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Qiang E, Xu H. PGE 2 synthesis and signaling in the liver physiology and pathophysiology: An update. Prostaglandins Other Lipid Mediat 2024; 174:106875. [PMID: 39019102 DOI: 10.1016/j.prostaglandins.2024.106875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/12/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024]
Abstract
The liver plays a central role in systemic metabolism and drug degradation. However, it is highly susceptible to damage due to various factors, including metabolic imbalances, excessive alcohol consumption, viral infections, and drug influences. These factors often result in conditions such as fatty liver, hepatitis, and acute or chronic liver injury. Failure to address these injuries could promptly lead to the development of liver cirrhosis and potentially hepatocellular carcinoma (HCC). Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid that belongs to the class of polyunsaturated fatty acids (PUFA) and is synthesized via the cyclooxygenase (COX) pathway. By binding to its G protein coupled receptors (i.e., EP1, EP2, EP3 and EP4), PGE2 has a wide range of physiological and pathophysiology effects, including pain, inflammation, fever, cardiovascular homeostasis, etc. Recently, emerging studies showed that PGE2 plays an indispensable role in liver health and disease. This review focus on the research progress of the role of PGE2 synthase and its receptors in liver physiological and pathophysiological processes and discuss the possibility of developing liver protective drugs targeting the COXs/PGESs/PGE2/EPs axis.
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Affiliation(s)
- Erjiao Qiang
- Department of Pathology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Hu Xu
- Health Science Center, East China Normal University, Shanghai 200241, China.
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Huang Y, Liang M, Liao Y, Ji Z, Lin W, Pu X, Wang L, Wang W. Investigating the Mechanisms of 15-PGDH Inhibitor SW033291 in Improving Type 2 Diabetes Mellitus: Insights from Metabolomics and Transcriptomics. Metabolites 2024; 14:509. [PMID: 39330516 PMCID: PMC11434390 DOI: 10.3390/metabo14090509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/09/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
This study focused on exploring the effects of SW033291, an inhibitor of 15-hydroxyprostaglandin dehydrogenase, on type 2 diabetes mellitus (T2DM) mice from a comprehensive perspective. Studies have demonstrated that SW033291 benefits tissue repair, organ function, and muscle mass in elderly mice. Our recent investigation initially reported the beneficial effect of SW033291 on T2DM progression. Herein, we used a T2DM mouse model induced by a high-fat diet and streptozotocin injection. Then, serum and liver metabolomics, as well as liver transcriptomic analyses, were performed to provide a systematic perspective of the SW033291-ameliorated T2DM. The results indicate SW033291 improved T2DM by regulating steroid hormone biosynthesis and linoleic/arachidonic acid metabolism. Furthermore, integrated transcriptomic and metabolomic analyses suggested that key genes and metabolites such as Cyp2c55, Cyp3a11, Cyp21a1, Myc, Gstm1, Gstm3, 9,10-dihydroxyoctadecenoic acid, 11-dehydrocorticosterone, and 12,13-dihydroxy-9Z-octadecenoic acid played crucial roles in these pathways. qPCR analysis validated the significant decreases in the hepatic gene expressions of Cyp2c55, Cyp3a11, Myc, Gstm1, and Gstm3 in the T2DM mice, which were reversed following SW033291 treatment. Meanwhile, the elevated mRNA level of Cyp21a1 in T2DM mice was decreased after SW033291 administration. Taken together, our findings suggest that SW033291 has promising potential in alleviating T2DM and could be a novel therapeutic candidate.
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Affiliation(s)
- Yuanfeng Huang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
| | - Mingjie Liang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
- Guangdong Nephrotic Drug Engineering Technology Research Center, Guangdong Consun Pharmaceutical Group, Institute of Consun Co. for Chinese Medicine in Kidney Diseases, Guangzhou 510700, China
| | - Yiwen Liao
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
| | - Zirui Ji
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
| | - Wanfen Lin
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
| | - Xiangjin Pu
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
| | - Lexun Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
| | - Weixuan Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, No. 280, Waihuan East Road, University Town, Guangzhou 510006, China; (Y.H.); (M.L.); (Y.L.); (Z.J.); (W.L.); (X.P.); (L.W.)
