|
1
|
Winterfeldt K, Tasin FR, Sekhar V, Siddiqi SA. Fenofibrate Treatment Inhibits Very-Low-Density Lipoprotein Transport Vesicle Formation by Reducing Sar1b Protein Expression. Int J Mol Sci 2025; 26:4720. [PMID: 40429862 PMCID: PMC12111837 DOI: 10.3390/ijms26104720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 05/06/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Dyslipidemia is a well-known risk factor in the development and progression of atherosclerosis. VLDL plays a crucial role in maintaining lipid homeostasis; however, even minor fluctuations in its production, intracellular trafficking, and secretion can contribute to the progression of atherosclerosis. Fenofibrate is an FDA-approved drug that effectively lowers plasma triglycerides and VLDL-associated cholesterol while simultaneously increasing HDL levels. Although fenofibrate is a known PPARα agonist with several proposed mechanisms for its lipid-altering effects, its impact on the intracellular trafficking of VLDL has not yet been investigated. We observed that treatment of HepG2 cells with 50 µM of fenofibrate resulted in a significant reduction in VLDL secretion, as evidenced by a significant decrease in the secretion of 3H-labeled TAG, fluorescent TAG, and ApoB100 protein into the media. Using confocal microscopy to monitor VLDL intracellular trafficking, we observed a distinct change in VLDL triglyceride localization, suggesting delayed transport through the endoplasmic reticulum and Golgi. An immunoblot analysis revealed a decrease in Sar1B protein expression, a key regulator of COPII protein recruitment, which is essential for VTV formation and intracellular VLDL trafficking, the rate-limiting step in VLDL secretion. Our data reveal a novel mechanism by which fenofibrate alters the lipid profile by interfering with intracellular VLDL trafficking in hepatocytes.
Collapse
Affiliation(s)
| | | | | | - Shadab A. Siddiqi
- Division of Metabolic & Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Room# 349, Orlando, FL 32827, USA; (K.W.); (F.R.T.); (V.S.)
| |
Collapse
|
|
2
|
Zisis M, Chondrogianni ME, Androutsakos T, Rantos I, Oikonomou E, Chatzigeorgiou A, Kassi E. Linking Cardiovascular Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): The Role of Cardiometabolic Drugs in MASLD Treatment. Biomolecules 2025; 15:324. [PMID: 40149860 PMCID: PMC11940321 DOI: 10.3390/biom15030324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 03/29/2025] Open
Abstract
The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.
Collapse
Affiliation(s)
- Marios Zisis
- Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (M.Z.); (I.R.)
| | - Maria Eleni Chondrogianni
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Ilias Rantos
- Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece; (M.Z.); (I.R.)
| | - Evangelos Oikonomou
- 3rd Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| |
Collapse
|
|
3
|
Xie Y, Jin Y, Wen J, Li G, Huai X, Duan Y, Ni F, Fu J, Li M, Li L, Yan M, Cao L, Xiao W, Yang H, Wang ZZ. A novel Alisma orientale extract alleviates non-alcoholic steatohepatitis in mice via modulation of PPARα signaling pathway. Biomed Pharmacother 2024; 176:116908. [PMID: 38850668 DOI: 10.1016/j.biopha.2024.116908] [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: 03/24/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/10/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the therapeutic effects and potential mechanism of a novel extract from traditional Chinese medicine Alisma orientale (Sam.) Juzep (AE) on free fatty acid (FFA)-induced HepG2 cell model and high-fat diet (HFD) + carbon tetrachloride (CCl4)-induced mouse model of NASH. C57BL/6 J mice were fed a HFD for 10 weeks. Subsequently, the mice were injected with CCl4 to induce NASH and simultaneously treated with AE at daily doses of 50, 100, and 200 mg/kg for 4 weeks. At the end of the treatment, animals were fasted for 12 h and then sacrificed. Blood samples and liver tissues were collected for analysis. Lipid profiles, oxidative stress, and histopathology were examined. Additionally, a polymerase chain reaction (PCR) array was used to predict the molecular targets and potential mechanisms involved, which were further validated in vivo and in vitro. The results demonstrated that AE reversed liver damage (plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte ballooning, hepatic steatosis, and NAS score), the accumulation of hepatic lipids (TG and TC), and oxidative stress (MDA and GSH). PCR array analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that AE protects against NASH by regulating the adipocytokine signaling pathway and influencing nuclear receptors such as PPARα. Furthermore, AE increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1α) and reversed the decreased expression of PPARα in NASH mice. Moreover, in HepG2 cells, AE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. Overall, our findings suggest that AE may serve as a potential therapeutic approach for NASH by inhibiting lipid accumulation and reducing oxidative stress specifically through the PPARα pathway.
Collapse
Affiliation(s)
- Yan Xie
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Kanion School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Yimin Jin
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Kanion School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, PR China
| | - Jianhui Wen
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Guiping Li
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Xue Huai
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Yueyang Duan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Fuyong Ni
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Juan Fu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Ming Li
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Liang Li
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Ming Yan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Liang Cao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Wei Xiao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China
| | - Hao Yang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200120, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China.
| | - Zhen-Zhong Wang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Lianyungang, Jiangsu 222001, PR China; Kanion School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210046, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu 222001, PR China.
| |
Collapse
|
|
4
|
Zhao L, Wang S, Xu X, Guo W, Yang J, Liu Y, Xie S, Piao G, Xu T, Wang Y, Xu Y. Integrated metabolomics and network pharmacology to reveal the lipid-lowering mechanisms of Qizha Shuangye granules in hyperlipidemic rats. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:3265-3274. [PMID: 38087399 DOI: 10.1002/jsfa.13213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/02/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND Qizha Shuangye granules (QSG) comprise six traditional Chinese herbal medicines (TCHMs), which have a long history of treating hyperlipidemia (HLP) in China. This study aimed to evaluate the potential lipid-lowering effects of QSG in an HLP rat model and investigate possible mechanisms. The HLP rat model was induced by a high-fat diet. Lipid-related indicators in serum were detected. Serum and liver metabolites were investigated using a liquid chromatography-mass spectrometry-based metabolomics approach. A herb-compound-target-metabolite (H-C-T-M) network was further constructed to reveal the possible molecular mechanism of QSG to alleviate HLP. RESULTS The administration of QSG inhibited the HLP-induced changes in total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and non-esterified fatty acid (NEFA) levels. Additionally, QSG significantly attenuated the liver histopathological changes induced by HLP. Metabolomic analysis showed the serum and liver metabolic disorders presented in HLP rats. QSG can reverse the abnormal metabolism caused by HLP. Through network pharmacology analysis, key proteins such as androgen receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and peroxisome proliferator-activated receptor-α were screened out, and they were speculated to be possible therapeutic targets for QSG to treat HLP. CONCLUSION The present study integrated metabolomics and network pharmacology analysis to reveal the efficacy and possible mechanism of QSG in treating HLP, which provides a new reference for the research and development of QSG as a functional food. © 2023 Society of Chemical Industry.
Collapse
Affiliation(s)
- Liang Zhao
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- College of Pharmacy, Yanbian University, Yanji, China
- Key Laboratory of Medicinal Materials, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| | - Shuyue Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaohang Xu
- Key Laboratory of Medicinal Materials, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| | - Wenjun Guo
- Key Laboratory of Medicinal Materials, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| | - Jingxuan Yang
- Key Laboratory of Medicinal Materials, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| | - Yue Liu
- Key Laboratory for Analysis Methods of Active Ingredients in Traditional Chinese Medicine, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| | - Shengxu Xie
- Key Laboratory for Analysis Methods of Active Ingredients in Traditional Chinese Medicine, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| | - Guangchun Piao
- College of Pharmacy, Yanbian University, Yanji, China
- Key Laboratory for Natural Resource of Changbai Mountain, Yanbian University, Yanji, China
| | - Tunhai Xu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yang Wang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Yajuan Xu
- Key Laboratory of Medicinal Materials, Jilin Academy of Chinese Medicine Sciences, Changchun, China
| |
Collapse
|
|
5
|
Xu S, Kong L, Li L, Wang C, Gu J, Luo H, Meng Q. Farnesoid X receptor overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in nonalcoholic fatty liver disease. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166930. [PMID: 37918680 DOI: 10.1016/j.bbadis.2023.166930] [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: 07/10/2023] [Revised: 10/10/2023] [Accepted: 10/26/2023] [Indexed: 11/04/2023]
Abstract
Oxidative stress-mediated activation of inflammasome has a significant effect on the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Farnesoid X receptor (NR1H4, FXR) has been implicated in biological function and many diseases, including NAFLD. The regulatory effect of FXR on oxidative stress and whether this process is related with the activation of absent melanoma 2 (AIM2) inflammasome in NAFLD remain unclear. In the present research, we confirmed that FXR in the livers of steatosis patients is significantly reduced compared with normal liver tissue by using the Gene Expression Omnibus (GEO) database and a palmitic acid (PA) - mediated steatosis model in AML-12 cells. Under the premise of ensuring the same food intake as the control group, overexpression of FXR in mice attenuated HFD-mediated weight gain and liver steatosis, facilitated lipid metabolism, improved fatty acid β-oxidation, lipolysis, and reduced fatty acid synthesis and intake, which also inhibited the activation of AIM2 inflammasome. Overexpression of FXR alleviated PA-induced triglyceride (TG) accumulation, imbalance of lipid homeostasis, and the activation of AIM2 inflammasome in hepatic steatosis cells, while FXR knockdown appeared the opposite effects. FXR overexpression suppressed PA- and HFD-induced oxidative stress, but FXR siRNA demonstrated the opposite influence. The decreased ROS generation may be the reason why FXR weakens AIM2 activation when a fatty acid overload occurs. In conclusion, our results confirm that other than regulating lipid homeostasis and blocking NLRP3 inflammasome activation, FXR improves hepatic steatosis by a novel mechanism that inhibits oxidative stress and AIM2 inflammasome activation.
Collapse
Affiliation(s)
- Shuai Xu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Lina Kong
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Lin Li
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Changyuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Jiangning Gu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Haifeng Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Qiang Meng
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China.
| |
Collapse
|
|
6
|
Babalola JA, Lang M, George M, Stracke A, Tam-Amersdorfer C, Itxaso I, Lucija D, Tadic J, Schilcher I, Loeffler T, Flunkert S, Prokesch M, Leitinger G, Lass A, Hutter-Paier B, Panzenboeck U, Hoefler G. Astaxanthin enhances autophagy, amyloid beta clearance and exerts anti-inflammatory effects in in vitro models of Alzheimer's disease-related blood brain barrier dysfunction and inflammation. Brain Res 2023; 1819:148518. [PMID: 37579986 DOI: 10.1016/j.brainres.2023.148518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/22/2023] [Accepted: 08/02/2023] [Indexed: 08/16/2023]
Abstract
Defective degradation and clearance of amyloid-β as well as inflammation per se are crucial players in the pathology of Alzheimer's disease (AD). A defective transport across the blood-brain barrier is causative for amyloid-β (Aβ) accumulation in the brain, provoking amyloid plaque formation. Using primary porcine brain capillary endothelial cells and murine organotypic hippocampal slice cultures as in vitro models of AD, we investigated the effects of the antioxidant astaxanthin (ASX) on Aβ clearance and neuroinflammation. We report that ASX enhanced the clearance of misfolded proteins in primary porcine brain capillary endothelial cells by inducing autophagy and altered the Aβ processing pathway. We observed a reduction in the expression levels of intracellular and secreted amyloid precursor protein/Aβ accompanied by an increase in ABC transporters ABCA1, ABCG1 as well as low density lipoprotein receptor-related protein 1 mRNA levels. Furthermore, ASX treatment increased autophagic flux as evidenced by increased lipidation of LC3B-II as well as reduced protein expression of phosphorylated S6 ribosomal protein and mTOR. In LPS-stimulated brain slices, ASX exerted anti-inflammatory effects by reducing the secretion of inflammatory cytokines while shifting microglia polarization from M1 to M2 phenotype. Our data suggest ASX as potential therapeutic compound ameliorating AD-related blood brain barrier impairment and inflammation.
