt signaling pathway, fatty acid biosynthesis, and the insulin signaling pathway. The DE lncRNAs when comparing day 9 vs. day 3 were involved in GO terms that associated with epigenetic modification and were involved in the KEGG pathway of cAMP signaling pathway. This study provides further insight into the regulatory function of lncRNAs in rabbit visceral adipose and facilitates a better understanding of different stages of preadipocyte differentiation.
Collapse
|
|
19
|
Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25:5897-5917. [PMID: 31660028 PMCID: PMC6815800 DOI: 10.3748/wjg.v25.i39.5897] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/15/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed “gut-liver axis”. Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.
Collapse
Affiliation(s)
- Benedikt Simbrunner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Mattias Mandorfer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
| | - Thomas Reiberger
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| |
Collapse
|
|
20
|
McIlvride S, Nikolova V, Fan HM, McDonald JAK, Wahlström A, Bellafante E, Jansen E, Adorini L, Shapiro D, Jones P, Marchesi JR, Marschall HU, Williamson C. Obeticholic acid ameliorates dyslipidemia but not glucose tolerance in mouse model of gestational diabetes. Am J Physiol Endocrinol Metab 2019; 317:E399-E410. [PMID: 31237448 PMCID: PMC6732461 DOI: 10.1152/ajpendo.00407.2018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 05/21/2019] [Accepted: 06/18/2019] [Indexed: 12/14/2022]
Abstract
Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.
Collapse
Affiliation(s)
- Saraid McIlvride
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Vanya Nikolova
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Hei Man Fan
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Julie A K McDonald
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Annika Wahlström
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Elena Bellafante
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Eugene Jansen
- National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | | | | | - Peter Jones
- School of Life Course Sciences, King's College London, London, United Kingdom
| | - Julian R Marchesi
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | | |
Collapse
|
|
21
|
Hou Y, Fan W, Yang W, Samdani AQ, Jackson AO, Qu S. Farnesoid X receptor: An important factor in blood glucose regulation. Clin Chim Acta 2019; 495:29-34. [PMID: 30910597 DOI: 10.1016/j.cca.2019.03.1626] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Revised: 03/13/2019] [Accepted: 03/21/2019] [Indexed: 12/12/2022]
Abstract
Farnesoid X receptor (FXR) is a transcription factor that can be activated by bile acid as well as influenced bile acid metabolism. β-cell bile acid metabolism is mediated by FXR and closely related to the regulation of blood glucose (BG). FXR can regulate BG through multiple pathways. This review summarises recent studies on FXR regulation of BG balance via bile acid regulation, lowering glucagon-like peptide-1 (GLP-1), inhibiting gluconeogenesis, increasing insulin secretion and enhancing insulin sensitivity. In addition, the current review provides additional insight into the relationship between FXR and BG which may provide a new theoretical basis for further study on the role of FXR.
Collapse
Affiliation(s)
- Yangfeng Hou
- Clinic Medicine Department, Hengyang Medical School, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Wenjing Fan
- Pathophysiology Department, University of South China, Hengyang City, Hunan Province 421001, PR China; Emergency Department, The Second Affiliated Hospital, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Wenling Yang
- Clinic Medicine Department, Hengyang Medical School, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Abdul Qadir Samdani
- Spinal Surgery Department, The First Affiliated Hospital, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Ampadu Okyere Jackson
- International College, Hengyang Medical School, University of South China, Hengyang City, Hunan Province 421001, PR China
| | - Shunlin Qu
- Pathophysiology Department, University of South China, Hengyang City, Hunan Province 421001, PR China.
| |
Collapse
|
|
22
|
Kassotis CD, Stapleton HM. Endocrine-Mediated Mechanisms of Metabolic Disruption and New Approaches to Examine the Public Health Threat. Front Endocrinol (Lausanne) 2019; 10:39. [PMID: 30792693 PMCID: PMC6374316 DOI: 10.3389/fendo.2019.00039] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 01/17/2019] [Indexed: 01/29/2023] Open
Abstract
Obesity and metabolic disorders are of great societal concern and generate substantial human health care costs globally. Interventions have resulted in only minimal impacts on disrupting this worsening health trend, increasing attention on putative environmental contributors. Exposure to numerous environmental contaminants have, over decades, been demonstrated to result in increased metabolic dysfunction and/or weight gain in cell and animal models, and in some cases, even in humans. There are numerous mechanisms through which environmental contaminants may contribute to metabolic dysfunction, though certain mechanisms, such as activation of the peroxisome proliferator activated receptor gamma or the retinoid x receptor, have received considerably more attention than less-studied mechanisms such as antagonism of the thyroid receptor, androgen receptor, or mitochondrial toxicity. As such, research on putative metabolic disruptors is growing rapidly, as is our understanding of molecular mechanisms underlying these effects. Concurrent with these advances, new research has evaluated current models of adipogenesis, and new models have been proposed. Only in the last several years have studies really begun to address complex mixtures of contaminants and how these mixtures may disrupt metabolic health in environmentally relevant exposure scenarios. Several studies have begun to assess environmental mixtures from various environments and study the mechanisms underlying their putative metabolic dysfunction; these studies hold real promise in highlighting crucial mechanisms driving observed organismal effects. In addition, high-throughput toxicity databases (ToxCast, etc.) may provide future benefits in prioritizing chemicals for in vivo testing, particularly once the causative molecular mechanisms promoting dysfunction are better understood and expert critiques are used to hone the databases. In this review, we will review the available literature linking metabolic disruption to endocrine-mediated molecular mechanisms, discuss the novel application of environmental mixtures and implications for in vivo metabolic health, and discuss the putative utility of applying high-throughput toxicity databases to answering complex organismal health outcome questions.