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou 510006, China
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Rocha S, Luísa Corvo M, Freitas M, Fernandes E. Liposomal quercetin: A promising strategy to combat hepatic insulin resistance and inflammation in type 2 diabetes mellitus. Int J Pharm 2024; 661:124441. [PMID: 38977164 DOI: 10.1016/j.ijpharm.2024.124441] [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: 02/20/2024] [Revised: 07/04/2024] [Accepted: 07/05/2024] [Indexed: 07/10/2024]
Abstract
In type 2 diabetes mellitus, hepatic insulin resistance is intricately associated with oxidative stress and inflammation. Nonetheless, the lack of therapeutic interventions directly targeting hepatic dysfunction represents a notable gap in current treatment options. Flavonoids have been explored due to their potential antidiabetic effects. However, these compounds are associated with low bioavailability and high metabolization. In the present study, four flavonoids, kaempferol, quercetin, kaempferol-7-O-glucoside and quercetin-7-O-glucoside, were studied in a cellular model of hepatic insulin resistance using HepG2 cells. Quercetin was selected as the most promising flavonoid and incorporated into liposomes to enhance its therapeutic effect. Quercetin liposomes had a mean size of 0.12 µm, with an incorporation efficiency of 93 %. Quercetin liposomes exhibited increased efficacy in modulating insulin resistance. This was achieved through the modulation of Akt expression and the attenuation of inflammation, particularly via the NF-κB pathway, as well as the regulation of PGE2 and COX-2 expression. Furthermore, quercetin liposomes displayed a significant advantage over free quercetin in attenuating the production of reactive pro-oxidant species. These findings open new avenues for developing innovative therapeutic strategies to manage diabetes, emphasizing the potential of quercetin liposomes as a promising approach for targeting both hepatic insulin resistance and associated inflammation.
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Affiliation(s)
- Sónia Rocha
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
| | - M Luísa Corvo
- Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
| | - Marisa Freitas
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
| | - Eduarda Fernandes
- LAQV, REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
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Hodeify R, Kreydiyyeh S, Zaid LMJ. Identified and potential internalization signals involved in trafficking and regulation of Na +/K + ATPase activity. Mol Cell Biochem 2024; 479:1583-1598. [PMID: 37634170 PMCID: PMC11254989 DOI: 10.1007/s11010-023-04831-y] [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: 05/04/2023] [Accepted: 08/14/2023] [Indexed: 08/29/2023]
Abstract
The sodium-potassium pump (NKA) or Na+/K+ ATPase consumes around 30-40% of the total energy expenditure of the animal cell on the generation of the sodium and potassium electrochemical gradients that regulate various electrolyte and nutrient transport processes. The vital role of this protein entails proper spatial and temporal regulation of its activity through modulatory mechanisms involving its expression, localization, enzymatic activity, and protein-protein interactions. The residence of the NKA at the plasma membrane is compulsory for its action as an antiporter. Despite the huge body of literature reporting on its trafficking between the cell membrane and intracellular compartments, the mechanisms controlling the trafficking process are by far the least understood. Among the molecular determinants of the plasma membrane proteins trafficking are intrinsic sequence-based endocytic motifs. In this review, we (i) summarize previous reports linking the regulation of Na+/K+ ATPase trafficking and/or plasma membrane residence to its activity, with particular emphasis on the endocytic signals in the Na+/K+ ATPase alpha-subunit, (ii) map additional potential internalization signals within Na+/K+ ATPase catalytic alpha-subunit, based on canonical and noncanonical endocytic motifs reported in the literature, (iii) pinpoint known and potential phosphorylation sites associated with NKA trafficking, (iv) highlight our recent studies on Na+/K+ ATPase trafficking and PGE2-mediated Na+/K+ ATPase modulation in intestine, liver, and kidney cells.
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Affiliation(s)
- Rawad Hodeify
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates.
| | - Sawsan Kreydiyyeh
- Department of Biology, Faculty of Arts & Sciences, American University of Beirut, Beirut, Lebanon
| | - Leen Mohammad Jamal Zaid
- Department of Biotechnology, School of Arts and Sciences, American University of Ras Al Khaimah, Ras Al Khaimah, United Arab Emirates
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Chen C, Chen F, Gu L, Jiang Y, Cai Z, Zhao Y, Chen L, Zhu Z, Liu X. Discovery and validation of COX2 as a target of flavonoids in Apocyni Veneti Folium: Implications for the treatment of liver injury. JOURNAL OF ETHNOPHARMACOLOGY 2024; 326:117919. [PMID: 38364933 DOI: 10.1016/j.jep.2024.117919] [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: 11/09/2023] [Revised: 02/09/2024] [Accepted: 02/13/2024] [Indexed: 02/18/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Apocyni Veneti Folium (AVF), a popular traditional Chinese medicine (TCM), is known for its effects in soothing the liver and nerves and eliminating heat and water. It is relevant from an ethnopharmacological perspective. Pharmacological research has confirmed its benefits on antihypertension, antihyperlipidemia, antidepression, liver protection, immune system boosting, antiaging, and diabetic vascular lesions. Previous studies have shown that flavonoids, the active ingredients, have a hepatoprotective effect. However, the exact mechanism has not been clarified. AIM OF THE STUDY This study aimed to identify the active flavonoids in AVF and their corresponding targets for liver injury. Multiple methods were introduced to confirm the targets. MATERIAL AND METHODS AVF compounds were analyzed using liquid chromatography-mass spectrometry (LC-MS). Then, network pharmacology was utilized to screen potential hepatoprotection targets of the compounds. An enzyme activity assay was performed to determine the effect of the compounds on the targets. Biolayer interferometry (BLI) was applied to confirm the direct interaction between the compounds and the targets. RESULTS A total of 71 compounds were identified by LC-MS and 19 compounds and 112 shared targets were screened using network pharmacology. These common targets were primarily involved in the TNF signaling pathway, cancer pathways, hepatitis B, drug responses, and negative regulation of the apoptotic process. Flavonoids were the primary pharmacological substance basis of AVF. The cyclooxygenase 2 (COX2) protein was one of the direct targets of flavonoids in AVF. The enzyme activity assay and BLI-based intermolecular interactions demonstrated that the compounds astragalin, isoquercitrin, and hyperoside exhibited stronger inhibition of enzyme activity and a higher affinity with COX2 compared to epigallocatechin, quercetin, and catechin. CONCLUSIONS COX2 was preliminarily identified as a target of flavonoids, and the mechanism of the hepatoprotective effect of AVF might be linked to flavonoids inhibiting the activity of COX2. The findings can establish the foundation for future research on the traditional hepatoprotective effect of AVF on the liver and for clinical studies on liver disorders.