Collapse
Affiliation(s)
| | - Magdalena Lang
- Otto Loewi Research Center, Division of Immunology, Medical University of Graz, Austria
| | - Meekha George
- Department of Obstetrics and Gynaecology, Medical University of Graz, Austria
| | - Anika Stracke
- Otto Loewi Research Center, Division of Immunology, Medical University of Graz, Austria
| | | | | | | | - Jelena Tadic
- Institute of Molecular Biosciences, University of Graz, Austria
| | | | | | | | | | - Gerd Leitinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz, Austria
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Austria
| | | | - Ute Panzenboeck
- Otto Loewi Research Center, Division of Immunology, Medical University of Graz, Austria
| | - Gerald Hoefler
- Diagnostic and Research Institute of Pathology, Medical University of Graz, Austria.
| |
Collapse
|
|
7
|
Staels B, Butruille L, Francque S. Treating NASH by targeting peroxisome proliferator-activated receptors. J Hepatol 2023; 79:1302-1316. [PMID: 37459921 DOI: 10.1016/j.jhep.2023.07.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 06/18/2023] [Accepted: 07/02/2023] [Indexed: 09/15/2023]
Abstract
The pathophysiology of non-alcoholic steatohepatitis (NASH) encompasses a complex set of intra- and extrahepatic driving mechanisms, involving numerous metabolic, inflammatory, vascular and fibrogenic pathways. The peroxisome proliferator-activated receptors (PPARs) α, β/δ and γ belong to the nuclear receptor family of ligand-activated transcription factors. Activated PPARs modulate target tissue transcriptomic profiles, enabling the body's adaptation to changing nutritional, metabolic and inflammatory environments. PPARs hence regulate several pathways involved in NASH pathogenesis. Whereas single PPAR agonists exert robust anti-NASH activity in several preclinical models, their clinical effects on histological endpoints of NASH resolution and fibrosis regression appear more modest. Simultaneous activation of several PPAR isotypes across different organs and within-organ cell types, resulting in pleiotropic actions, enhances the therapeutic potential of PPAR agonists as pharmacological agents for NASH and NASH-related hepatic and extrahepatic morbidity, with some compounds having already shown clinical efficacy on histological endpoints.
Collapse
Affiliation(s)
- Bart Staels
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
| | - Laura Butruille
- University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sven Francque
- Department of Gastroenterology Hepatology, Antwerp University Hospital, Drie Eikenstraat 655, B-2650, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610, Wilrijk, Belgium.
| |
Collapse
|
|
8
|
Huang SM, Lin CH, Chang WF, Shih CC. Antidiabetic and antihyperlipidemic activities of Phyllanthus emblica L. extract in vitro and the regulation of Akt phosphorylation, gluconeogenesis, and peroxisome proliferator-activated receptor α in streptozotocin-induced diabetic mice. Food Nutr Res 2023; 67:9854. [PMID: 37850072 PMCID: PMC10578056 DOI: 10.29219/fnr.v67.9854] [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: 07/25/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 10/19/2023] Open
Abstract
Background The fruits of Phyllanthus emblica L. are high in nutrients and have excellent health care function and developmental value. There are many management strategies available for diabetes and hyperlipidemia. Nevertheless, there is a lack of an effective and nontoxic drug. Objective The present study was designed to first screen four extracts of P. emblica L. on insulin signaling target gene expression levels, including glucose transporter 4 (GLUT4) and p-Akt/t-Akt. The ethyl acetate extract of P. emblica L. (EPE) exhibited the most efficient activity among the four extracts and was thus chosen to explore the antidiabetic and antihyperlipidemic activities in streptozotocin (STZ)-induced type 1 diabetic mice. Design All mice (in addition to one control (CON) group) were administered STZ injections (intraperitoneal) for 5 consecutive days, and then STZ-induced mice were administered EPE (at 100, 200, or 400 mg/kg body weight), fenofibrate (Feno) (at 250 mg/kg body weight), glibenclamide (Glib) (at 10 mg/kg body weight), or vehicle by oral gavage once daily for 4 weeks. Finally, histological examination, blood biochemical parameters, and target gene mRNA expression levels were measured, and liver tissue was analyzed for the levels of malondialdehyde (MDA), a maker of lipid peroxidation. Results EPE treatment resulted in decreased levels of blood glucose, HbA1C, triglycerides (TGs), and total cholesterol and increased levels of insulin compared with the vehicle-treated STZ group. EPE treatment decreased blood levels of HbA1C and MDA but increased glutathione levels in liver tissue, implying that EPE exerts antioxidant activity and could prevent oxidative stress and diabetes. The EPE-treated STZ mice displayed an improvement in the sizes and numbers of insulin-expressing β cells. EPE treatment increased the membrane expression levels of skeletal muscular GLUT4, and also reduced hepatic mRNA levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase thereby inhibiting hepatic gluconeogenesis. This resulted in a net glucose lowering effect in EPE-treated STZ mice. Furthermore, EPE increased the expression levels of p-AMPK/t-AMPK in both the skeletal muscle and liver tissue compared with vehicle-treated STZ mice. EPE-treated STZ mice showed enhanced expression levels of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα), but reduced expression levels of lipogenic genes including fatty acid synthase, as well as decreased mRNA levels of sterol regulatory element binding protein 1c (SREBP1c), apolipoprotein-CIII (apo-CIII), and diacylglycerol acyltransferase-2 (DGAT2). This resulted in a reduction in plasma TG levels. EPE-treated STZ mice also showed reduced expression levels of PPAR γ. This resulted in decreased adipogenesis, fatty acid synthesis, and lipid accumulation within liver tissue, and consequently, lower TG levels in liver tissue and blood. Furthermore, EPE treatment not only displayed an increase in the Akt activation in liver tissue, but also in C2C12 myotube in the absence of insulin. These results implied that EPE acts as an activator of AMPK and /or as a regulator of the insulin (Akt) pathway. Conclusions Taken together, EPE treatment exhibited amelioration of the diabetic and hyperlipidemic state in STZ-induced diabetic mice.
Collapse
Affiliation(s)
- Shin-Ming Huang
- Department of Gastroenterology, Jen-Ai Hospital, Dali Branch, Taichung City, Taiwan
| | - Cheng-Hsiu Lin
- Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Taichung City, Taiwan
| | - Wen-Fang Chang
- Department of Cardiology, Jen-Ai Hospital, Taichung City, Taiwan
| | - Chun-Ching Shih
- Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, Taichung City, Taiwan
| |
Collapse
|
|
9
|
Du K, Huang X, Peng A, Yang Q, Chen D, Zhang J, Qi R. Engineered Fenofibrate as Oxidation-Sensitive Nanoparticles with ROS Scavenging and PPARα-Activating Bioactivity to Ameliorate Nonalcoholic Fatty Liver Disease. Mol Pharm 2023; 20:159-171. [PMID: 36342356 DOI: 10.1021/acs.molpharmaceut.2c00549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in western countries and China. Fenofibrate (FNB) can activate peroxisome proliferator-activated receptor α (PPARα) to increase fatty acid oxidation and ameliorate NAFLD. However, the application of FNB is limited in clinic due to its poor water solubility and low oral bioavailability. In this study, FNB-loaded nanoparticles (FNB-NP) based on a reactive oxygen species (ROS)-responsive peroxalate ester derived from vitamin E (OVE) and an amphiphilic conjugate 1,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG) were developed to enhance the preventive effects of FNB against NAFLD. In in vitro studies, FNB-NP displayed a high encapsulation efficiency of 97.25 ± 0.6% and a drug loading efficiency of 29.67 ± 0.1%, with a size of 197.0 ± 0.2 nm. FNB released from FNB-NP was dramatically accelerated in the medium with high H2O2 concentrations. Moreover, FNB-NP exhibited well storage stability and plasma stability. In pharmacokinetic (PK) studies, FNB-NP, compared with FNB crude drug, significantly increased the AUC0→t and AUC0→∞ of the plasma FNB acid by 3.3- and 3.4-fold, respectively. In pharmacodynamics (PD) studies, compared with an equal dose of FNB crude drug, FNB-NP more significantly reduced hepatic lipid deposition via facilitating FNB release in the liver and further upregulating PPARα expression in NAFLD mice. Meanwhile, oxidative stress in NAFLD was significantly suppressed after FNB-NP administration, suggesting that OVE plays a synergistic effect on antioxidation. Therefore, ROS-sensitive FNB delivery formulations FNB-NP enhance the preventive effects of FNB against NAFLD and could be further studied as a promising drug for the treatment of NAFLD in clinic.
Collapse
Affiliation(s)
- Kaiyue Du
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing100191, China.,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing100191, China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing100191, China
| | - Xin Huang
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing100191, China.,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing100191, China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing100191, China
| | - Ankang Peng
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing100191, China.,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing100191, China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing100191, China
| | - Qinghua Yang
- Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing400038, China
| | - Du Chen
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing100191, China.,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing100191, China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing100191, China
| | - Jianxiang Zhang
- Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing400038, China
| | - Rong Qi
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing100191, China.,Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing100191, China.,Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing100191, China
| |
Collapse
|
|
10
|
Huang X, Yuan Z, Liu X, Wang Z, Lu J, Wu L, Lin X, Zhang Y, Pi W, Cai D, Chu F, Wang P, Lei H. Integrative multi-omics unravels the amelioration effects of Zanthoxylum bungeanum Maxim. on non-alcoholic fatty liver disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 109:154576. [PMID: 36610127 DOI: 10.1016/j.phymed.2022.154576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/26/2022] [Accepted: 11/20/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND The effect of Zanthoxylum bungeanum Maxim. (ZBM) on anti-obesity, lipid-lowering and liver protection has been identified, but the effect on the development of NAFLD induced by high-fat diet remains unclear. PURPOSE To evaluate the alleviation effect of ZBM on NAFLD in vivo and explore the mechanisms by analyzing the liver transcriptome, microbiota and fecal metabolites. METHODS NAFLD model was induced in C57BL/6J mice by feeding with high-fat diet (HFD). The potential mechanism of ZBM in improving NAFLD was studied by liver transcriptome analysis, real-time PCR, immunofluorescence, 16s rRNA sequencing and non-targeted metabonomics. RESULTS ZBM has alleviation effects on HFD-induced NAFLD. The liver transcriptome, real-time PCR and immunofluorescence analysis showed that ZBM could efficiently regulate fatty acid and cholesterol metabolism. The 16S rRNA sequencing and LC-MS based metabonomic demonstrated that ZBM could rebalance gut microbiota dysbiosis and regulate metabolic profiles in HFD-induced NAFLD mice. Spearman correlation analysis revealed a strong correlation between gut microbiota and biochemical, pathological indexes and differential metabolic biomarkers. CONCLUSION ZBM ameliorates HFD-induced NAFLD by regulating fatty acid and cholesterol metabolism, gut microbiota and metabolic profile.