Collapse
|
|
23
|
Do Androgens Modulate the Pathophysiological Pathways of Inflammation? Appraising the Contemporary Evidence. J Clin Med 2018; 7:jcm7120549. [PMID: 30558178 PMCID: PMC6306858 DOI: 10.3390/jcm7120549] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/09/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022] Open
Abstract
The role of testosterone in the pathophysiology of inflammation is of critical clinical importance; however, no universal mechanism(s) has been advanced to explain the complex and interwoven pathways of androgens in the attenuation of the inflammatory processes. PubMed and EMBASE searches were performed, including the following key words: "testosterone", "androgens", "inflammatory cytokines", "inflammatory biomarkers" with focus on clinical studies as well as basic scientific studies in human and animal models. Significant benefits of testosterone therapy in ameliorating or attenuating the symptoms of several chronic inflammatory diseases were reported. Because anti⁻tumor necrosis factor therapy is the mainstay for the treatment of moderate-to-severe inflammatory bowel disease; including Crohn's disease and ulcerative colitis, and because testosterone therapy in hypogonadal men with chronic inflammatory conditions reduce tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6, we suggest that testosterone therapy attenuates the inflammatory process and reduces the burden of disease by mechanisms inhibiting inflammatory cytokine expression and function. Mechanistically, androgens regulate the expression and function of inflammatory cytokines, including TNF-α, IL-1β, IL-6, and CRP (C-reactive protein). Here, we suggest that testosterone regulates multiple and overlapping cellular and molecular pathways involving a host of immune cells and biochemical factors that converge to contribute to attenuation of the inflammatory process.
Collapse
|
|
24
|
Parafati M, Kirby RJ, Khorasanizadeh S, Rastinejad F, Malany S. A nonalcoholic fatty liver disease model in human induced pluripotent stem cell-derived hepatocytes, created by endoplasmic reticulum stress-induced steatosis. Dis Model Mech 2018; 11:11/9/dmm033530. [PMID: 30254132 PMCID: PMC6176998 DOI: 10.1242/dmm.033530] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 08/08/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatic steatosis, a reversible state of metabolic dysregulation, can promote the onset of nonalcoholic steatohepatitis (NASH), and its transition is thought to be critical in disease evolution. The association between endoplasmic reticulum (ER) stress response and hepatocyte metabolism disorders prompted us to characterize ER stress-induced hepatic metabolic dysfunction in human induced pluripotent stem cell-derived hepatocytes (hiPSC-Hep), to explore regulatory pathways and validate a phenotypic in vitro model for progression of liver steatosis. We treated hiPSC-Hep with a ratio of unsaturated and saturated fatty acids in the presence of an inducer of ER stress to synergistically promote triglyceride accumulation and dysregulate lipid metabolism. We monitored lipid accumulation by high-content imaging and measured gene regulation by RNA sequencing and reverse transcription quantitative PCR analyses. Our results show that ER stress potentiated intracellular lipid accumulation by 5-fold in hiPSC-Hep in the absence of apoptosis. Transcriptome pathway analysis identified ER stress pathways as the most significantly dysregulated of all pathways affected. Obeticholic acid dose dependently inhibited lipid accumulation and modulated gene expression downstream of the farnesoid X receptor. We were able to identify modulation of hepatic markers and gene pathways known to be involved in steatosis and nonalcoholic fatty liver disease (NAFLD), in support of a hiPSC-Hep disease model that is relevant to clinical data for human NASH. Our results show that the model can serve as a translational discovery platform for the understanding of molecular pathways involved in NAFLD, and can facilitate the identification of novel therapeutic molecules based on high-throughput screening strategies. Summary: Our study demonstrates expanded use of human induced pluripotent stem cell-derived hepatocytes for molecular studies and drug screening, to evaluate new therapeutics with an antisteatotic mechanism of action for nonalcoholic fatty liver disease.
Collapse
Affiliation(s)
- Maddalena Parafati
- Translational Biology, Conrad Prebys Center for Chemical Genomics, Orlando, FL 32827, USA
| | - R Jason Kirby
- Translational Biology, Conrad Prebys Center for Chemical Genomics, Orlando, FL 32827, USA
| | - Sepideh Khorasanizadeh
- Center for Metabolic Origins of Disease, Sanford Burham Prebys Medical Discovery Institute, 6400 Sanger Rd, Orlando, FL 32827, USA
| | - Fraydoon Rastinejad
- Center for Metabolic Origins of Disease, Sanford Burham Prebys Medical Discovery Institute, 6400 Sanger Rd, Orlando, FL 32827, USA
| | - Siobhan Malany
- Translational Biology, Conrad Prebys Center for Chemical Genomics, Orlando, FL 32827, USA
| |
Collapse
|
|
25
|
Sadie-Van Gijsen H. Adipocyte biology: It is time to upgrade to a new model. J Cell Physiol 2018; 234:2399-2425. [PMID: 30192004 DOI: 10.1002/jcp.27266] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 07/25/2018] [Indexed: 12/15/2022]
Abstract
Globally, the obesity pandemic is profoundly affecting quality of life and economic productivity, but efforts to address this, especially on a pharmacological level, have generally proven unsuccessful to date, serving as a stark demonstration that our understanding of adipocyte biology and pathophysiology is incomplete. To deliver better insight into adipocyte function and obesity, we need improved adipocyte models with a high degree of fidelity in representing the in vivo state and with a diverse range of experimental applications. Adipocyte cell lines, especially 3T3-L1 cells, have been used extensively over many years, but these are limited in terms of relevance and versatility. In this review, I propose that primary adipose-derived stromal/stem cells (ASCs) present a superior model with which to study adipocyte biology ex vivo. In particular, ASCs afford us the opportunity to study adipocytes from different, functionally distinct, adipose depots and to investigate, by means of in vivo/ex vivo studies, the effects of many different physiological and pathophysiological factors, such as age, body weight, hormonal status, diet and nutraceuticals, as well as disease and pharmacological treatments, on the biology of adipocytes and their precursors. This study will give an overview of the characteristics of ASCs and published studies utilizing ASCs, to highlight the areas where our knowledge is lacking. More comprehensive studies in primary ASCs will contribute to an improved understanding of adipose tissue, in healthy and dysfunctional states, which will enhance our efforts to more successfully manage and treat obesity.