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Affiliation(s)
- Cuihua Chen
- College of Traditional Chinese Medicine & College of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Feiyan Chen
- College of Traditional Chinese Medicine & College of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Ling Gu
- College of Traditional Chinese Medicine & College of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yucui Jiang
- College of Traditional Chinese Medicine & College of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Zhichen Cai
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yunan Zhao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Lin Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Zhu Zhu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Xunhong Liu
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Lone JB, Long JZ, Svensson KJ. Size matters: the biochemical logic of ligand type in endocrine crosstalk. LIFE METABOLISM 2024; 3:load048. [PMID: 38425548 PMCID: PMC10904031 DOI: 10.1093/lifemeta/load048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/21/2023] [Accepted: 12/04/2023] [Indexed: 03/02/2024]
Abstract
The endocrine system is a fundamental type of long-range cell-cell communication that is important for maintaining metabolism, physiology, and other aspects of organismal homeostasis. Endocrine signaling is mediated by diverse blood-borne ligands, also called hormones, including metabolites, lipids, steroids, peptides, and proteins. The size and structure of these hormones are fine-tuned to make them bioactive, responsive, and adaptable to meet the demands of changing environments. Why has nature selected such diverse ligand types to mediate communication in the endocrine system? What is the chemical, signaling, or physiologic logic of these ligands? What fundamental principles from our knowledge of endocrine communication can be applied as we continue as a field to uncover additional new circulating molecules that are claimed to mediate long-range cell and tissue crosstalk? This review provides a framework based on the biochemical logic behind this crosstalk with respect to their chemistry, temporal regulation in physiology, specificity, signaling actions, and evolutionary development.
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Affiliation(s)
- Jameel Barkat Lone
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Jonathan Z Long
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
- Department of Chemistry, Stanford University, Stanford, CA 94305, United States
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, United States
- Sarafan ChEM-H, Stanford University, Stanford, CA 94305, United States
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA 94305, United States
| | - Katrin J Svensson
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305, United States
- Sarafan ChEM-H, Stanford University, Stanford, CA 94305, United States
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA 94305, United States
- Stanford Cardiovascular Institute, Stanford University School of Medicine, CA 94305, United States
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Williams LA, Hamilton MC, Edin ML, Lih FB, Eccles-Miller JA, Tharayil N, Leonard E, Baldwin WS. Increased Perfluorooctanesulfonate (PFOS) Toxicity and Accumulation Is Associated with Perturbed Prostaglandin Metabolism and Increased Organic Anion Transport Protein (OATP) Expression. TOXICS 2024; 12:106. [PMID: 38393201 PMCID: PMC10893382 DOI: 10.3390/toxics12020106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 01/12/2024] [Accepted: 01/23/2024] [Indexed: 02/25/2024]
Abstract
Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver disease and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than those of Cyp2b-null mice, with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity. Overt toxicity was greater in hCYP2B6-Tg mice (especially females) as measured by mortality; however, steatosis occurred more readily in Cyp2b-null mice despite the lower PFOS liver concentrations. Targeted lipidomics and transcriptomics from PFOS-treated Cyp2b-null and hCYP2B6-Tg mouse livers were performed and compared to PFOS retention and serum markers of toxicity using PCA. Several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabolites, are associated or inversely associated with PFOS toxicity. Both lipidomics and transcriptomics indicate PFOS toxicity is associated with PPAR activity in all models. GO terms associated with reduced steatosis were sexually dimorphic with lipid metabolism and transport increased in females and circadian rhythm associated genes increased in males. However, we cannot rule out that steatosis was initially protective from PFOS toxicity. Moreover, several transporters are associated with increased retention, probably due to increased uptake. The strongest associations are the organic anion transport proteins (Oatp1a4-6) genes and a long-chain fatty acid transport protein (fatp1), enriched in female hCYP2B6-Tg mice. PFOS uptake was also reduced in cultured murine hepatocytes by OATP inhibitors. The role of OATP1A6 and FATP1 in PFOS transport has not been tested. In summary, Cyp2b-null and hCYP2B6-Tg mice provided unique models for estimating the importance of novel mechanisms in PFOS retention and toxicity.