Collapse
Affiliation(s)
- Xuemei Huang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhihua Yuan
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaojing Liu
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Zhijia Wang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Jihui Lu
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Linying Wu
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiaoyu Lin
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yaozhi Zhang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Wenmin Pi
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Desheng Cai
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Fuhao Chu
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Penglong Wang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Haimin Lei
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 102488, China.
| |
Collapse
|
|
11
|
Coptis chinensis, and extracts of guava and mulberry leaves present good inhibiting potential on obesity and associated metabolic disorders in high-fat diet obesity mice model. J Tradit Complement Med 2023; 13:270-276. [PMID: 37128193 PMCID: PMC10148135 DOI: 10.1016/j.jtcme.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/03/2022] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
This study aimed to investigate the anti-obesity effects of Coptis chinensis (CC), BALASAN (combinational guava leaf extract and mulberry leaf extract), and CC/BALASAN (CC/BAL) on high-fat diet-induced obese C57BL/6 mice and to explore possible mediating mechanisms in 3T3-L1 pre-adipocytes. Oil red-O stain was used to test the effects of CC, BALASAN, and CC/BAL on the differentiation of 3T3-L1 pre-adipocytes. Additionally, real-time PCR was used to detect the expression of genes involved in adipocyte differentiation and inflammation-related genes in adipose tissue of mice that were fed a high-fat diet. CC, BALASAN, and CC/BAL inhibited the differentiation of 3T3-L1 pre-adipocytes and exhibited excellent inhibitory ability against the expression of PPARγ and RXRα genes associated with adipocyte differentiation. Replenishing mice with a high-fat diet with CC, BALASAN, and CC/BAL reduced body weight gaining and blood glucose and plasma cholesterol levels. CC also effectively reduced liver weight, whereas BALASAN and CC/BAL had no inhibitory effect. In addition, CC effectively inhibited the expression of C/EBP-α in adipose tissue. Interestingly, BALASAN not only inhibited the expression of C/EBP-α, but also that of PPARγ, RXRα, and TNFα. Such data indicated that CC, BALASAN, and CC/BAL may have potentially beneficial effects against obesity and associated metabolic disorders by down-regulating the PPARγ/RXRα pathway.
Collapse
|
|
12
|
Zhou T, Yan K, Zhang Y, Zhu L, Liao Y, Zheng X, Chen Y, Li X, Liu Z, Zhang Z. Fenofibrate suppresses corneal neovascularization by regulating lipid metabolism through PPARα signaling pathway. Front Pharmacol 2022; 13:1000254. [PMID: 36588740 PMCID: PMC9800935 DOI: 10.3389/fphar.2022.1000254] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Purpose: The purpose of this study was to explore the potential underlying mechanism of anti-vascular effects of peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate against corneal neovascularization (CNV) through the changes of lipid metabolism during CNV. Methods: A suture-induced CNV model was established and the clinical indications were evaluated from day 1 to day 7. Treatments of vehicle and fenofibrate were performed for 5 days after suture and the CNV areas were compared among the groups. The eyeballs were collected for histological analysis, malondialdehyde (MDA) measurement, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining, western blot, quantitative real-time PCR (qRT-PCR) assays and immunohistochemical (IHC) staining to elucidate pathological changes and the underlying mechanism. Results: Lipi-Green staining and MDA measurement showed that lipid deposition and peroxidation were increased in the CNV cornea while the expression of long-chain acyl-coenzyme A synthetase 1 (ACSL1), carnitine palmitoyltransterase 1A(CPT1A) and medium-chain acyl-coenzyme A dehydrogenase (ACADM), which are key enzymes of fatty acid β-oxidation (FAO) and targeted genes of peroxisome proliferator-activated receptor alpha (PPARα) pathway, were decreased in CNV cornea. Fenofibrate suppressed lipid accumulation and peroxidation damage in the CNV cornea. Fenofibrate upregulated the expression levels of PPARα, ACSL1, CPT1A, and ACADM compared with vehicle group. IHC staining indicated that fenofibrate also decreased the expression of VEGFa, VEGFc, TNFα, IL1β and CD68. Conclusion: Disorder of lipid metabolism may be involved in the formation of suture-induced CNV and fenofibrate played anti-neovascularization and anti-inflammatory roles on cornea by regulating the key enzymes of lipid metabolism and ameliorating lipid peroxidation damage of cornea through PPARα signaling pathway.
Collapse
Affiliation(s)
- Tong Zhou
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Department of Pharmacy, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China
| | - Ke Yan
- The First Affiliated Hospital, Department of Ophthalmology, Hengyang Medical School, University of South China, Hengyang, China
| | - Yuhan Zhang
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China
| | - Linfangzi Zhu
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China
| | - Yi Liao
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China
| | - Xiaoxiang Zheng
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China
| | - Yongxiong Chen
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China
| | - Xiaoxin Li
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China,Department of Ophthalmology and Clinical Centre of Optometry, Peking University People’s Hospital, Beijing, China,*Correspondence: Zhaoqiang Zhang, ; Zuguo Liu, ; Xiaoxin Li,
| | - Zuguo Liu
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China,The First Affiliated Hospital, Department of Ophthalmology, Hengyang Medical School, University of South China, Hengyang, China,*Correspondence: Zhaoqiang Zhang, ; Zuguo Liu, ; Xiaoxin Li,
| | - Zhaoqiang Zhang
- Eye Institute and Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China,Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Fujian Provincial Key Laboratory of Corneal and Ocular Surface Diseases, Xiamen, China,*Correspondence: Zhaoqiang Zhang, ; Zuguo Liu, ; Xiaoxin Li,
| |
Collapse
|
|
13
|
Lu Z, Li Y, Li AJ, Syn WK, Wank SA, Lopes-Virella MF, Huang Y. Loss of GPR40 in LDL receptor-deficient mice exacerbates high-fat diet-induced hyperlipidemia and nonalcoholic steatohepatitis. PLoS One 2022; 17:e0277251. [PMID: 36331958 PMCID: PMC9635748 DOI: 10.1371/journal.pone.0277251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
GPR40, a G protein-coupled receptor for free fatty acids (FFAs), is considered as a therapeutic target for type 2 diabetes mellitus (T2DM) since GPR40 activation in pancreatic beta cells enhances glucose-stimulated insulin secretion. Nonalcoholic fatty liver disease (NAFLD) is a common complication of T2DM or metabolic syndrome (MetS). However, the role of GPR40 in NAFLD associated with T2DM or MetS has not been well established. Given that it is known that cholesterol and FFAs are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH) and LDL receptor (LDLR)-deficient mice are a good animal model for human hyperlipidemia including high cholesterol and FFAs, we generated GPR40 and LDLR double knockout (KO) mice in this study to determine the effect of GPR40 KO on hyperlipidemia-promoted NASH. We showed that GPR40 KO increased plasma levels of cholesterol and FFAs in high-fat diet (HFD)-fed LDLR-deficient mice. We also showed that GPR40 KO exacerbated HFD-induced hepatic steatosis, inflammation and fibrosis. Further study demonstrated that GPR40 KO led to upregulation of hepatic CD36 and genes involved in lipogenesis, fatty acid oxidation, fibrosis and inflammation. Finally, our in vitro mechanistic studies showed that while CD36 was involved in upregulation of proinflammatory molecules in macrophages by palmitic acid (PA) and lipopolysaccharide (LPS), GPR40 activation in macrophages exerts anti-inflammatory effects. Taken together, this study demonstrated for the first time that loss of GPR40 in LDLR-deficient mice exacerbated HFD-induced hyperlipidemia, hepatic steatosis, inflammation and fibrosis potentially through a CD36-dependent mechanism, suggesting that GPR40 may play a beneficial role in hyperlipidemia-associated NASH in LDLR-deficient mice.
Collapse
Affiliation(s)
- Zhongyang Lu
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Yanchun Li
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Ai-Jun Li
- Programs in Neuroscience, Washington State University, Pullman, Washington, United States of America
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, United States of America
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, Euskal Herriko Unibertsitatea/Universidad del País Vasco, Leioa, Spain
| | - Stephen A. Wank
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States of America
| | - Maria F. Lopes-Virella
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America
| | - Yan Huang
- Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America
- * E-mail:
| |
Collapse
|
|
14
|
Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin Sci (Lond) 2022; 136:1347-1366. [PMID: 36148775 PMCID: PMC9508552 DOI: 10.1042/cs20220572] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 01/30/2023]
Abstract
The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.
Collapse
|
|
15
|
Lian B, Cai L, Zhang Z, Lin F, Li Z, Zhang XK, Jiang F. The anti-inflammatory effect of Pien Tze Huang in non-alcoholic fatty liver disease. Biomed Pharmacother 2022; 151:113076. [PMID: 35550529 DOI: 10.1016/j.biopha.2022.113076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease that may progress to nonalcoholic steatohepatitis (NASH), hepatic tissue fibrosis, liver cirrhosis, and hepatocellular carcinoma. In this study, we investigated the effects of Pien Tze Huang (PTH), a well-known traditional Chinese herbal formula with liver protective effect, in methionine-choline deficient diet (MCD)- and high-fat diet (HFD)-induced NASH mouse models. Our results showed that PTH could exert hepatoprotective effects by improving liver weight and steatosis and reducing the fibrosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) in both animal models. The effects of PTH was accompanied with the reduction of infiltrated macrophages, the inhibition of the expression of cytokines, and the induction of adiponectin expression. Mechanistically, we found that PTH could inhibit the activation of proinflammatory transcription factor nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor of κBα (IκBα). These results demonstrate that PTH can improve NAFLD largely due to its suppression of the NF-κB inflammatory pathway.