Collapse
Affiliation(s)
- Hanél Sadie-Van Gijsen
- Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa.,Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Parow, South Africa
| |
Collapse
|
|
26
|
Comeglio P, Cellai I, Mello T, Filippi S, Maneschi E, Corcetto F, Corno C, Sarchielli E, Morelli A, Rapizzi E, Bani D, Guasti D, Vannelli GB, Galli A, Adorini L, Maggi M, Vignozzi L. INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function. J Endocrinol 2018; 238:107-127. [PMID: 29945982 DOI: 10.1530/joe-17-0557] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 05/29/2018] [Indexed: 12/12/2022]
Abstract
The bile acid receptors, farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), regulate multiple pathways, including glucose and lipid metabolism. In a rabbit model of high-fat diet (HFD)-induced metabolic syndrome, long-term treatment with the dual FXR/TGR5 agonist INT-767 reduces visceral adipose tissue accumulation, hypercholesterolemia and nonalcoholic steatohepatitis. INT-767 significantly improves the hallmarks of insulin resistance in visceral adipose tissue (VAT) and induces mitochondrial and brown fat-specific markers. VAT preadipocytes isolated from INT-767-treated rabbits, compared to preadipocytes from HFD, show increased mRNA expression of brown adipogenesis markers. In addition, INT-767 induces improved mitochondrial ultrastructure and dynamic, reduced superoxide production and improved insulin signaling and lipid handling in preadipocytes. Both in vivo and in vitro treatments with INT-767 counteract, in preadipocytes, the HFD-induced alterations by upregulating genes related to mitochondrial biogenesis and function. In preadipocytes, INT-767 behaves mainly as a TGR5 agonist, directly activating dose dependently the cAMP/PKA pathway. However, in vitro experiments also suggest that FXR activation by INT-767 contributes to the insulin signaling improvement. INT-767 treatment counteracts HFD-induced liver histological alterations and normalizes the increased pro-inflammatory genes. INT-767 also induces a significant reduction of fatty acid synthesis and fibrosis markers, while increasing lipid handling, insulin signaling and mitochondrial markers. In conclusion, INT-767 significantly counteracts HFD-induced liver and fat alterations, restoring insulin sensitivity and prompting preadipocytes differentiation toward a metabolically healthy phenotype.
Collapse
Affiliation(s)
- Paolo Comeglio
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | - Ilaria Cellai
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | - Tommaso Mello
- Gastroenterology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | - Sandra Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of ReproductionDepartment of NEUROFARBA, University of Florence, Florence, Italy
| | - Elena Maneschi
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | - Francesca Corcetto
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | - Chiara Corno
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | - Erica Sarchielli
- Department of Experimental and Clinical MedicineUniversity of Florence, Florence, Italy
| | - Annamaria Morelli
- Department of Experimental and Clinical MedicineUniversity of Florence, Florence, Italy
| | - Elena Rapizzi
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio'University of Florence, Florence, Italy
| | - Daniele Bani
- Department of Experimental and Clinical MedicineUniversity of Florence, Florence, Italy
| | - Daniele Guasti
- Department of Experimental and Clinical MedicineUniversity of Florence, Florence, Italy
| | | | - Andrea Galli
- Gastroenterology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| | | | - Mario Maggi
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
- I.N.B.B. - Istituto Nazionale Biostrutture e BiosistemiRome, Italy
| | - Linda Vignozzi
- Sexual Medicine and Andrology UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
- I.N.B.B. - Istituto Nazionale Biostrutture e BiosistemiRome, Italy
- Gynecologic Endocrinology Research UnitDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
| |
Collapse
|
|
27
|
Biochemical and Ultrastructural Cardiac Changes Induced by High-Fat Diet in Female and Male Prepubertal Rabbits. Anal Cell Pathol (Amst) 2018; 2018:6430696. [PMID: 29850391 PMCID: PMC5904822 DOI: 10.1155/2018/6430696] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 02/12/2018] [Accepted: 02/21/2018] [Indexed: 11/30/2022] Open
Abstract
Early weight gain induced by high-fat diet has been identified as a predictor for cardiac disease, one of the most serious public health problems. Our goal is to study the influence of a HFD on biochemical, oxidant stress parameters, and the cardiac ultrastructure in both male and female prepubertal models. Experiments were carried on 24 prepubertal New Zealand white rabbits, randomly assigned to male and female control (MC and FC, resp.) or HFD (MHFD and FHFD, resp.) groups (n = 6) for 3 months. Body and heart weights and some biochemical and oxidative stress parameters such as lipids, calcium, CKMB, MDA, uric acid, ascorbic acid, and AOA are evaluated in plasma and the left ventricle. Under HFD effect, plasma parameters, such as lipids (TL, PL, and LDL-C), MDA, and CK-MB, increase more significantly in male than in female groups, when AA decreases. Some cardiac parameters such as TG and UA increase, when AA and AOA decrease; these variations are more significant in FHFD. In both male and female rabbits, HFD caused changes in heart ultrastructure, junctional complexes, mitochondria size and form, and so on. Early HFD feeding induced overweight, oxidative stress, and metabolic alterations in plasma and the heart of prepubertal rabbits, whereas lipotoxicity has especially a negative impact on male plasma but affects more the female heart ultrastructure.
Collapse
|
|
28
|
Menchetti L, Canali C, Castellini C, Boiti C, Brecchia G. The different effects of linseed and fish oil supplemented diets on insulin sensitivity of rabbit does during pregnancy. Res Vet Sci 2018; 118:126-133. [DOI: 10.1016/j.rvsc.2018.01.024] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 01/18/2018] [Accepted: 01/31/2018] [Indexed: 10/18/2022]
|
|
29
|
Papazyan R, Liu X, Liu J, Dong B, Plummer EM, Lewis RD, Roth JD, Young MA. FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver. J Lipid Res 2018; 59:982-993. [PMID: 29559521 PMCID: PMC5983391 DOI: 10.1194/jlr.m081935] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 03/01/2018] [Indexed: 12/15/2022] Open
Abstract
Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.
Collapse
Affiliation(s)
| | - Xueqing Liu
- Intercept Pharmaceuticals, Inc., San Diego, CA 92121
| | - Jingwen Liu
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
| | - Bin Dong
- Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
| | | | | | | | - Mark A Young
- Intercept Pharmaceuticals, Inc., San Diego, CA 92121.
| |
Collapse
|
|
30
|
Haczeyni F, Bell-Anderson KS, Farrell GC. Causes and mechanisms of adipocyte enlargement and adipose expansion. Obes Rev 2018; 19:406-420. [PMID: 29243339 DOI: 10.1111/obr.12646] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/28/2017] [Accepted: 10/23/2017] [Indexed: 02/06/2023]
Abstract
Adipose tissue plays a significant role in whole body energy homeostasis. Obesity-associated diabetes, fatty liver and metabolic syndrome are closely linked to adipose stress and dysfunction. Genetic predisposition, overeating and physical inactivity influence the expansion of adipose tissues. Under conditions of constant energy surplus, adipocytes become hypertrophic and adipose tissues undergo hyperplasia so as to increase their lipid storage capacity, thereby keeping circulating blood glucose and fatty acids below toxic levels. Nonetheless, adipocytes have a saturation point where they lose capacity to store more lipids. At this stage, when adipocytes are fully lipid-engorged, they express stress signals. Adipose depots (particularly visceral compartments) from obese individuals with a severe metabolic phenotype are characterized by the high proportion of hypertrophic adipocytes. This review focuses on the mechanisms of adipocyte enlargement in relation to adipose fatty acid and cholesterol metabolism, and considers how this may be related to adipose dysfunction.