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Affiliation(s)
- Lanie A. Williams
- Biological Sciences, Clemson University, Clemson, SC 29634, USA; (L.A.W.); (M.C.H.); (J.A.E.-M.)
| | - Matthew C. Hamilton
- Biological Sciences, Clemson University, Clemson, SC 29634, USA; (L.A.W.); (M.C.H.); (J.A.E.-M.)
| | - Matthew L. Edin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, Washington, NC 27709, USA; (M.L.E.); (F.B.L.)
| | - Fred B. Lih
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, Washington, NC 27709, USA; (M.L.E.); (F.B.L.)
| | - Jazmine A. Eccles-Miller
- Biological Sciences, Clemson University, Clemson, SC 29634, USA; (L.A.W.); (M.C.H.); (J.A.E.-M.)
| | - Nishanth Tharayil
- Plant and Environmental Sciences, Clemson University, Clemson, SC 29634, USA; (N.T.); (E.L.)
| | - Elizabeth Leonard
- Plant and Environmental Sciences, Clemson University, Clemson, SC 29634, USA; (N.T.); (E.L.)
| | - William S. Baldwin
- Biological Sciences, Clemson University, Clemson, SC 29634, USA; (L.A.W.); (M.C.H.); (J.A.E.-M.)
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Kwanten W(WJ, Francque SM. The liver sinusoid in chronic liver disease: NAFLD and NASH. SINUSOIDAL CELLS IN LIVER DISEASES 2024:263-284. [DOI: 10.1016/b978-0-323-95262-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liang M, Zhan W, Wang L, Bei W, Wang W. Ginsenoside Rb1 Promotes Hepatic Glycogen Synthesis to Ameliorate T2DM Through 15-PGDH/PGE 2/EP4 Signaling Pathway. Diabetes Metab Syndr Obes 2023; 16:3223-3234. [PMID: 37867629 PMCID: PMC10590136 DOI: 10.2147/dmso.s431423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/11/2023] [Indexed: 10/24/2023] Open
Abstract
Purpose Ginsenoside Rb1 (Rb1), one of the crucial bioactive constituents in Panax ginseng C. A. Mey., possesses anti-type 2 diabetes mellitus (T2DM) property. Nevertheless, the precise mechanism, particularly the impact of Rb1 on hepatic glycogen production, a crucial process in the advancement of T2DM, remains poorly understood. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is responsible for prostaglandin E2 (PGE2) inactivation. A recent study has reported that inhibition of 15-PGDH promoted hepatic glycogen synthesis and improved T2DM. Therefore, herein, we aimed to investigate whether Rb1 ameliorated T2DM through 15-PGDH/PGE2-regulated hepatic glycogen synthesis. Methods By combining streptozotocin with a high-fat diet, we successfully established a mouse model for T2DM. Afterward, these mice were administered Rb1 or metformin for 8 weeks. An insulin-resistant cell model was established by incubating LO2 cells with palmitic acid. Liver glycogen and PGE2 levels, the expression levels of 15-PGDH, serine/threonine kinase AKT (AKT), and glycogen synthase kinase 3 beta (GSK3β) were measured. Molecular docking was used to predict the binding affinity between 15-PGDH and Rb1. Results Rb1 administration increased the phosphorylation levels of AKT and GSK3β to enhance glycogen synthesis in the liver of T2DM mice. Molecular docking indicated that Rb1 had a high affinity for 15-PGDH. Moreover, Rb1 treatment resulted in the suppression of elevated 15-PGDH levels and the elevation of decreased PGE2 levels in the liver of T2DM mice. Furthermore, in vitro experiments showed that Rb1 administration might enhance glycogen production by modulating the 15-PGDH/PGE2/PGE2 receptor EP4 pathway. Conclusion Our findings indicate that Rb1 may enhance liver glycogen production through a 15-PGDH-dependent pathway to ameliorate T2DM, thereby offering a new explanation for the positive impact of Rb1 on T2DM and supporting its potential as an effective therapeutic approach for T2DM.
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Affiliation(s)
- Mingjie Liang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Wenjing Zhan
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Lexun Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Weijian Bei
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
| | - Weixuan Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, People’s Republic of China
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Kholodenko IV, Kholodenko RV, Yarygin KN. The Crosstalk between Mesenchymal Stromal/Stem Cells and Hepatocytes in Homeostasis and under Stress. Int J Mol Sci 2023; 24:15212. [PMID: 37894893 PMCID: PMC10607347 DOI: 10.3390/ijms242015212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ's own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte-MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange.