Collapse
Affiliation(s)
- Baohuan Lian
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.; NucMito Pharmaceuticals Co. Ltd., Xiamen, 361101, China
| | - Lijun Cai
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Zhaoqiang Zhang
- Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, China
| | - Fen Lin
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Zongxi Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China
| | - Xiao-Kun Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China..
| | - Fuquan Jiang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China..
| |
Collapse
|
|
16
|
Mahmoudi A, Moallem SA, Johnston TP, Sahebkar A. Liver Protective Effect of Fenofibrate in NASH/NAFLD Animal Models. PPAR Res 2022; 2022:5805398. [PMID: 35754743 PMCID: PMC9232374 DOI: 10.1155/2022/5805398] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/19/2022] [Accepted: 06/02/2022] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is initiated by excessive fat buildup in the liver, affecting around 35% of the world population. Various circumstances contribute to the initiation and progression of NAFLD, and it encompasses a wide range of disorders, from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. Although several treatments have been proposed, there is no definitive cure for NAFLD. In recent decades, several medications related to other metabolic disorders have been evaluated in preclinical studies and in clinical trials due to the correlation of NAFLD with other metabolic diseases. Fenofibrate is a fibrate drug approved for dyslipidemia that could be used for modulation of hepatic fat accumulation, targeting peroxisome proliferator-activator receptors, and de novo lipogenesis. This drug offers potential therapeutic efficacy for NAFLD due to its capacity to decrease the accumulation of hepatic lipids, as well as its antioxidant, anti-inflammatory, and antifibrotic properties. To better elucidate the pathophysiological processes underlying NAFLD, as well as to test therapeutic agents/interventions, experimental animal models have been extensively used. In this article, we first reviewed experimental animal models that have been used to evaluate the protective effects of fenofibrate on NAFLD/NASH. Next, we investigated the impact of fenofibrate on the hepatic microcirculation in NAFLD and then summarized the beneficial effects of fenofibrate, as compared to other drugs, for the treatment of NAFLD. Lastly, we discuss possible adverse side effects of fenofibrate on the liver.
Collapse
Affiliation(s)
- Ali Mahmoudi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Seyed Adel Moallem
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P. Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
17
|
Mahmoudi A, Jamialahmadi T, Johnston TP, Sahebkar A. Impact of fenofibrate on NAFLD/NASH: A genetic perspective. Drug Discov Today 2022; 27:2363-2372. [PMID: 35569762 DOI: 10.1016/j.drudis.2022.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/13/2022] [Accepted: 05/09/2022] [Indexed: 11/26/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD), caused by an accumulation of fat deposits in hepatocytes, prevalently affects at least one-third of the world's population. The progression of this disorder can potentially include a spectrum of consecutive stages, specifically: steatosis, steatohepatitis and cirrhosis. Fenofibrate exhibits potential therapeutic efficacy for NAFLD owing to several properties, which include antioxidant, apoptotic, anti-inflammatory and antifibrotic activity. In the present review, we discuss the direct or indirect impact of fenofibrate on genes involved at various stages in the progression of NAFLD. Moreover, we have reviewed studies that compare fenofibrate with other drugs in treating NAFLD, as well as recent clinical trials, in an attempt to identify reliable scientific and clinical evidence concerning the therapeutic effects and benefits of fenofibrate on NAFLD. Teaser.
Collapse
Affiliation(s)
- Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Iran
| | - Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
18
|
Hu N, Chen C, Wang J, Huang J, Yao D, Li C. Atorvastatin Ester Regulates Lipid Metabolism in Hyperlipidemia Rats via the PPAR-signaling Pathway and HMGCR Expression in the Liver. Int J Mol Sci 2021; 22:11107. [PMID: 34681767 PMCID: PMC8538474 DOI: 10.3390/ijms222011107] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 12/22/2022] Open
Abstract
Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model. The lipid level and liver function of the hyperlipidemia rats were studied by the levels of TG, TC, LDL, HDL, ALT, and AST in serum after intragastric administration with different doses of Ate. HE staining was used to observe the pathological changes of the rat liver and gastrocnemius muscle. The lipid deposits in the liver of rats were observed by staining with ORO. The genes in the rat liver were sequenced by RNA-sequencing. The results of the RNA-sequencing were further examined by qRT-PCR and western blotting. Biochemical test results indicated that Ate could obviously improve the metabolic disorder and reduce both the ALT and AST levels in serum of the hyperlipidemia rats. Pathological results showed that Ate could improve HFD-induced lipid deposition and had no muscle toxicity. The RNA-sequencing results suggested that Ate affected liver lipid metabolism and cholesterol, metabolism in the hyperlipidemia-model rats may vary via the PPAR-signaling pathway. The western blotting and qRT-PCR results demonstrated the Ate-regulated lipid metabolism in the hyperlipidemia model through the PPAR-signaling pathway and HMGCR expression. In brief, Ate can significantly regulate the blood lipid level of the model rats, which may be achieved by regulating the PPAR-signaling pathway and HMGCR gene expression.
Collapse
Affiliation(s)
- Nan Hu
- Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China;
| | - Chunyun Chen
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China;
| | - Jinhui Wang
- School of Pharmacy, Harbin Medical University, Harbin 150000, China; (J.W.); (J.H.)
| | - Jian Huang
- School of Pharmacy, Harbin Medical University, Harbin 150000, China; (J.W.); (J.H.)
| | - Dahong Yao
- School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen 518060, China;
| | - Chunli Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China;
| |
Collapse
|
|
19
|
Lee K, Yu H, Shouse S, Kong B, Lee J, Lee SH, Ko KS. RNA-Seq Reveals Different Gene Expression in Liver-Specific Prohibitin 1 Knock-Out Mice. Front Physiol 2021; 12:717911. [PMID: 34539442 PMCID: PMC8446661 DOI: 10.3389/fphys.2021.717911] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/27/2021] [Indexed: 12/24/2022] Open
Abstract
Prohibitin 1 (PHB1) is an evolutionarily conserved and ubiquitously expressed protein that stabilizes mitochondrial chaperone. Our previous studies showed that liver-specific Phb1 deficiency induced liver injuries and aggravated lipopolysaccharide (LPS)-induced innate immune responses. In this study, we performed RNA-sequencing (RNA-seq) analysis with liver tissues to investigate global gene expression among liver-specific Phb1−/−, Phb1+/−, and WT mice, focusing on the differentially expressed (DE) genes between Phb1+/− and WT. When 78 DE genes were analyzed for biological functions, using ingenuity pathway analysis (IPA) tool, lipid metabolism-related genes, including insulin receptor (Insr), sterol regulatory element-binding transcription factor 1 (Srebf1), Srebf2, and SREBP cleavage-activating protein (Scap) appeared to be downregulated in liver-specific Phb1+/− compared with WT. Diseases and biofunctions analyses conducted by IPA verified that hepatic system diseases, including liver fibrosis, liver hyperplasia/hyperproliferation, and liver necrosis/cell death, which may be caused by hepatotoxicity, were highly associated with liver-specific Phb1 deficiency in mice. Interestingly, of liver disease-related 5 DE genes between Phb1+/− and WT, the mRNA expressions of forkhead box M1 (Foxm1) and TIMP inhibitor of metalloproteinase (Timp1) were matched with validation for RNA-seq in liver tissues and AML12 cells transfected with Phb1 siRNA. The results in this study provide additional insights into molecular mechanisms responsible for increasing susceptibility of liver injuries associated with hepatic Phb1.
Collapse
Affiliation(s)
- Kyuwon Lee
- Department of Nutritional Science and Food Management, College of Science and Industry Convergence, Ewha Womans University, Seoul, South Korea
| | - Hyeonju Yu
- Department of Nutritional Science and Food Management, College of Science and Industry Convergence, Ewha Womans University, Seoul, South Korea
| | - Stephanie Shouse
- Center of Excellence for Poultry Science, University of Arkansas System Division of Agriculture, Fayetteville, AR, United States
| | - Byungwhi Kong
- Center of Excellence for Poultry Science, University of Arkansas System Division of Agriculture, Fayetteville, AR, United States
| | - Jihye Lee
- Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD, United States
| | - Seong-Ho Lee
- Department of Nutrition and Food Science, College of Agriculture and Natural Resources, University of Maryland, College Park, MD, United States
| | - Kwang Suk Ko
- Department of Nutritional Science and Food Management, College of Science and Industry Convergence, Ewha Womans University, Seoul, South Korea.,Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Beverly Hills, CA, United States
| |
Collapse
|
|
20
|
Zhou Y, Wu C, Wang X, Li P, Fan N, Zhang W, Liu Z, Zhang W, Tang B. Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease. Anal Chem 2021; 93:9609-9620. [PMID: 34191493 DOI: 10.1021/acs.analchem.1c01776] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Peroxisome proliferator-activated receptor alpha (PPAR-a) is a crucial nuclear transcription regulator of lipid metabolism, which is closely associated with the initiation and development of nonalcoholic fatty liver disease (NAFLD). Because PPAR-a can directly decide the level of peroxisomal metabolic enzymes, its changes might directly cause variations in peroxisomal polarity. Therefore, we developed a new two-photon fluorescence imaging probe, PX-P, in which the triphenylamine and cyanide moieties can real-time sense peroxisomal polarity changes. Using PX-P, we observed a prominent decrease in the peroxisomal polarity in the liver of mice with NAFLD for the first time. More importantly, we discovered that intracellular excessive peroxynitrite (ONOO-) and hydrogen peroxide (H2O2) underwent nitrification and oxidation, respectively, with various sites of PPAR-a. Interestingly, the key site of PPAR-a was nitrated by a low concentration of ONOO- rather than being oxidized by the high level of H2O2. These drastically reduced the activity of PPAR-a, accelerating the occurrence of NAFLD. Moreover, through activating PPARs with pioglitazone, peroxisomal polarity markedly increased compared with that of NAFLD. Altogether, our work presents a new approach for the early diagnosis of NAFLD and identifies potential therapeutic targets.
Collapse
Affiliation(s)
- Yongqing Zhou
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Chuanchen Wu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Xin Wang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Ping Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Nannan Fan
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Wei Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Zhenzhen Liu
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Wen Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Biomedical Science, Shandong Normal University, Jinan 250014, People's Republic of China
| |
Collapse
|
|
21
|
Ukiya M, Motegi K, Sato D, Kimura H, Satsu H, Koketsu M, Ninomiya M, Myint LM, Nishina A. Effect of Compounds from Moringa oleifera Lam. on in Vitro Non-Alcoholic Fatty Liver Disease (NAFLD) Model System. Chem Biodivers 2021; 18:e2100243. [PMID: 34128328 DOI: 10.1002/cbdv.202100243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/27/2021] [Indexed: 11/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in the world, with a prevalence of 25 % in many countries. To date, no drug has been approved to treat NAFLD, therefore, the use of phytochemicals to prevent this disease is meaningful. In this study, we focused on the effects of Moringa oleifera Lam. on diabetes, attempted to isolate compounds that regulate NAFLD. Compounds 1 and 2 were isolated from the ethyl acetate fraction of M. oleifera. Spectral data revealed that they were 1-hydroxy-3-phenylpropan-2-yl benzoate (1) and benzyl benzylcarbamate (2), respectively. The three-dimensional structure of compound 1 was determined by single crystal X-ray structural analysis. Neither compound was toxic to HepG2 cells, and compound 1 was found to have a concentration-dependent inhibitory effect on intracellular lipid accumulation induced by stimulation of linoleic acid (LA). As a result of measuring the effects of compound 1 on the intracellular lipid production-related protein, it was found that compound 1 enhanced protein expression that promotes lipolysis. On the other hand, since the action of compound 1 was similar to that of PPARα agonists, it is deduced that compound 1 enhanced the activity of PPARα and further enhanced the expression of lipolytic proteins, which is related to the suppression of intracellular lipid accumulation. Furthermore, as the result of docking simulation, compound 1 had a higher binding affinity to the ligand binding site of PPARα than fenofibrate, which is a PPARα agonist, and thus compound 1 was considered to be promising as an agonist of PPARα.