Collapse
Affiliation(s)
- F Haczeyni
- Liver Research Group, Australian National University Medical School at The Canberra Hospital, Canberra, ACT, Australia
| | - K S Bell-Anderson
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia
| | - G C Farrell
- Liver Research Group, Australian National University Medical School at The Canberra Hospital, Canberra, ACT, Australia
| |
Collapse
|
|
31
|
Sèdes L, Thirouard L, Maqdasy S, Garcia M, Caira F, Lobaccaro JMA, Beaudoin C, Volle DH. Cholesterol: A Gatekeeper of Male Fertility? Front Endocrinol (Lausanne) 2018; 9:369. [PMID: 30072948 PMCID: PMC6060264 DOI: 10.3389/fendo.2018.00369] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022] Open
Abstract
Cholesterol is essential for mammalian cell functions and integrity. It is an important structural component maintaining the permeability and fluidity of the cell membrane. The balance between synthesis and catabolism of cholesterol should be tightly regulated to ensure normal cellular processes. Male reproductive function has been demonstrated to be dependent on cholesterol homeostasis. Here we review data highlighting the impacts of cholesterol homeostasis on male fertility and the molecular mechanisms implicated through the signaling pathways of some nuclear receptors.
Collapse
|
|
32
|
Comeglio P, Morelli A, Adorini L, Maggi M, Vignozzi L. Beneficial effects of bile acid receptor agonists in pulmonary disease models. Expert Opin Investig Drugs 2017; 26:1215-1228. [PMID: 28949776 DOI: 10.1080/13543784.2017.1385760] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions. Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.
Collapse
Affiliation(s)
- Paolo Comeglio
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| | - Annamaria Morelli
- b Department of Experimental and Clinical Medicine , University of Florence , Florence , Italy
| | | | - Mario Maggi
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| | - Linda Vignozzi
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| |
Collapse
|
|
33
|
Zheng Z, Zhao Z, Li S, Lu X, Jiang M, Lin J, An Y, Xie Y, Xu M, Shen W, Guo GL, Huang Y, Li S, Zhang X, Xie W. Altenusin, a Nonsteroidal Microbial Metabolite, Attenuates Nonalcoholic Fatty Liver Disease by Activating the Farnesoid X Receptor. Mol Pharmacol 2017; 92:425-436. [PMID: 28739572 PMCID: PMC5588546 DOI: 10.1124/mol.117.108829] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/07/2017] [Indexed: 01/04/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose, and lipids. FXR agonists have shown promise for the treatment of NAFLD. In this study, we report altenusin (2076A), a natural nonsteroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3.2 ± 0.2 μM. Administration of 2076A protected mice from high-fat diet (HFD)-induced obesity by reducing the body weight and fat mass by 22.9% and 50.0%, respectively. Administration of 2076A also decreased the blood glucose level from 178.3 ± 12.4 mg/dl to 116.2 ± 4.1 mg/dl and the serum insulin level from 1.4 ± 0.6 ng/dl to 0.4 ± 0.1 ng/dl. Moreover, 2076A treatment nearly reversed HFD-induced hepatic lipid droplet accumulation and macrovesicular steatosis. These metabolic effects were abolished in FXR knockout mice. Mechanistically, the metabolic benefits of 2076A might have been accounted for by the increased insulin sensitivity and suppression of genes that are involved in hepatic gluconeogenesis and lipogenesis. In summary, we have uncovered a new class of nonsteroidal FXR agonist that shows promise in treating NAFLD and the associated metabolic syndrome.
Collapse
Affiliation(s)
- Zhihui Zheng
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Zanmei Zhao
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Shuqiang Li
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Xinhua Lu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Mengxi Jiang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Jie Lin
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Yunqi An
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Yang Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Wenbin Shen
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Grace L Guo
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Yixian Huang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Song Li
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Xuexia Zhang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Zh.Z., Za.Z., M.J., Y.A., Y.X., M.X., Y.H., S.L., W.X.) and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; New Drug Research and Development Center, North China Pharmaceutical Group, Shijiazhuang, Hebei, China (Zh.Z., X.L., J.L., W.S., X.Z.); Occupational Disease Department, Peking University Third Hospital, Beijing, China (Za.Z., S.L.); and Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey (G.L.G.)
| |
Collapse
|
|
34
|
Ghosh Laskar M, Eriksson M, Rudling M, Angelin B. Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III. J Intern Med 2017; 281:575-585. [PMID: 28145001 DOI: 10.1111/joim.12594] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). RESULTS Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. CONCLUSIONS Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.
Collapse
Affiliation(s)
- M Ghosh Laskar
- Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.,Molecular Nutrition Unit, Center for Innovative Medicine (CIMED), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.,KI/AZ Integrated CardioMetabolic Center (ICMC), Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - M Eriksson
- Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - M Rudling
- Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.,Molecular Nutrition Unit, Center for Innovative Medicine (CIMED), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.,KI/AZ Integrated CardioMetabolic Center (ICMC), Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - B Angelin
- Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.,Molecular Nutrition Unit, Center for Innovative Medicine (CIMED), Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.,KI/AZ Integrated CardioMetabolic Center (ICMC), Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden
| |
Collapse
|
|
35
|
Haczeyni F, Poekes L, Wang H, Mridha AR, Barn V, Geoffrey Haigh W, Ioannou GN, Yeh MM, Leclercq IA, Teoh NC, Farrell GC. Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice. Obesity (Silver Spring) 2017; 25:155-165. [PMID: 27804232 PMCID: PMC5849463 DOI: 10.1002/oby.21701] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/02/2016] [Accepted: 10/03/2016] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes. METHODS OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg. RESULTS OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg. CONCLUSIONS OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH.