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Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
| | - Roman V. Kholodenko
- Laboratory of Molecular Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia;
| | - Konstantin N. Yarygin
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
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Zhou Y, Dai Z, Deng K, Wang Y, Ying J, Chu D, Zhou J, Tang C. Eight Zhes Decoction ameliorates the lipid dysfunction of nonalcoholic fatty liver disease using integrated lipidomics, network pharmacology and pharmacokinetics. J Pharm Anal 2023; 13:1058-1069. [PMID: 37842659 PMCID: PMC10568095 DOI: 10.1016/j.jpha.2023.05.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/19/2023] [Accepted: 05/21/2023] [Indexed: 10/17/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has developed into the most common chronic liver disease and can lead to liver cancer. Our laboratory previously developed a novel prescription for NAFLD, "Eight Zhes Decoction" (EZD), which has shown good curative effects in clinical practice. However, the pharmacodynamic material basis and mechanism have not yet been revealed. A strategy integrating lipidomics, network pharmacology and pharmacokinetics was used to reveal the active components and mechanisms of EZD against NAFLD. The histopathological results showed that EZD attenuated the degrees of collagen deposition and steatosis in the livers of nonalcoholic steatofibrosis model mice. Furthermore, glycerophospholipid metabolism, arachidonic acid metabolism, glycerolipid metabolism and linoleic acid metabolism with phospholipase A2 group IVA (PLA2G4A) and cytochrome P450 as the core targets and 12,13-cis-epoxyoctadecenoic acid, 12(S)-hydroxyeicosatetraenoic acid, leukotriene B4, prostaglandin E2, phosphatidylcholines (PCs) and triacylglycerols (TGs) as the main lipids were found to be involved in the treatment of NAFLD by EZD. Importantly, naringenin, artemetin, canadine, and bicuculline were identified as the active ingredients of EZD against NAFLD; in particular, naringenin reduces PC consumption by inhibiting the expression of PLA2G4A and thus promotes sufficient synthesis of very-low-density lipoprotein to transport excess TGs in the liver. This research provides valuable data and theoretical support for the application of EZD against NAFLD.
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Affiliation(s)
- Yuping Zhou
- The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315020, China
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
- Institute of Digestive Disease of Ningbo University, Ningbo, Zhejiang, 315020, China
| | - Ze Dai
- The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315020, China
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Kaili Deng
- The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315020, China
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Yubin Wang
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Jiamin Ying
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Donghui Chu
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Jinyue Zhou
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Chunlan Tang
- The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, 315020, China
- School of Public Health, Health Science Center, Ningbo University, Ningbo, Zhejiang, 315211, China
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12
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Hoch J, Burkhard N, Zhang S, Rieder M, Marchini T, Geest V, Krauel K, Zahn T, Schommer N, Hamad MA, Bauer C, Gauchel N, Stallmann D, Normann C, Wolf D, Scharf RE, Duerschmied D, Schanze N. Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding. Front Immunol 2023; 14:1184010. [PMID: 37520561 PMCID: PMC10372416 DOI: 10.3389/fimmu.2023.1184010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 06/13/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far. Methods SERT-deficient (Sert -/-) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, Sert -/- and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization. Results After 19 weeks of high-fat diet, Sert -/- and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in Sert -/-. In obese Sert -/- animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese Sert -/- mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, Sert -/- mice fed a control diet did not display adipose tissue inflammation. Discussion Our observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.
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Affiliation(s)
- Johannes Hoch
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Niklas Burkhard
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Shanshan Zhang
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Marina Rieder
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Translational Cardiology, Department of Cardiology, Inselspital, Bern, Switzerland
| | - Timoteo Marchini
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Vincent Geest
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Krystin Krauel
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Timm Zahn
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nicolas Schommer
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Muataz Ali Hamad
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Carolina Bauer
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nadine Gauchel
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Daniela Stallmann
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Claus Normann
- Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dennis Wolf
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rüdiger Eberhard Scharf
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
- Division of Experimental and Clinical Hemostasis, Hemotherapy, and Transfusion Medicine, Blood and Hemophilia Comprehensive Care Center, Institute of Transplantation Diagnostics and Cell Therapy, Heinrich Heine University Medical Center, Düsseldorf, Germany
| | - Daniel Duerschmied
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) Partner Site Heidelberg/Mannheim, Mannheim, Germany
| | - Nancy Schanze
- Cardiology and Angiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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Musso G, Saba F, Cassader M, Gambino R. Lipidomics in pathogenesis, progression and treatment of nonalcoholic steatohepatitis (NASH): Recent advances. Prog Lipid Res 2023; 91:101238. [PMID: 37244504 DOI: 10.1016/j.plipres.2023.101238] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/20/2023] [Accepted: 05/21/2023] [Indexed: 05/29/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting up to 30% of the general adult population. NAFLD encompasses a histological spectrum ranging from pure steatosis to non-alcoholic steatohepatitis (NASH). NASH can progress to cirrhosis and is becoming the most common indication for liver transplantation, as a result of increasing disease prevalence and of the absence of approved treatments. Lipidomic readouts of liver blood and urine samples from experimental models and from NASH patients disclosed an abnormal lipid composition and metabolism. Collectively, these changes impair organelle function and promote cell damage, necro-inflammation and fibrosis, a condition termed lipotoxicity. We will discuss the lipid species and metabolic pathways leading to NASH development and progression to cirrhosis, as well as and those species that can contribute to inflammation resolution and fibrosis regression. We will also focus on emerging lipid-based therapeutic opportunities, including specialized proresolving lipid molecules and macrovesicles contributing to cell-to-cell communication and NASH pathophysiology.