Collapse
Affiliation(s)
- Motohiko Ukiya
- Department of Applied Chemistry, College of Science and Technology, Nihon University, 1-5-1 Kandasurugadai, Chiyoda, Tokyo, 101-0062, Japan
| | - Kazuki Motegi
- Department of Applied Chemistry, College of Science and Technology, Nihon University, 1-5-1 Kandasurugadai, Chiyoda, Tokyo, 101-0062, Japan
| | - Daisuke Sato
- Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Johnan, Yonezawa, 992-8510, Japan
| | - Hirokazu Kimura
- School of Medical Technology, Faculty of Health Science, Gunma Paz University, 1-7-1 Tonyamachi, Takasaki, Gunma, 370-0006, Japan
| | - Hideo Satsu
- Department of Biotechnology, Maebashi Institute of Technology, 460-1 Kamisadorimachi, Maebashi, Gunma, 371-0816, Japan
| | - Mamoru Koketsu
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Masayuki Ninomiya
- Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Lwin Mon Myint
- FAME Pharmaceuticals Industry Co., Ltd, Mingyi Mahar Min Gaung Street, Yangon, Myamar
| | - Atsuyoshi Nishina
- Department of Applied Chemistry, College of Science and Technology, Nihon University, 1-5-1 Kandasurugadai, Chiyoda, Tokyo, 101-0062, Japan
| |
Collapse
|
|
22
|
Villaret-Cazadamont J, Poupin N, Tournadre A, Batut A, Gales L, Zalko D, Cabaton NJ, Bellvert F, Bertrand-Michel J. An Optimized Dual Extraction Method for the Simultaneous and Accurate Analysis of Polar Metabolites and Lipids Carried out on Single Biological Samples. Metabolites 2020; 10:E338. [PMID: 32825089 PMCID: PMC7570216 DOI: 10.3390/metabo10090338] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/16/2020] [Accepted: 08/17/2020] [Indexed: 12/11/2022] Open
Abstract
The functional understanding of metabolic changes requires both a significant investigation into metabolic pathways, as enabled by global metabolomics and lipidomics approaches, and the comprehensive and accurate exploration of specific key pathways. To answer this pivotal challenge, we propose an optimized approach, which combines an efficient sample preparation, aiming to reduce the variability, with a biphasic extraction method, where both the aqueous and organic phases of the same sample are used for mass spectrometry analyses. We demonstrated that this double extraction protocol allows working with one single sample without decreasing the metabolome and lipidome coverage. It enables the targeted analysis of 40 polar metabolites and 82 lipids, together with the absolute quantification of 32 polar metabolites, providing comprehensive coverage and quantitative measurement of the metabolites involved in central carbon energy pathways. With this method, we evidenced modulations of several lipids, amino acids, and energy metabolites in HepaRG cells exposed to fenofibrate, a model hepatic toxicant, and metabolic modulator. This new protocol is particularly relevant for experiments involving limited amounts of biological material and for functional metabolic explorations and is thus of particular interest for studies aiming to decipher the effects and modes of action of metabolic disrupting compounds.
Collapse
Affiliation(s)
- Joran Villaret-Cazadamont
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France; (J.V.-C.); (N.P.); (D.Z.); (N.J.C.)
| | - Nathalie Poupin
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France; (J.V.-C.); (N.P.); (D.Z.); (N.J.C.)
| | - Anthony Tournadre
- MetaboHUB-MetaToul-Lipidomics Core Facility, Inserm U1048, 31432 Toulouse, France; (A.T.); (A.B.)
- MetaboHUB-MetaToul, National Infrastructure for Metabolomics and Fluxomics, 31077 Toulouse, France;
| | - Aurélie Batut
- MetaboHUB-MetaToul-Lipidomics Core Facility, Inserm U1048, 31432 Toulouse, France; (A.T.); (A.B.)
- MetaboHUB-MetaToul, National Infrastructure for Metabolomics and Fluxomics, 31077 Toulouse, France;
| | - Lara Gales
- MetaboHUB-MetaToul, National Infrastructure for Metabolomics and Fluxomics, 31077 Toulouse, France;
- Toulouse Biotechnology Institute, Université de Toulouse, CNRS, INRAE, INSA, 31400 Toulouse, France
| | - Daniel Zalko
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France; (J.V.-C.); (N.P.); (D.Z.); (N.J.C.)
| | - Nicolas J. Cabaton
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France; (J.V.-C.); (N.P.); (D.Z.); (N.J.C.)
| | - Floriant Bellvert
- MetaboHUB-MetaToul, National Infrastructure for Metabolomics and Fluxomics, 31077 Toulouse, France;
- Toulouse Biotechnology Institute, Université de Toulouse, CNRS, INRAE, INSA, 31400 Toulouse, France
| | - Justine Bertrand-Michel
- MetaboHUB-MetaToul-Lipidomics Core Facility, Inserm U1048, 31432 Toulouse, France; (A.T.); (A.B.)
- MetaboHUB-MetaToul, National Infrastructure for Metabolomics and Fluxomics, 31077 Toulouse, France;
| |
Collapse
|
|
23
|
Jin M, Zhu T, Tocher DR, Luo J, Shen Y, Li X, Pan T, Yuan Y, Betancor MB, Jiao L, Sun P, Zhou Q. Dietary fenofibrate attenuated high-fat-diet-induced lipid accumulation and inflammation response partly through regulation of pparα and sirt1 in juvenile black seabream (Acanthopagrus schlegelii). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 109:103691. [PMID: 32251698 DOI: 10.1016/j.dci.2020.103691] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 06/11/2023]
Abstract
An 8-week feeding trail was conducted in Acanthopagrus schlegelii with an initial body weight of 8.34 ± 0.01g. Three isonitrogenous diets were formulated, (1) Control: medium-fat diet (12%); (2) HFD: high-fat diet (18%); (3) HFD + FF: high-fat diet with fenofibrate (0.15%). Liver histological analysis revealed that, compared to HFD, vacuolar fat drops were smaller and fewer in fish fed fenofibrate. Expression of lipid catabolism regulator peroxisome proliferator-activated receptor alpha (pparα) was up-regulated by fenofibrate compared with HFD. In addition, fenofibrate significantly increased the expression level of silent information regulator 1 (sirt1). Meanwhile, the expression level of anti-inflammatory cytokine interleukin 10 (il-10) in intestine was up-regulated, while pro-inflammatory cytokine interleukin 1β (il-1β) in liver and intestine were down-regulated by dietary fenofibrate supplementation. Overall, the present study indicated that fenofibrate reduced fat deposition and attenuated inflammation response caused by HFD partly through a pathway involving regulation of pparα and sirt1.
Collapse
Affiliation(s)
- Min Jin
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Tingting Zhu
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Douglas R Tocher
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling, FK9 4LA, Scotland, UK
| | - Jiaxiang Luo
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Yuedong Shen
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Xuejiao Li
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Tingting Pan
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Ye Yuan
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Mónica B Betancor
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling, FK9 4LA, Scotland, UK
| | - Lefei Jiao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Peng Sun
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Qicun Zhou
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| |
Collapse
|
|
24
|
Yang Q, Shu F, Gong J, Ding P, Cheng R, Li J, Tong R, Ding L, Sun H, Huang W, Wang Z, Yang L. Sweroside ameliorates NAFLD in high-fat diet induced obese mice through the regulation of lipid metabolism and inflammatory response. JOURNAL OF ETHNOPHARMACOLOGY 2020; 255:112556. [PMID: 31926984 DOI: 10.1016/j.jep.2020.112556] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 12/19/2019] [Accepted: 01/07/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sweroside, an iridoid derived from Traditional Chinese Medicine, is an active component in Swertia pseudochinensis Hara. Swertia pseudochinensis Hara is first recorded in "Inner Mongolia Chinese Herb Medicine"and is considered as a folk medicine for treating hepatitis in northern China. AIM OF THE STUDY This study sought to elucidate the role of sweroside in high fat diet induced obesity and fatty liver by using mouse model and investigated the primary molecular mechanism via transcriptomics analysis. MATERIALS AND METHODS C57BL/6 mice were fed high-fat diet (HFD) for 14 weeks to induce obesity, hyperglycemia, and fatty liver. These mice were subsequently treated with HFD alone or mixed with sweroside (at a daily dosage of 60 mg per kg of BW, 120 mg per kg of BW and 240 mg per kg of BW) for 6 weeks. BW and food intake was monitored weekly. Biochemical and pathological analysis were conducted to investigate the effect of sweroside on NAFLD. RNA-sequence and RT-qPCR analysis were performed to analyze the potential mechanism. RESULTS The mice treated with sweroside were resistant to HFD-induced body weight gain, insulin resistance and hepatic steatosis. Ingenuity pathway analysis (IPA) demonstrated that hepatic gene networks related to lipid metabolism and inflammatory response were down-regulated in the HFD + sweroside group. PPAR-ɑ was located in the center of the hepatic gene network, and the significantly altered genes were CD36 and FGF21, which are related to hepatic inflammation and lipid metabolism. Consistently, upstream-regulators analysis revealed that the main enriched upstream-regulator was PPAR-ɑ. CONCLUSION Our results indicate that sweroside may ameliorate obesity with fatty liver via the regulation of lipid metabolism and inflammatory responses. The beneficial effects of sweroside might be closely associated with the regulation of PPAR-α.
Collapse
Affiliation(s)
- Qiaoling Yang
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200040, China; Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Fangfang Shu
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Junting Gong
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ping Ding
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Rongrong Cheng
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jinmei Li
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Renchao Tong
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lili Ding
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Huajun Sun
- Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200040, China
| | - Wendong Huang
- Department of Diabetes Complications & Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Zhengtao Wang
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Li Yang
- The MOE Key Laboratory of Standardization of Chinese Medicines and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| |
Collapse
|
|
25
|
Gordon DM, Neifer KL, Hamoud ARA, Hawk CF, Nestor-Kalinoski AL, Miruzzi SA, Morran MP, Adeosun SO, Sarver JG, Erhardt PW, McCullumsmith RE, Stec DE, Hinds TD. Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator-activated receptor α. J Biol Chem 2020; 295:9804-9822. [PMID: 32404366 DOI: 10.1074/jbc.ra120.013700] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/11/2020] [Indexed: 12/18/2022] Open
Abstract
Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator-activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.