Collapse
Affiliation(s)
- Fahrettin Haczeyni
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Laurence Poekes
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Hans Wang
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Auvro R Mridha
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Vanessa Barn
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - W Geoffrey Haigh
- Department of Medicine, VA Medical Center, University of Washington, Seattle, Washington, USA
| | - George N Ioannou
- Department of Medicine, VA Medical Center, University of Washington, Seattle, Washington, USA
| | - Matthew M Yeh
- Department of Pathology, University of Washington, Seattle, Washington, USA
| | - Isabelle A Leclercq
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Narcissus C Teoh
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Geoffrey C Farrell
- Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia
| |
Collapse
|
|
36
|
Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro 2016; 39:93-103. [PMID: 27939613 DOI: 10.1016/j.tiv.2016.11.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/23/2016] [Accepted: 11/29/2016] [Indexed: 01/11/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on patho-physiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations. Primary hepatocytes experienced 48-hour exposure to OCA at concentrations approximating therapeutic (0.5μM) and supratherapeutic (10μM) levels. Global transcriptomics by RNAseq was complimented by cellular viability (MTT), CYP activity assays, and secreted FGF19 levels in the media. Dose-dependent, transcriptional effects suggested suppression of bile acid synthesis (↓CYP7A1, ↓CYP27A1) and increased bile efflux (↑ABCB4, ↑ABCB11, ↑OSTA, ↑OSTB). Pleiotropic effects included suppression of TGFβ and IL-6 signaling pathways, and signatures suggestive of HDL suppression (↑SCARB1, ↓ApoAI, ↓LCAT) and LDL elevation (↑ApoB, ↓CYP7A1). OCA exhibited direct FXR-mediated effects with increased FGF19 secretion. Transcriptomics revealed regulation of metabolic, anti-inflammatory, and anti-fibrotic pathways beneficial in NASH, and predicted cholesterol profiles consistent with clinical findings. Follow-up studies under lipotoxic/inflammatory conditions would corroborate these effects in a disease-relevant environment.
Collapse
|
|
37
|
Cox-York KA, Erickson CB, Pereira RI, Bessesen DH, Van Pelt RE. Region-specific effects of oestradiol on adipose-derived stem cell differentiation in post-menopausal women. J Cell Mol Med 2016; 21:677-684. [PMID: 27862950 PMCID: PMC5345675 DOI: 10.1111/jcmm.13011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/18/2016] [Indexed: 12/25/2022] Open
Abstract
The goal of this study was to determine the effect of acute transdermal 17β‐oestradiol (E2) on the adipogenic potential of subcutaneous adipose‐derived stem cells (ASC) in post‐menopausal women. Post‐menopausal women (n = 11; mean age 57 ± 4.5 years) were treated for 2 weeks, in a randomized, cross‐over design, with transdermal E2 (0.15 mg) or placebo patches. Biopsies of abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) were obtained after each treatment and mature adipocytes were analysed for cell size and ASC for their capacity for proliferation (growth rate), differentiation (triglyceride accumulation) and susceptibility to tumour necrosis factor alpha‐induced apoptosis. Gene expression of oestrogen receptors α and β (ESR1 and ESR2), perilipin 1 and hormone‐sensitive lipase (HSL), was also assessed. In FEM SAT, but not AB SAT, 2 weeks of E2 significantly (P = 0.03) increased ASC differentiation and whole SAT HSL mRNA expression (P = 0.03) compared to placebo. These changes were not associated with mRNA expression of oestrogen receptors α and β, but HSL expression was significantly increased in FEM SAT with transdermal E2 treatment. Adipose‐derived stem cells proliferation and apoptosis did not change in either SAT depot after E2 compared with placebo. Short‐term E2 appeared to increase the adipogenic potential of FEM, but not AB, SAT in post‐menopausal women with possible implications for metabolic disease. Future studies are needed to determine longer term impact of E2 on regional SAT accumulation in the context of positive energy imbalance.
Collapse
Affiliation(s)
| | - Christopher B Erickson
- Department of Medicine, Division of Geriatric Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rocio I Pereira
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Denver Health and Hospital Authority, Denver, CO, USA
| | - Daniel H Bessesen
- Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.,Denver Health and Hospital Authority, Denver, CO, USA
| | - Rachael E Van Pelt
- Department of Medicine, Division of Geriatric Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| |
Collapse
|
|
38
|
Maneschi E, Cellai I, Aversa A, Mello T, Filippi S, Comeglio P, Bani D, Guasti D, Sarchielli E, Salvatore G, Morelli A, Mazzanti B, Corcetto F, Corno C, Francomano D, Galli A, Vannelli GB, Lenzi A, Mannucci E, Maggi M, Vignozzi L. Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits. Mol Cell Endocrinol 2016; 424:50-70. [PMID: 26805634 DOI: 10.1016/j.mce.2016.01.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 01/18/2016] [Accepted: 01/18/2016] [Indexed: 12/15/2022]
Abstract
Development of metabolically healthy adipocytes within dysfunctional adipose tissue may represent an attractive way to counteract metabolic syndrome (MetS). In an experimental animal model of high fat diet (HFD)-induced MetS, in vivo, long- and short-term tadalafil treatments were able to reduce visceral adipose tissue (VAT) accumulation and hypertriglyceridemia, and to induce the expression in VAT of the brown fat-specific marker, uncoupling protein 1 (UCP1). VAT preadipocytes (PAD), isolated from the tadalafil-treated HFD rabbits, showed: i) a multilocular morphology; ii) an increased expression of brown fat-specific genes (such as UCP1 and CIDEA); iii) improved mitochondrial structure and dynamic and reduced superoxide production; iv) improved insulin sensitivity. Similar effects were obtained after in vitro tadalafil treatment in HFD rPAD. In conclusion, tadalafil counteracted HFD-associated VAT alterations, by restoring insulin-sensitivity and prompting preadipocytes differentiation towards a metabolically healthy phenotype.