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Affiliation(s)
- Giovanni Musso
- Dept of Emergency Medicine, San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy.
| | - Francesca Saba
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Maurizio Cassader
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - Roberto Gambino
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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14
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Wang W, Liang M, Wang L, Bei W, Guo J. 15-Hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates hepatic abnormal lipid metabolism, ER stress, and inflammation through PGE 2/EP4 in T2DM mice. Bioorg Chem 2023; 137:106646. [PMID: 37285764 DOI: 10.1016/j.bioorg.2023.106646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/13/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a rapidly growing epidemic that results in increased morbidity, mortality, and soaring medical costs. Prostaglandin E2 (PGE2), a vital lipid mediator, has been reported to protect against hepatic steatosis, inflammation, endoplasmic reticulum (ER) stress, and insulin resistance, indicating its potential therapeutic role in T2DM. PGE2 can be degraded by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). SW033291, an inhibitor of 15-PGDH, has been reported to increase PGE2 levels, however, the effect of SW033291 in T2DM remains to be explored. This study aims to evaluate whether SW033291 protects against T2DM and explore its potential mechanisms. A T2DM mouse model was established through high-fat diet/streptozotocin injection, while palmitic acid-treated mouse primary hepatocytes were used as insulin-resistant cell models. SW033291 treatment reduced body weight, fat weight, fasting blood glucose, and improved impaired glucose tolerance and insulin resistance in T2DM mice. More importantly, SW033291 alleviated steatosis, inflammation, and ER stress in the liver of T2DM mice. Mechanistically, SW033291 decreased the expressions of SREBP-1c and ACC1, and increased the expression of PPARα in T2DM mice. Additionally, SW033291 inhibited NF-κB and eIF2α/CHOP signaling in T2DM mice. Further, we showed that the protective effects of SW033291 on the above-mentioned pathophysiological processes could be hindered by inhibition of the PGE2 receptor EP4. Overall, our study reveals a novel role of SW033291 in alleviating T2DM and suggests its potential as a new therapeutic strategy for T2DM.
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Affiliation(s)
- Weixuan Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Mingjie Liang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Lexun Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Weijian Bei
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Jiao Guo
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China.
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15
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Wang L, Zhang K, Zeng Y, Luo Y, Peng J, Zhang J, Kuang T, Fan G. Gut mycobiome and metabolic diseases: The known, the unknown, and the future. Pharmacol Res 2023; 193:106807. [PMID: 37244385 DOI: 10.1016/j.phrs.2023.106807] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023]
Abstract
Metabolic diseases, such as type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD) and obesity, have become a major public health problem worldwide. In recent years, most research on the role of gut microbes in metabolic diseases has focused on bacteria, whereas fungal microbes have been neglected. This review aims to provide a comprehensive overview of gut fungal alterations in T2DM, obesity, and NAFLD, and to discuss the mechanisms associated with disease development. In addition, several novel strategies targeting gut mycobiome and/or their metabolites to improve T2DM, obesity and NAFLD, including fungal probiotics, antifungal drugs, dietary intervention, and fecal microbiota transplantation, are critically discussed. The accumulated evidence suggests that gut mycobiome plays an important role in the occurrence and development of metabolic diseases. The possible mechanisms by which the gut mycobiome affects metabolic diseases include fungal-induced immune responses, fungal-bacterial interactions, and fungal-derived metabolites. Candida albicans, Aspergillus and Meyerozyma may be potential pathogens of metabolic diseases because they can activate the immune system and/or produce harmful metabolites. Moreover, Saccharomyces boulardii, S. cerevisiae, Alternaria, and Cochliobolus fungi may have the potential to improve metabolic diseases. The information may provide an important reference for the development of new therapeutics for metabolic diseases based on gut mycobiome.
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Affiliation(s)
- Lijie Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Kun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yujiao Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuting Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jiayan Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jing Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tingting Kuang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Gang Fan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy and School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan, 620010, China.