Collapse
Affiliation(s)
- Darren M Gordon
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.,Center for Diabetes and Endocrine Research (CeDER), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Kari L Neifer
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Abdul-Rizaq Ali Hamoud
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Charles F Hawk
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Andrea L Nestor-Kalinoski
- Advanced Microscopy and Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Scott A Miruzzi
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Michael P Morran
- Advanced Microscopy and Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| | - Samuel O Adeosun
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Jeffrey G Sarver
- Center for Drug Design and Development (CD3), Department of Pharmacology and Experimental Therapeutics, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio, USA
| | - Paul W Erhardt
- Center for Drug Design and Development (CD3), Department of Medicinal and Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, Ohio, USA
| | - Robert E McCullumsmith
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.,ProMedica, Toledo, Ohio, USA
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Terry D Hinds
- Department of Neurosciences, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA .,Center for Diabetes and Endocrine Research (CeDER), University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
| |
Collapse
|
|
26
|
Merry TL, Hedges CP, Masson SW, Laube B, Pöhlmann D, Wueest S, Walsh ME, Arnold M, Langhans W, Konrad D, Zarse K, Ristow M. Partial impairment of insulin receptor expression mimics fasting to prevent diet-induced fatty liver disease. Nat Commun 2020; 11:2080. [PMID: 32350271 PMCID: PMC7190665 DOI: 10.1038/s41467-020-15623-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 03/19/2020] [Indexed: 12/28/2022] Open
Abstract
Excessive insulin signaling through the insulin receptor (IR) may play a role in the pathogenesis of diet-induced metabolic disease, including obesity and type 2 diabetes. Here we investigate whether heterozygous impairment of insulin receptor (IR) expression limited to peripheral, i.e. non-CNS, tissues of adult mice impacts the development of high-fat diet-induced metabolic deterioration. While exhibiting some features of insulin resistance, PerIRKO+/− mice display a hepatic energy deficit accompanied by induction of energy-sensing AMPK, mitochondrial biogenesis, PPARα, unexpectedly leading to protection from, and reversal of hepatic lipid accumulation (steatosis hepatis, NAFLD). Consistently, and unlike in control mice, the PPARα activator fenofibrate fails to further affect hepatic lipid accumulation in PerIRKO+/− mice. Taken together, and opposing previously established diabetogenic features of insulin resistance, incomplete impairment of insulin signaling may mimic central aspects of calorie restriction to limit hepatic lipid accumulation during conditions of metabolic stress. Hyper-insulinemia associated with excess calorie intake may cause metabolic dysfunction. Here the authors report that mice with partially reduced insulin receptor expression in peripheral tissues are protected from and experience reversal of fatty liver disease.
Collapse
Affiliation(s)
- Troy L Merry
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland. .,Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand. .,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
| | - Chris P Hedges
- Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
| | - Stewart W Masson
- Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.,Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
| | - Beate Laube
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Doris Pöhlmann
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland
| | - Michael E Walsh
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Myrtha Arnold
- Physiology and Behavior Laboratory, Institute of Food and Nutrition, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Wolfgang Langhans
- Physiology and Behavior Laboratory, Institute of Food and Nutrition, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology and Children's Research Centre, University Children's Hospital, Zurich, Switzerland
| | - Kim Zarse
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland
| | - Michael Ristow
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland.
| |
Collapse
|
|
27
|
Lundåsen T, Pedrelli M, Bjørndal B, Rozell B, Kuiper RV, Burri L, Pavanello C, Turri M, Skorve J, Berge RK, Alexson SEH, Tillander V. The PPAR pan-agonist tetradecylthioacetic acid promotes redistribution of plasma cholesterol towards large HDL. PLoS One 2020; 15:e0229322. [PMID: 32176696 PMCID: PMC7075573 DOI: 10.1371/journal.pone.0229322] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 02/04/2020] [Indexed: 12/16/2022] Open
Abstract
Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the β-position. This modification renders TTA unable to undergo complete β-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.
Collapse
Affiliation(s)
- Thomas Lundåsen
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Matteo Pedrelli
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Bodil Bjørndal
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Sports, Physical activity and Food, Faculty of Education, Arts and Sports, Western Norway University of Applied Sciences, Bergen, Norway
- * E-mail: (BB); (VT)
| | - Björn Rozell
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Raoul V. Kuiper
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Lena Burri
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Chiara Pavanello
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro Enrica Grossi Paoletti, Università degli Studi di Milano, Milan, Italy
| | - Marta Turri
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Centro Enrica Grossi Paoletti, Università degli Studi di Milano, Milan, Italy
| | - Jon Skorve
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Rolf K. Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | | | - Veronika Tillander
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden
- * E-mail: (BB); (VT)
| |
Collapse
|
|
28
|
Wang Z, Ma C, Shang Y, Yang L, Zhang J, Yang C, Ren C, Liu J, Fan G, Liu J. Simultaneous co-assembly of fenofibrate and ketoprofen peptide for the dual-targeted treatment of nonalcoholic fatty liver disease (NAFLD). Chem Commun (Camb) 2020; 56:4922-4925. [DOI: 10.1039/d0cc00513d] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
An ingenious co-assembled nanosystem based on fenofibrate and ketoprofen peptide for the dual-targeted treatment of NAFLD by reducing hepatic lipid accumulation and inflammatory responses.
Collapse
|
|
29
|
Shama N, Kumari R, Bais S, Shrivastava A. Some important peptides and their role in obesity-current insights. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.obmed.2019.100144] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
30
|
Fischer A, Lüersen K, Schultheiß G, de Pascual-Teresa S, Mereu A, Ipharraguerre IR, Rimbach G. Supplementation with nitrate only modestly affects lipid and glucose metabolism in genetic and dietary-induced murine models of obesity. J Clin Biochem Nutr 2019; 66:24-35. [PMID: 32001953 PMCID: PMC6983433 DOI: 10.3164/jcbn.19-43] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 09/11/2019] [Indexed: 01/07/2023] Open
Abstract
To gain a better understanding of how nitrate may affect carbohydrate and lipid metabolism, female wild-type mice were fed a high-fat, high-fructose diet supplemented with either 0, 400, or 800 mg nitrate/kg diet for 28 days. Additionally, obese female db/db mice were fed a 5% fat diet supplemented with the same levels and source of nitrate. Nitrate decreased the sodium-dependent uptake of glucose by ileal mucosa in wild-type mice. Moreover, nitrate significantly decreased triglyceride content and mRNA expression levels of Pparγ in liver and Glut4 in skeletal muscle. Oral glucose tolerance as well as plasma cholesterol, triglyceride, insulin, leptin, glucose and the activity of ALT did not significantly differ between experimental groups but was higher in db/db mice than in wild-type mice. Nitrate changed liver fatty acid composition and mRNA levels of Fads only slightly. Further hepatic genes encoding proteins involved in lipid and carbohydrate metabolism were not significantly different between the three groups. Biomarkers of inflammation and autophagy in the liver were not affected by the different dietary treatments. Overall, the present data suggest that short-term dietary supplementation with inorganic nitrate has only modest effects on carbohydrate and lipid metabolism in genetic and dietary-induced mouse models of obesity.
Collapse
Affiliation(s)
- Alexandra Fischer
- Institute of Human Nutrition and Food Science, Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany
| | - Kai Lüersen
- Institute of Human Nutrition and Food Science, Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany
| | - Gerhard Schultheiß
- Animal Welfare Officer, University of Kiel, Hermann-Rodewald-Strasse 12, 24118 Kiel, Germany
| | - Sonia de Pascual-Teresa
- Department of Metabolism and Nutrition, Institute of Food Science, Food Technology and Nutrition (ICTAN-CSIC), José Antonio Novais 10, 28040 Madrid, Spain
| | - Alessandro Mereu
- Yara Iberian, C/ Infanta Mercedes 31 - 2nd floor, 28020 Madrid, Spain
| | - Ignacio R Ipharraguerre
- Institute of Human Nutrition and Food Science, Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany
| | - Gerald Rimbach
- Institute of Human Nutrition and Food Science, Food Science, University of Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany
| |
Collapse
|
|
31
|
Dong Y, Lu H, Li Q, Qi X, Li Y, Zhang Z, Chen J, Ren J. (5R)-5-hydroxytriptolide ameliorates liver lipid accumulation by suppressing lipid synthesis and promoting lipid oxidation in mice. Life Sci 2019; 232:116644. [DOI: 10.1016/j.lfs.2019.116644] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 07/07/2019] [Accepted: 07/09/2019] [Indexed: 02/06/2023]
|
|
32
|
Affiliation(s)
- Terry D Hinds
- From the Department of Physiology and Pharmacology, University of Toledo College of Medicine, OH (T.D.H.)
| | - David E Stec
- Department of Physiology and Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson (D.E.S.)
| |
Collapse
|
|
33
|
Li X, Wang Z, Klaunig JE. The effects of perfluorooctanoate on high fat diet induced non-alcoholic fatty liver disease in mice. Toxicology 2019; 416:1-14. [DOI: 10.1016/j.tox.2019.01.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/21/2019] [Accepted: 01/29/2019] [Indexed: 01/28/2023]
|
|
34
|
Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats. Arh Hig Rada Toksikol 2019; 70:30-35. [PMID: 30956215 DOI: 10.2478/aiht-2019-70-3215] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 02/01/2019] [Indexed: 01/02/2023] Open
Abstract
The study objective was to test the hypothesis that simvastatin and fenofibrate should cause an increase in butyrylcholinesterase (BuChE) activity not only in the plasma and liver but also in the brain of normolipidemic and hyperlipidemic rats. Catalytic enzyme activity was measured using acetylthiocholine (ATCh) and butyrylthiocholine (BTCh) as substrates. Normolipidemic and hyperlipidemic rats were divided in four groups receiving 50 mg/kg of simvastatin a day or 30 mg/kg of fenofibrate a day for three weeks and three control groups receiving saline. Simvastatin and fenofibrate caused an increase in brain BuChE activity in both normo- and hyperlipidemic rats regardless of the substrate. The increase with BTCh as substrate was significant and practically the same in normolipidemic and hyperlipidemic rats after simvastatin treatment (14-17% vs controls). Simvastatin and fenofibrate also increased liver and plasma BuChE activity in both normolipidemic and hyperlipidemic rats regardless of the substrate. In most cases the increase was significant. Considering the important role of BuChE in cholinergic transmission as well as its pharmacological function, it is necessary to continue investigations of the effects of lipid-lowering drugs on BuChE activity.