Collapse
Affiliation(s)
- Elena Maneschi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Ilaria Cellai
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Antonio Aversa
- Department of Experimental Medicine, Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Tommaso Mello
- Gastroenterology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Italy
| | - Sandra Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neuroscience, Drug Research and Child Care, Viale Pieraccini 6, 50139 University of Florence, Florence, Italy
| | - Paolo Comeglio
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Daniele Bani
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134, University of Florence, Italy
| | - Daniele Guasti
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134, University of Florence, Italy
| | - Erica Sarchielli
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134, University of Florence, Italy
| | - Giulia Salvatore
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Annamaria Morelli
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134, University of Florence, Italy
| | - Benedetta Mazzanti
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134, University of Florence, Italy
| | - Francesca Corcetto
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Chiara Corno
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Davide Francomano
- Department of Experimental Medicine, Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Andrea Galli
- Gastroenterology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Italy
| | - Gabriella Barbara Vannelli
- Department of Experimental and Clinical Medicine, Largo Brambilla 3, 50134, University of Florence, Italy
| | - Andrea Lenzi
- Department of Experimental Medicine, Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Edoardo Mannucci
- Diabetes Section Geriatric Unit, Department of Critical Care, Careggi Hospital, Largo Brambilla 3, 50134, Florence, Italy
| | - Mario Maggi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy
| | - Linda Vignozzi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy.
| |
Collapse
|
|
39
|
Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Lonardo A. The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans. Adv Ther 2016; 33:291-319. [PMID: 26921205 DOI: 10.1007/s12325-016-0306-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.
Collapse
Affiliation(s)
| | - Fabio Nascimbeni
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
- University of Modena and Reggio Emilia, Modena, Italy
| | - Dante Romagnoli
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
| | | | - Amedeo Lonardo
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy.
| |
Collapse
|
|
40
|
Corona G, Vignozzi L, Sforza A, Mannucci E, Maggi M. Obesity and late-onset hypogonadism. Mol Cell Endocrinol 2015; 418 Pt 2:120-33. [PMID: 26143633 DOI: 10.1016/j.mce.2015.06.031] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 06/01/2015] [Accepted: 06/05/2015] [Indexed: 12/20/2022]
Abstract
Obesity and male hypogonadism (HG) are often associated, as demonstrated in all cross-sectional studies. Prospective studies have indicated that i) having HG at baseline increases the risk of visceral obesity (and metabolic syndrome) and that ii) obesity induces incident HG. Hence, there is a bidirectional relationship between the two conditions. This is the main topic of this review, along with some pathogenic considerations. Meta-analysis of intervention studies indicates that treating obesity is a very efficient treatment for obesity-induced HG. The mechanism by which obesity induces HG has not yet been completely understood, but dietary-induced hypothalamic inflammation, along with a decreased GnRH release, is plausible. Among patients seeking medical care for obesity, the proportion of HG is relatively high. The prevalence of obesity among patients referring for sexual dysfunction is also elevated. Hence, in symptomatic, obese, hypogonadal subjects, testosterone supplementation (TS) can be considered. Whereas long-term uncontrolled register studies suggest that TS could decrease weight, analysis of controlled studies only support a parallel increase in lean mass and decrease in fat mass, with a resulting null effect on weight. Considering that T induces an increase in muscle mass, it is conceivable that the amount of activity obese people can undertake after TS will increase, allowing a closer adherence to physical exercise programs. Some studies, here meta-analyzed, support this concept.
Collapse
Affiliation(s)
- G Corona
- Endocrinology Unit, Maggiore-Bellaria Hospital, Medical Department, Azienda-Usl Bologna, Bologna, Italy
| | - L Vignozzi
- Sexual Medicine and Andrology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
| | - A Sforza
- Endocrinology Unit, Maggiore-Bellaria Hospital, Medical Department, Azienda-Usl Bologna, Bologna, Italy
| | - E Mannucci
- Diabetes Agency, Careggi Hospital, Florence, Italy
| | - M Maggi
- Sexual Medicine and Andrology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy.
| |
Collapse
|
|
41
|
Demir M, Lang S, Steffen HM. Nonalcoholic fatty liver disease - current status and future directions. J Dig Dis 2015; 16:541-57. [PMID: 26406351 DOI: 10.1111/1751-2980.12291] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 09/23/2015] [Accepted: 09/23/2015] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6-33%, depending on the studied populations. It encompasses a spectrum of liver manifestations ranging from simple steatosis (also known as nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NAFLD is strongly associated with the components of metabolic syndrome, mainly obesity and type 2 diabetes mellitus. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality. Current paradigm suggests a benign course for NAFL whereas NASH is considered to be the progressive phenotype. Although previously under-recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. Liver biopsy remains the gold standard for definitive diagnosis, but the majority of patients can be diagnosed accurately by noninvasive methods. Approved therapies for NAFLD are still lacking and lifestyle modifications aiming at weight loss remain the mainstay of NAFLD treatment. Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. In this review we summarized the current knowledge of NAFLD epidemiology, natural history, diagnosis, pathogenesis and treatment and considered future directions.
Collapse
Affiliation(s)
- Münevver Demir
- Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany
| | - Sonja Lang
- Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany
| | - Hans-Michael Steffen
- Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany
| |
Collapse
|
|
42
|
Corona G, Rastrelli G, Filippi S, Vignozzi L, Mannucci E, Maggi M. Erectile dysfunction and central obesity: an Italian perspective. Asian J Androl 2015; 16:581-91. [PMID: 24713832 PMCID: PMC4104087 DOI: 10.4103/1008-682x.126386] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Erectile dysfunction (ED) is a frequent complication of obesity. The aim of this review is to critically analyze the framework of obesity and ED, dissecting the connections between the two pathological entities. Current clinical evidence shows that obesity, and in particular central obesity, is associated with both arteriogenic ED and reduced testosterone (T) levels. It is conceivable that obesity-associated hypogonadism and increased cardiovascular risk might partially justify the higher prevalence of ED in overweight and obese individuals. Conversely, the psychological disturbances related to obesity do not seem to play a major role in the pathogenesis of obesity-related ED. However, both clinical and preclinical data show that the association between ED and visceral fat accumulation is independent from known obesity-associated comorbidities. Therefore, how visceral fat could impair penile microcirculation still remains unknown. This point is particularly relevant since central obesity in ED subjects categorizes individuals at high cardiovascular risk, especially in the youngest ones. The presence of ED in obese subjects might help healthcare professionals in convincing them to initiate a virtuous cycle, where the correction of sexual dysfunction will be the reward for improved lifestyle behavior. Unsatisfying sexual activity represents a meaningful, straightforward motivation for consulting healthcare professionals, who, in turn, should take advantage of the opportunity to encourage obese patients to treat, besides ED, the underlying unfavorable conditions, thus not only restoring erectile function, but also overall health.