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16
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Liang M, Wang L, Wang W. The 15-hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates abnormal hepatic glucose metabolism through PGE 2-EP4 receptor-AKT signaling in a type 2 diabetes mellitus mouse model. Cell Signal 2023; 108:110707. [PMID: 37164143 DOI: 10.1016/j.cellsig.2023.110707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/21/2023] [Accepted: 05/03/2023] [Indexed: 05/12/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with high rates of morbidity and mortality worldwide. Prostaglandin E2 (PGE2) is a lipid signaling molecule that can ameliorate the symptoms of some metabolic diseases, including T2DM, and improve tissue repair and regeneration. Although SW033291 can increase PGE2 levels through its action as a small molecule inhibitor of the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase, its effects on T2DM remain unclear. In the present study, we evaluated whether SW033291 treatment exerts a protective effect against T2DM and explored the underlying mechanisms. A T2DM mouse model was established using a high-fat diet combined with streptozotocin treatment. Palmitic acid-treated LO2 cells were used as an insulin-resistant cell model. SW033291 treatment reduced body weight and fasting blood glucose levels as well as serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels in vivo. In addition to ameliorating glucose and insulin tolerance, SW033291 treatment reversed the T2DM-induced decrease in glycogen synthesis and increase in gluconeogenesis in the liver. Furthermore, SW033291 administration increased hepatic glycogen synthase kinase 3 beta (GSK3β) phosphorylation levels to promote glycogen synthesis. SW033291 treatment also inhibited gluconeogenesis by upregulating AKT serine/threonine kinase (AKT) and forkhead box O1 (FOXO1) phosphorylation and reducing glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 expression in the livers of T2DM model mice. Additionally, SW033291 treatment improved abnormal hepatic glucose metabolism through the PGE2-EP4 receptor-AKT-GSK3β/FOXO1 signaling pathway in vitro. These results suggest a novel role of SW033291 in improving T2DM and support its potential as a novel therapeutic agent.
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Affiliation(s)
- Mingjie Liang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Lexun Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Weixuan Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China; Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangzhou, Guangdong Province, China; Key Laboratory of Glucolipid Metabolic Diseases, Ministry of Education, Guangzhou, Guangdong Province, China; Guangdong Provincial TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China.
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17
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Kotsos D, Tziomalos K. Microsomal Prostaglandin E Synthase-1 and -2: Emerging Targets in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:3049. [PMID: 36769370 PMCID: PMC9918023 DOI: 10.3390/ijms24033049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects a substantial proportion of the general population and is even more prevalent in obese and diabetic patients. NAFLD, and particularly the more advanced manifestation of the disease, nonalcoholic steatohepatitis (NASH), increases the risk for both liver-related and cardiovascular morbidity. The pathogenesis of NAFLD is complex and multifactorial, with many molecular pathways implicated. Emerging data suggest that microsomal prostaglandin E synthase-1 and -2 might participate in the development and progression of NAFLD. It also appears that targeting these enzymes might represent a novel therapeutic approach for NAFLD. In the present review, we discuss the association between microsomal prostaglandin E synthase-1 and -2 and NAFLD.
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Affiliation(s)
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
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18
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Petri BJ, Piell KM, Wahlang B, Head KZ, Andreeva K, Rouchka EC, Cave MC, Klinge CM. Polychlorinated biphenyls alter hepatic m6A mRNA methylation in a mouse model of environmental liver disease. ENVIRONMENTAL RESEARCH 2023; 216:114686. [PMID: 36341798 PMCID: PMC10120843 DOI: 10.1016/j.envres.2022.114686] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/30/2022] [Accepted: 10/25/2022] [Indexed: 05/21/2023]
Abstract
Exposure to polychlorinated biphenyls (PCBs) has been associated with liver injury in human cohorts and with nonalcoholic steatohepatitis (NASH) in mice fed a high fat diet (HFD). N (6)-methyladenosine (m6A) modification of mRNA regulates transcript fate, but the contribution of m6A modification on the regulation of transcripts in PCB-induced steatosis and fibrosis is unknown. This study tested the hypothesis that PCB and HFD exposure alters the levels of m6A modification in transcripts that play a role in NASH in vivo. Male C57Bl6/J mice were fed a HFD (12 wks) and administered a single oral dose of Aroclor1260, PCB126, or Aroclor1260 + PCB126. Genome-wide identification of m6A peaks was accomplished by m6A mRNA immunoprecipitation sequencing (m6A-RIP) and the mRNA transcriptome identified by RNA-seq. Exposure of HFD-fed mice to Aroclor1260 decreased the number of m6A peaks and m6A-containing genes relative to PCB vehicle control whereas PCB126 or the combination of Aroclor1260 + PCB126 increased m6A modification frequency. ∼41% of genes had one m6A peak and ∼49% had 2-4 m6A peaks. 117 m6A peaks were common in the four experimental groups. The Aroclor1260 + PCB126 exposure group showed the highest number (52) of m6A-peaks. qRT-PCR confirmed enrichment of m6A-containing fragments of the Apob transcript with PCB exposure. A1cf transcript abundance, m6A peak count, and protein abundance was increased with Aroclor1260 + PCB126 co-exposure. Irrespective of the PCB type, all PCB groups exhibited enriched pathways related to lipid/lipoprotein metabolism and inflammation through the m6A modification. Integrated analysis of m6A-RIP-seq and mRNA-seq identified 242 differentially expressed genes (DEGs) with increased or reduced number of m6A peaks. These data show that PCB exposure in HFD-fed mice alters the m6A landscape offering an additional layer of regulation of gene expression affecting a subset of gene responses in NASH.