Collapse
|
|
35
|
Oscarsson J, Önnerhag K, Risérus U, Sundén M, Johansson L, Jansson PA, Moris L, Nilsson PM, Eriksson JW, Lind L. Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease: A double-blind, randomized, placebo-controlled study. J Clin Lipidol 2018; 12:1390-1403.e4. [PMID: 30197273 DOI: 10.1016/j.jacl.2018.08.003] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/04/2018] [Accepted: 08/01/2018] [Indexed: 12/31/2022]
Abstract
BACKGROUND Treatment with omega-3 fatty acids and fenofibrates reduces serum triglyceride levels, but few studies have compared the effect of these agents on liver fat. OBJECTIVE The aim of the EFFECT I trial (NCT02354976) was to determine the effects of free omega-3 carboxylic acids (OM-3CA) and fenofibrate on liver fat in overweight or obese individuals with non-alcoholic fatty liver disease and hypertriglyceridemia. METHODS Seventy-eight patients were randomized to receive oral doses of 4 g OM-3CA (n = 25), 200 mg fenofibrate (n = 27), or placebo (n = 26) for 12 weeks in a double-blind, parallel-group study. Liver proton density fat fraction (PDFF) and volume, pancreas volume, and adipose tissue volumes were assessed by magnetic resonance imaging. RESULTS Changes in liver PDFF at 12 weeks were not significantly different across treatment groups (relative changes from baseline: placebo, +4%; OM-3CA, -2%; and fenofibrate, +17%). The common PNPLA3 genetic polymorphism (I148M) did not significantly influence the effects of OM-3CA or fenofibrate on liver PDFF. Fenofibrate treatment significantly increased liver and pancreas volumes vs placebo treatment, and the changes in liver and pancreas volumes were positively correlated (rho 0.45, P = .02). Total liver fat volume increased significantly in patients using fenofibrate vs OM-3CA (+23% vs -3%, P = .04). Compared with OM-3CA, fenofibrate increased total liver fat and liver volume. Serum triglycerides decreased with OM-3CA (-26%, P = .02) and fenofibrate (-38%, P < .001) vs placebo. In contrast to OM-3CA, fenofibrate reduced plasma docosahexaenoic acid levels and increased plasma acetylcarnitine and butyrylcarnitine levels, estimated delta-9 desaturase activity and the concentration of urine F2-isoprostanes. CONCLUSIONS OM-3CA and fenofibrate reduced serum triglycerides but did not reduce liver fat. Fenofibrate increased total liver volume and total liver fat volume vs OM-3CA, indicating a complex effect of fenofibrate on human hepatic lipid metabolism.
Collapse
Affiliation(s)
| | | | - Ulf Risérus
- Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
| | | | | | - Per-Anders Jansson
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Linda Moris
- Karolinska Trial Alliance, Karolinska University Hospital, Solna, Sweden
| | - Peter M Nilsson
- Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
36
|
Park SS, Lee YJ, Song S, Kim B, Kang H, Oh S, Kim E. Lactobacillus acidophilus NS1 attenuates diet-induced obesity and fatty liver. J Endocrinol 2018; 237:87-100. [PMID: 29507043 DOI: 10.1530/joe-17-0592] [Citation(s) in RCA: 33] [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: 02/13/2018] [Accepted: 03/05/2018] [Indexed: 12/25/2022]
Abstract
Obesity is a major threat to public health, and it is strongly associated with insulin resistance and fatty liver disease. Here, we demonstrated that administration of Lactobacillus acidophilus NS1 (LNS1) significantly reduced obesity and hepatic lipid accumulation, with a concomitant improvement in insulin sensitivity, in high-fat diet (HFD)-fed mice. Furthermore, administration of LNS1 inhibited the effect of HFD feeding on the SREBP-1c and PPARα signaling pathways and reduced lipogenesis with an increase in fatty acid oxidation in ex vivo livers from HFD-fed mice. These LNS1 effects were confirmed in HepG2 cells and ex vivo livers by treatment with LNS1 culture supernatant (LNS1-CS). Interestingly, AMPK phosphorylation and activity in the liver of HFD-fed mice were increased by administration of LNS1. Consistently, chemical inhibition of AMPK with compound C, a specific inhibitor of AMPK, dramatically reduced the effect of LNS1-CS on lipid metabolism in HepG2 cells and ex vivo livers by modulating the SREBP-1c and PPARα signaling pathways. Furthermore, administration of LNS1 to HFD-fed mice significantly improved insulin resistance and increased Akt phosphorylation in the liver, white adipose tissue and skeletal muscle. Together, these data suggest that LNS1 may prevent diet-induced obesity and related metabolic disorders by improving lipid metabolism and insulin sensitivity through an AMPK→SREBP-1c/PPARα signaling pathway.
Collapse
Affiliation(s)
- Sung-Soo Park
- Department of Biological SciencesCollege of Natural Sciences, Chonnam National University, Gwangju, South Korea
| | - Yeon-Joo Lee
- Department of Biological SciencesCollege of Natural Sciences, Chonnam National University, Gwangju, South Korea
| | - Sooyeon Song
- Division of Animal ScienceCollege of Agriculture & Life Science, Chonnam National University, Gwangju, South Korea
| | - Boyong Kim
- Gwangju CenterKorea Basic Science Institute, Gwangju, South Korea
| | - Hyuno Kang
- Gwangju CenterKorea Basic Science Institute, Gwangju, South Korea
| | - Sejong Oh
- Division of Animal ScienceCollege of Agriculture & Life Science, Chonnam National University, Gwangju, South Korea
| | - Eungseok Kim
- Department of Biological SciencesCollege of Natural Sciences, Chonnam National University, Gwangju, South Korea
| |
Collapse
|
|
37
|
Rojas Á, Gallego P, Gil-Gómez A, Muñoz-Hernández R, Rojas L, Maldonado R, Gallego R, García-Valdecasas M, Del Campo JA, Bautista JD, Romero-Gómez M. Natural Extracts Abolished Lipid Accumulation in Cells Harbouring non-favourable PNPLA3 genotype. Ann Hepatol 2018; 17:242-249. [PMID: 29469041 DOI: 10.5604/01.3001.0010.8642] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
UNLABELLED Background & aims. G-allele of PNPLA3 (rs738409) favours triglycerides accumulation and steatosis. In this study, we examined the effect of quercetin and natural extracts from mushroom and artichoke on reducing lipid accumulation in hepatic cells. MATERIAL AND METHODS Huh7.5 cells were exposed to oleic acid (OA) and treated with quercetin and extracts to observe the lipid accumulation, the intracellular-TG concentration and the LD size. Sterol regulatory element binding proteins-1 (SREBP-1), peroxisome proliferator-activated receptor (PPARα-γ) and cholesterol acyltransferase (ACAT) gene expression levels were analysed. RESULTS Quercetin decreased the intracellular lipids, LD size and the levels of intracellular-TG through the down-regulation of SREBP-1c, PPARγ and ACAT1 increasing PPARα. The natural-extracts suppressed OA-induced lipid accumulation and the intracellular-TG. They down-regulate the hepatic lipogenesis through SREBP-1c, besides the activation of lipolysis through the increasing of PPARα expression. CONCLUSIONS Quercetin and the aqueous extracts decrease intracellular lipid accumulation by down-regulation of lipogenesis and up-regulation of lipolysis.
Collapse
Affiliation(s)
- Ángela Rojas
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS)
| | - Paloma Gallego
- Hospital Universitario de Valme, Sevilla, Spain. UGC de enfermedades hepáticas y digestivas, CIBERehd
| | - Antonio Gil-Gómez
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Gil-Gómez
| | - Rocío Muñoz-Hernández
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS)
| | - Lourdes Rojas
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS)
| | - Rosario Maldonado
- Hospital Universitario de Valme, Seville, Spain. Unidad de Farmacología Clínica y Experimental
| | - Rocío Gallego
- Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS). Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
| | - Marta García-Valdecasas
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS)
| | - José A Del Campo
- Hospital Universitario de Valme, Sevilla, Spain. UGC de enfermedades hepáticas y digestivas, CIBERehd
| | - Juan D Bautista
- Universidad de Sevilla, Seville, Spain. Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia
| | - Manuel Romero-Gómez
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. Laboratorio de Investigación clínica y traslacional en enfermedades hepáticas y digestivas y CIBERehd. Instituto de Biomedicina de Sevilla (IBiS)
| |
Collapse
|
|
38
|
Hamoud AR, Weaver L, Stec DE, Hinds TD. Bilirubin in the Liver-Gut Signaling Axis. Trends Endocrinol Metab 2018; 29:140-150. [PMID: 29409713 PMCID: PMC5831340 DOI: 10.1016/j.tem.2018.01.002] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/02/2018] [Accepted: 01/05/2018] [Indexed: 02/08/2023]
Abstract
Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver-gut axis, as well as its capacity to mediate these processes.
Collapse
Affiliation(s)
- Abdul-Rizaq Hamoud
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Lauren Weaver
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - David E Stec
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Terry D Hinds
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA.
| |
Collapse
|
|
39
|
Hansen HH, Feigh M, Veidal SS, Rigbolt KT, Vrang N, Fosgerau K. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today 2017; 22:1707-1718. [PMID: 28687459 DOI: 10.1016/j.drudis.2017.06.007] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 06/06/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH. Available mouse models of NASH address different aspects of the disease, have varying clinical translatability, and, therefore, also show different utility in drug discovery.
Collapse
Affiliation(s)
- Henrik H Hansen
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark.
| | - Michael Feigh
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| | - Sanne S Veidal
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| | | | - Niels Vrang
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| | - Keld Fosgerau
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| |
Collapse
|
|
40
|
Mecitoglu Z, Topal O, Kacar Y, Batmaz H. Comparing the effects of treatment with ammonium molybdate versus ammonium molybdate and phenoxy-2-methyl-2-propionic acid on liver functions in natural copper poisoning of sheep. Small Rumin Res 2017. [DOI: 10.1016/j.smallrumres.2017.03.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
41
|
Ning LJ, He AY, Lu DL, Li JM, Qiao F, Li DL, Zhang ML, Chen LQ, Du ZY. Nutritional background changes the hypolipidemic effects of fenofibrate in Nile tilapia (Oreochromis niloticus). Sci Rep 2017; 7:41706. [PMID: 28139735 PMCID: PMC5282496 DOI: 10.1038/srep41706] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 12/29/2016] [Indexed: 12/15/2022] Open
Abstract
Peroxisome proliferation activated receptor α (PPARα) is an important transcriptional regulator of lipid metabolism and is activated by high-fat diet (HFD) and fibrates in mammals. However, whether nutritional background affects PPARα activation and the hypolipidemic effects of PPARα ligands have not been investigated in fish. In the present two-phase study of Nile tilapia (Oreochromis niloticus), fish were first fed a HFD (13% fat) or low-fat diet (LFD; 1% fat) diet for 10 weeks, and then fish from the first phase were fed the HFD or LFD supplemented with 200 mg/kg body weight fenofibrate for 4 weeks. The results indicated that the HFD did not activate PPARα or other lipid catabolism-related genes. Hepatic fatty acid β-oxidation increased significantly in the HFD and LFD groups after the fenofibrate treatment, when exogenous substrates were sufficiently provided. Only in the HFD group, fenofibrate significantly increased hepatic PPARα mRNA and protein expression, and decreased liver and plasma triglyceride concentrations. This is the first study to show that body fat deposition and dietary lipid content affects PPARα activation and the hypolipidemic effects of fenofibrate in fish, and this could be due to differences in substrate availability for lipid catabolism in fish fed with different diets.