Collapse
Affiliation(s)
| | | | | | | | | | - Mario Maggi
- Sexual Medicine and Andrology Unit, Department of Experimental, Clinical and Biomedical Sciences, University of Florence, Florence, Italy
| |
Collapse
|
|
43
|
Abstract
Nonalcoholic fatty liver disease is a common cause of liver related morbidity and mortality. It is closely linked to underlying insulin resistance. It has recently been shown that bile acids modulate insulin signaling and can improve insulin resistance in cell based and animal studies. These effects are mediated in part by activation of farnesoid x receptors by bile acids. In human studies, FXR agonists improve insulin resistance and have recently been shown to improve NAFLD. The basis for the use of FXR agonists for the treatment of NAFLD and early human experience with such agents is reviewed in this paper.
Collapse
Affiliation(s)
- Arun J Sanyal
- Virgnia Commonwealth University School of Medicine, Richmond, Va., USA
| |
Collapse
|
|
44
|
Cortese R, Khalyfa A, Bao R, Andrade J, Gozal D. Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation. Int J Obes (Lond) 2015; 39:1135-42. [PMID: 25801690 PMCID: PMC4496299 DOI: 10.1038/ijo.2015.38] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 02/11/2015] [Accepted: 03/14/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood. OBJECTIVES To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring. METHODS Time-pregnant mice were exposed to LG-SF or sleep control during LG (LG-SC) conditions during the last 6 days of gestation. At 24 weeks of age, lipid profiles and metabolic parameters were assessed in the offspring. We performed large-scale DNA methylation analyses using methylated DNA immunoprecipitation (MeDIP) coupled with microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice per group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks. RESULTS We detected significant increases in body weight (31.7 vs 28.8 g; P=0.001), visceral (642.1 vs 497.0 mg; P=0.002) and subcutaneous (293.1 vs 250.1 mg; P=0.001) fat mass, plasma cholesterol (110.6 vs 87.6 mg dl(-1); P=0.001), triglycerides (87.3 vs 84.1 mg dl(-1); P=0.003) and homeostatic model assessment-insulin resistance values (8.1 vs 6.1; P=0.007) in the LG-SF group. MeDIP analyses revealed that 2148 DMRs (LG-SF vs LG-SC; P<0.0001, model-based analysis of tilling-arrays algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome, such as Cartpt, Akt2, Apoe, Insr1 and so on. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response. CONCLUSIONS Our findings show a major role for epigenomic regulation of pathways associated with the metabolic processes and inflammatory responses in VWAT. LG-SF-induced epigenetic alterations may underlie increases in the susceptibility to obesity and metabolic syndrome in the offspring.
Collapse
Affiliation(s)
- R Cortese
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA
| | - A Khalyfa
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA
| | - R Bao
- Bioinformatics Core Facility, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
| | - J Andrade
- Bioinformatics Core Facility, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA
| | - D Gozal
- Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA
| |
Collapse
|
|
45
|
Jiao Y, Lu Y, Li XY. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015; 36:44-50. [PMID: 25500875 DOI: 10.1038/aps.2014.116] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 09/01/2014] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia.
Collapse
|
|
46
|
Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Marchetta M, Maggi M. Estrogen mediates metabolic syndrome-induced erectile dysfunction: a study in the rabbit. J Sex Med 2014; 11:2890-902. [PMID: 25243860 DOI: 10.1111/jsm.12695] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Estrogen receptor (ER) α is critical in mediating the harmful effects of hyperestrogenism in fetal or neonatal life on the developing penis. In contrast, little is known on the impact of an excess of estrogens on penile function in adulthood. AIM To investigate the effect of estrogens on metabolic syndrome (MetS)-associated erectile dysfunction (ED). METHODS We employed a recently established animal model of high fat diet (HFD)-induced MetS. Subgroups of MetS rabbits were dosed with either testosterone (T) or tamoxifen. We evaluated penile responsiveness to acetylcholine (Ach) as well as the expression of genes related to penile smooth muscle relaxation and contractility. MAIN OUTCOME MEASURE Associations between MetS-induced penile alterations and sex steroids were investigated in an animal model of HFD-induced MetS. To understand the role of either androgen deficiency or estrogen excess on ED, we treated subgroups of MetS rabbits with either T or tamoxifen, a classical ER antagonist. RESULTS Feeding an HFD-induced MetS was associated to elevated estradiol (E2) and low T levels. E2, but not T, was independently and negatively associated with genes able to affect penile erection. Smooth muscle-related markers decreased as a function of E2 and were positively associated with all the variables investigated. Increasing concentrations of circulating E2 were negatively associated with Ach-induced relaxation. In HFD rabbits, in vivo T dosing significantly improved MetS and completely normalized circulating E2. Conversely, in vivo tamoxifen dosing reduced visceral adiposity and partially restored T level. Ach-induced relaxation was severely impaired by HFD and significantly restored, up to the control level, by both tamoxifen and T dosing. In rabbit smooth muscle cells cultures 17β-E2 (1 nM) significantly reduced the expression of α-smooth muscle actin, transgelin, and phosphodiesterase type 5. The effects of 17β-E2 were completely reverted by tamoxifen (100 nM). CONCLUSIONS This study demonstrates, for the first time, that HFD-induced ED is more associated with a high E2, rather than to a low T, milieu. HFD-induced ED is partially restored by in vivo treatment not only with T but also with the nonsteroidal ER antagonist, tamoxifen.