Collapse
Affiliation(s)
- Li-Jun Ning
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - An-Yuan He
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Dong-Liang Lu
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Jia-Min Li
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Fang Qiao
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Dong-Liang Li
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Mei-Ling Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Li-Qiao Chen
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| | - Zhen-Yu Du
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, China
| |
Collapse
|
|
42
|
López-Riera M, Conde I, Tolosa L, Zaragoza Á, Castell JV, Gómez-Lechón MJ, Jover R. New microRNA Biomarkers for Drug-Induced Steatosis and Their Potential to Predict the Contribution of Drugs to Non-alcoholic Fatty Liver Disease. Front Pharmacol 2017; 8:3. [PMID: 28179883 PMCID: PMC5263149 DOI: 10.3389/fphar.2017.00003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 01/04/2017] [Indexed: 12/13/2022] Open
Abstract
Background and Aims: Drug-induced steatosis is a major reason for drug failure in clinical trials and post-marketing withdrawal; and therefore, predictive biomarkers are essential. These could be particularly relevant in non-alcoholic fatty liver disease (NAFLD), where most patients show features of the metabolic syndrome and are prescribed with combined chronic therapies, which can contribute to fatty liver. However, specific biomarkers to assess the contribution of drugs to NAFLD are lacking. We aimed to find microRNAs (miRNAs) responsive to steatotic drugs and to investigate if they could become circulating biomarkers for drug-induced steatosis. Methods: Human HepG2 cells were treated with drugs and changes in miRNA levels were measured by microarray and qRT-PCR. Drug-induced fat accumulation in HepG2 was analyzed by high-content screening and enzymatic methods. miRNA biomarkers were also analyzed in the sera of 44 biopsy-proven NAFLD patients and in 10 controls. Results: We found a set of 10 miRNAs [miR-22-5p, -3929, -24-2-5p, -663a, -29a-3p, -21 (5p and 3p), -27a-5p, -1260 and -202-3p] that were induced in human HepG2 cells and secreted to the culture medium upon incubation with model steatotic drugs (valproate, doxycycline, cyclosporin A and tamoxifen). Moreover, cell exposure to 17 common drugs for NAFLD patients showed that some of them (e.g., irbesartan, fenofibrate, and omeprazole) also induced these miRNAs and increased intracellular triglycerides, particularly in combinations. Finally, we found that most of these miRNAs (60%) were detected in human serum, and that NAFLD patients under fibrates showed both induction of these miRNAs and a more severe steatosis grade. Conclusion: Steatotic drugs induce a common set of hepatic miRNAs that could be used in drug screening during preclinical development. Moreover, most of these miRNAs are serum circulating biomarkers that could become useful in the diagnosis of iatrogenic steatosis.
Collapse
Affiliation(s)
- Mireia López-Riera
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La Fe Valencia, Spain
| | - Isabel Conde
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La FeValencia, Spain; Servicio Medicina Digestiva, Sección Hepatología, Hospital Universitari i Politècnic La FeValencia, Spain
| | - Laia Tolosa
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La Fe Valencia, Spain
| | - Ángela Zaragoza
- Servicio Medicina Digestiva, Sección Hepatología, Hospital Universitari i Politècnic La Fe Valencia, Spain
| | - José V Castell
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La FeValencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos IIIMadrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universitat de ValènciaValencia, Spain
| | - María J Gómez-Lechón
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La FeValencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos IIIMadrid, Spain
| | - Ramiro Jover
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe, Hospital Universitari i Politècnic La FeValencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos IIIMadrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universitat de ValènciaValencia, Spain
| |
Collapse
|
|
43
|
Das KP, Wood CR, Lin MT, Starkov AA, Lau C, Wallace KB, Corton JC, Abbott BD. Perfluoroalkyl acids-induced liver steatosis: Effects on genes controlling lipid homeostasis. Toxicology 2016; 378:37-52. [PMID: 28049043 DOI: 10.1016/j.tox.2016.12.007] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 12/21/2016] [Accepted: 12/29/2016] [Indexed: 02/07/2023]
Abstract
Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to their extensive use in industrial and consumer products, and their slow decay. Biochemical tests in rodent demonstrated that these chemicals are potent modifiers of lipid metabolism and cause hepatocellular steatosis. However, the molecular mechanism of PFAAs interference with lipid metabolism remains to be elucidated. Currently, two major hypotheses are that PFAAs interfere with mitochondrial beta-oxidation of fatty acids and/or they affect the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) in liver. To determine the ability of structurally-diverse PFAAs to cause steatosis, as well as to understand the underlying molecular mechanisms, wild-type (WT) and PPARα-null mice were treated with perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), or perfluorohexane sulfonate (PFHxS), by oral gavage for 7days, and their effects were compared to that of PPARα agonist WY-14643 (WY), which does not cause steatosis. Increases in liver weight and cell size, and decreases in DNA content per mg of liver, were observed for all compounds in WT mice, and were also seen in PPARα-null mice for PFOA, PFNA, and PFHxS, but not for WY. In Oil Red O stained sections, WT liver showed increased lipid accumulation in all treatment groups, whereas in PPARα-null livers, accumulation was observed after PFNA and PFHxS treatment, adding to the burden of steatosis observed in control (untreated) PPARα-null mice. Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs and in PPARα-null mice only by PFNA. In vitro β-oxidation of palmitoyl carnitine by isolated rat liver mitochondria was not inhibited by any of the 7 PFAAs tested. Likewise, neither PFOA nor PFOS inhibited palmitate oxidation by HepG2/C3A human liver cell cultures. Microarray analysis of livers from PFAAs-treated mice indicated that the PFAAs induce the expression of the lipid catabolism genes, as well as those involved in fatty acid and triglyceride synthesis, in WT mice and, to a lesser extent, in PPARα-null mice. These results indicate that most of the PFAAs increase liver TG load and promote steatosis in mice We hypothesize that PFAAs increase steatosis because the balance of fatty acid accumulation/synthesis and oxidation is disrupted to favor accumulation.
Collapse
Affiliation(s)
- Kaberi P Das
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA
| | - Carmen R Wood
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA
| | - Mimi T Lin
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA
| | - Anatoly A Starkov
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA
| | - Christopher Lau
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA
| | - Kendall B Wallace
- Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA
| | - J Christopher Corton
- Integrated System Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA
| | - Barbara D Abbott
- Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA.
| |
Collapse
|
|
44
|
Hinds TD, Burns KA, Hosick PA, McBeth L, Nestor-Kalinoski A, Drummond HA, AlAmodi AA, Hankins MW, Vanden Heuvel JP, Stec DE. Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3β Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α. J Biol Chem 2016; 291:25179-25191. [PMID: 27738106 DOI: 10.1074/jbc.m116.731703] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 09/30/2016] [Indexed: 01/21/2023] Open
Abstract
Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P)73 of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.
Collapse
Affiliation(s)
- Terry D Hinds
- the Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology,
| | - Katherine A Burns
- the Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and.,the Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
| | - Peter A Hosick
- From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216.,the Department of Exercise Science and Physical Education, Montclair State University, Montclair, New Jersey 07043
| | - Lucien McBeth
- the Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology
| | - Andrea Nestor-Kalinoski
- Advanced Microscopy & Imaging Center, Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo Ohio 43614
| | - Heather A Drummond
- From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216
| | - Abdulhadi A AlAmodi
- From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216
| | - Michael W Hankins
- From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216
| | - John P Vanden Heuvel
- the Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16802, and
| | - David E Stec
- From the Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, Jackson, Mississippi 39216,
| |
Collapse
|
|
45
|
Hinds TD, Adeosun SO, Alamodi AA, Stec DE. Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor? Med Hypotheses 2016; 95:54-57. [PMID: 27692168 PMCID: PMC5433619 DOI: 10.1016/j.mehy.2016.08.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 08/05/2016] [Accepted: 08/31/2016] [Indexed: 12/15/2022]
Abstract
Several large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of obesity, hepatic steatosis, and cardiovascular disease. Despite the strong correlative data demonstrating the protective role of bilirubin, the mechanism by which bilirubin can protect against these pathologies remains unknown. Bilirubin has long been known as a powerful antioxidant and also has anti-inflammatory actions, each of which may contribute to the protection afforded by increased levels. We have recently described a novel function of bilirubin as a ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), which we show specifically binds to the nuclear receptor. Bilirubin may function as a selective PPAR modulator (SPPARM) to control lipid accumulation and blood glucose. However, it is not known to what degree bilirubin activation of PPARα is responsible for the protection afforded to reduce hepatic steatosis. We hypothesize that bilirubin, acting as a novel SPPARM, increases hepatic fatty acid metabolism through a PPARα-dependent mechanism which reduces hepatic lipid accumulation and protects against hepatic steatosis and non-alcoholic fatty liver disease (NAFLD).
Collapse
Affiliation(s)
- Terry D Hinds
- Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614, USA
| | - Samuel O Adeosun
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA
| | - Abdulhadi A Alamodi
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA
| | - David E Stec
- Department of Physiology & Biophysics, Mississippi Center for Obesity Research, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216, USA.
| |
Collapse
|
|
46
|
Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease. Mol Cell Biol 2016; 36:2553-67. [PMID: 27457618 DOI: 10.1128/mcb.00227-16] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 07/19/2016] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein α-subunit (MTPα) functions as a critical enzyme for fatty acid β-oxidation, but whether dysregulation of MTPα is pathogenically connected to NAFLD is poorly understood. We show that MTPα is acetylated at lysine residues 350, 383, and 406 (MTPα-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTPα-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTPα. Replacement of MTPα-3K with either MTPα-3KR or MTPα-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTPα-3K mutant expression in mouse livers, and MTPα-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTPα and MTPα-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTPα regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.
Collapse
|
|
47
|
Sesamin ameliorates hepatic steatosis and inflammation in rats on a high-fat diet via LXRα and PPARα. Nutr Res 2016; 36:1022-1030. [DOI: 10.1016/j.nutres.2016.06.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 06/18/2016] [Accepted: 06/24/2016] [Indexed: 11/20/2022]
|
|
48
|
Stec DE, John K, Trabbic CJ, Luniwal A, Hankins MW, Baum J, Hinds TD. Bilirubin Binding to PPARα Inhibits Lipid Accumulation. PLoS One 2016; 11:e0153427. [PMID: 27071062 PMCID: PMC4829185 DOI: 10.1371/journal.pone.0153427] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 03/29/2016] [Indexed: 01/31/2023] Open
Abstract
Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.
Collapse
Affiliation(s)
- David E. Stec
- Cardiovascular-Renal Research Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, Mississippi, 39216, United States of America
| | - Kezia John
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, United States of America
| | - Christopher J. Trabbic
- Center for Drug Design and Development, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, United States of America
| | - Amarjit Luniwal
- Center for Drug Design and Development, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, 43614, United States of America
- North American Science Associates, Inc. (NAMSA), 6750 Wales Rd, Northwood, Ohio, 43619, United States of America
| | - Michael W. Hankins
- Cardiovascular-Renal Research Center, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, Mississippi, 39216, United States of America
| | - Justin Baum
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, United States of America
| | - Terry D. Hinds
- Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, 43614, United States of America
- * E-mail:
| |
Collapse
|
|
49
|
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
|
|
50
|
Jia Y, Wu C, Kim J, Kim B, Lee SJ. Astaxanthin reduces hepatic lipid accumulations in high-fat-fed C57BL/6J mice via activation of peroxisome proliferator-activated receptor (PPAR) alpha and inhibition of PPAR gamma and Akt. J Nutr Biochem 2016; 28:9-18. [DOI: 10.1016/j.jnutbio.2015.09.015] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 09/08/2015] [Accepted: 09/11/2015] [Indexed: 02/06/2023]
|