Collapse
Affiliation(s)
- Linda Vignozzi
- Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Russo GI, Cimino S, Fragalà E, Privitera S, La Vignera S, Condorelli R, Calogero AE, Chisari M, Castelli T, Favilla V, Morgia G. Relationship between non-alcoholic fatty liver disease and benign prostatic hyperplasia/lower urinary tract symptoms: new insights from an Italian cross-sectional study. World J Urol 2014; 33:743-51. [PMID: 25189458 DOI: 10.1007/s00345-014-1392-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 07/31/2014] [Indexed: 01/02/2023] Open
Abstract
PURPOSE To investigate the prevalence of non-alcoholic fatty liver disease (NAFLD) assessed by the fatty liver index (FLI), in lower urinary tract symptoms (LUTS) patients and to estimate its ability in predicting LUTS. METHODS We performed a cross-sectional analysis of 448 consecutive patients affected by LUTS. LUTS were evaluated using the IPSS questionnaire and metabolic syndrome (MetS) criteria (by International Diabetes Federation). FLI, prostate volume (PV), serum prostate-specific antigen, total testosterone (TT) and homeostasis model assessment (HOMA) index were evaluated. A value of FLI ≥40 was set to predict NAFLD. Patients were divided into Group A (FLI <40) and Group B (FLI ≥40). Odds ratios (OR) for having moderate-severe LUTS were calculated. Logistic regression model was fitted adjusting for confounding factors. RESULTS Group B showed higher prevalence of MetS, IR, moderate-severe LUTS and ED, higher IPSS, IPSS-storage, IPSS-voiding, total prostate volume, insulin, HOMA and lower TT and IIEF-5. Univariate logistic regression analysis demonstrated that continuous FLI (OR = 1.03, p < 0.05) and FLI ≥40 (OR = 2.41, p < 0.01) significantly increase the risk of moderate-severe LUTS. Continuous FLI (OR = 1.12, p < 0.01) and FLI ≥40 (OR = 5.39, p < 0.01) were independent predictors of moderate-severe LUTS at the multivariate logistic regression analysis, after adjusting for confounding factors. Subjects with MetS and FLI ≥40 had 2.0-fold the risk of moderate-severe LUTS (OR = 2.10, p < 0.01). CONCLUSIONS Non-alcoholic fatty liver disease (NAFLD) subjects have higher risk of LUTS. The presence of FLI ≥40 can be used to predict subjects at high risk of LUTS.
Collapse
Affiliation(s)
- Giorgio Ivan Russo
- Department of Urology, School of Medicine Policlinico Hospital, University of Catania, Catania, Italy,
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Lanthier N, Leclercq IA. Adipose tissues as endocrine target organs. Best Pract Res Clin Gastroenterol 2014; 28:545-58. [PMID: 25194174 DOI: 10.1016/j.bpg.2014.07.002] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 06/05/2014] [Accepted: 07/05/2014] [Indexed: 01/31/2023]
Abstract
In the context of obesity, white adipocyte hypertrophy and adipose tissue macrophage infiltration result in the production of pro-inflammatory adipocytokines inducing insulin resistance locally but also in distant organs and contributing to low grade inflammatory status associated with the metabolic syndrome. Visceral adipose tissue is believed to play a prominent role. Brown and beige adipose tissues are capable of energy dissipation, but also of cytokine production and their role in dysmetabolic syndrome is emerging. This review focuses on metabolic and inflammatory changes in these adipose depots and contribution to metabolic syndrome. Also we will review surgical and pharmacological procedures to target adiposity as therapeutic interventions to treat obesity-associated disorders.
Collapse
Affiliation(s)
- Nicolas Lanthier
- Laboratoire de Gastroentérologie et Hépatologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; Service d'Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
| | - Isabelle A Leclercq
- Laboratoire de Gastroentérologie et Hépatologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; Service d'Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
| |
Collapse
|
|
49
|
Roda A, Pellicciari R, Gioiello A, Neri F, Camborata C, Passeri D, De Franco F, Spinozzi S, Colliva C, Adorini L, Montagnani M, Aldini R. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat. J Pharmacol Exp Ther 2014; 350:56-68. [PMID: 24784847 DOI: 10.1124/jpet.114.214650] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate was secreted in bile unmodified and as 3-glucuronide. Therefore, minor structural modifications profoundly influence the metabolism and biodistribution in the target organs where these analogs exert therapeutic effects by interacting with FXR and/or TGR5 receptors.
Collapse
Affiliation(s)
- Aldo Roda
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Roberto Pellicciari
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Antimo Gioiello
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Flavia Neri
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Cecilia Camborata
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Daniela Passeri
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Francesca De Franco
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Silvia Spinozzi
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Carolina Colliva
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Luciano Adorini
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Marco Montagnani
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| | - Rita Aldini
- Dipartimento di Chimica "G. Ciamician" Alma Mater Studiorum-University of Bologna, Italy (A.R., C:C:, S.S.); Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia, Italy (R.P., A.G.); Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-University of Bologna, Italy (F.N., M.M.); TES Pharma S.r.l., Corciano, Italy (R.P., D.P., F.D.F., C.C.); Intercept Pharmaceuticals, Inc., New York, New York; and Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-University of Bologna, Bologna, Italy (R.A.)
| |
Collapse
|
|
50
|
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Approved therapies for this disorder, however, are still lacking. In the last decade, pathophysiological insights into this disease have been tremendous. Various aspects, such as insulin resistance, innate immunity, metabolic inflammation and the microbiota, have been characterized as major players. Indeed, at least 1 in 10 sufferers will have the disease escalate toward its inflammatory phenotype, non-alcoholic steatohepatitis (NASH). These pathways currently represent the most attractive treatment targets. Furthermore, interference with insulin resistance has shown some efficacy in the past, although more focused therapies, which also act anti-inflammatory, are needed. AREAS COVERED In this review, the authors highlight the current most promising treatment strategies in NASH/NAFLD. EXPERT OPINION Treatment of NAFLD is still in its infancy, although large controlled studies have demonstrated some efficacy for pioglitazone or vitamin E. The natural course of this disease demands long-term treatments besides diet and lifestyle changes. Based on the current view of NAFLD pathophysiology, effective therapies have to target metabolic inflammation, glucose and lipid metabolism. The search for agents interfering with all of these pathways has recently generated promising candidates for the treatment of NAFLD such as farnesoid X receptor, peroxisome proliferator-activated receptor-α/δ agonists or AdipoR small-molecule agonists.
Collapse
Affiliation(s)
- Herbert Tilg
- Medical University Innsbruck, Department of Internal Medicine I, Endocrinology, Gastroenterology and Metabolism , Innsbruck , Austria +43 512 504 23539 ; +43 512 504 23538 ;
| | | |
Collapse
|