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Affiliation(s)
- Belinda J Petri
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Kellianne M Piell
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA
| | - Banrida Wahlang
- University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA; University of Louisville Hepatobiology and Toxicology Center, USA; The University of Louisville Superfund Research Center, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Kimberly Z Head
- University of Louisville Hepatobiology and Toxicology Center, USA
| | - Kalina Andreeva
- KY INBRE Bioinformatics Core, University of Louisville, USA; Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Eric C Rouchka
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA; KY INBRE Bioinformatics Core, University of Louisville, USA
| | - Matthew C Cave
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA; Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, USA
| | - Carolyn M Klinge
- Department of Biochemistry & Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, 40292, USA; University of Louisville Center for Integrative Environmental Health Sciences (CIEHS), USA.
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Ishizawa S, Nishi A, Kaifuchi N, Shimobori C, Nahata M, Yamada C, Iizuka S, Ohbuchi K, Nishiyama M, Fujitsuka N, Kono T, Yamamoto M. Integrated analysis of effect of daisaikoto, a traditional Japanese medicine, on the metabolome and gut microbiome in a mouse model of nonalcoholic fatty liver disease. Gene X 2022; 846:146856. [PMID: 36067864 DOI: 10.1016/j.gene.2022.146856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/04/2022] Open
Abstract
Dysregulation of lipid metabolism and diabetes are risk factors for nonalcoholic fatty liver disease (NAFLD), and the gut-liver axis and intestinal microbiome are known to be highly associated with the pathogenesis of this disease. In Japan, the traditional medicine daisaikoto (DST) is prescribed for individuals affected by hepatic dysfunction. Herein, we evaluated the therapeutic potential of DST for treating NAFLD through modification of the liver and stool metabolome and microbiome by using STAM mice as a model of NAFLD. STAM mice were fed a high-fat diet with or without 3 % DST for 3 weeks. Plasma and liver of STAM, STAM with DST, and C57BL/6J ("Normal") mice were collected at 9 weeks, and stools at 4, 6, and 9 weeks of age. The liver pathology, metabolome and stool microbiome were analyzed. DST ameliorated the NAFLD activity score of STAM mice and decreased the levels of several liver lipid mediators such as arachidonic acid and its derivatives. In normal mice, nine kinds of family accounted for 94.1 % of microbiome composition; the total percentage of these family was significantly decreased in STAM mice (45.6 %), and DST administration improved this imbalance in microbiome composition (65.2 %). In stool samples, DST increased ursodeoxycholic acid content and altered several amino acids, which were correlated with changes in the gut microbiome and liver metabolites. In summary, DST ameliorates NAFLD by decreasing arachidonic acid metabolism in the liver; this amelioration seems to be associated with crosstalk among components of the liver, intestinal environment, and microbiome.
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Affiliation(s)
- Shiori Ishizawa
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Akinori Nishi
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan.
| | - Noriko Kaifuchi
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Chika Shimobori
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Miwa Nahata
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Chihiro Yamada
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Seiichi Iizuka
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Katsuya Ohbuchi
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Mitsue Nishiyama
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Naoki Fujitsuka
- Tsumura Kampo Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
| | - Toru Kono
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido 060-8638, Japan; Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido 065-0033, Japan
| | - Masahiro Yamamoto
- Tsumura Advanced Technology Research Laboratories, Tsumura & Co., Ami, Ibaraki 300-1192, Japan
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Civelek E, Ozen G. The biological actions of prostanoids in adipose tissue in physiological and pathophysiological conditions. Prostaglandins Leukot Essent Fatty Acids 2022; 186:102508. [PMID: 36270150 DOI: 10.1016/j.plefa.2022.102508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 07/29/2022] [Accepted: 10/06/2022] [Indexed: 12/29/2022]
Abstract
Adipose tissue has been established as an endocrine organ that plays an important role in maintaining metabolic homeostasis. Adipose tissue releases several bioactive molecules called adipokines. Inflammation, dysregulation of adipokine synthesis, and secretion are observed in obesity and related diseases and cause adipose tissue dysfunction. Prostanoids, belonging to the eicosanoid family of lipid mediators, can be synthesized in adipose tissue and play a critical role in adipose tissue biology. In this review, we summarized the current knowledge regarding the interaction of prostanoids with adipokines, the expression of prostanoid receptors, and prostanoid synthase enzymes in adipose tissues in health and disease. Furthermore, the involvement of prostanoids in the physiological function or dysfunction of adipose tissue including inflammation, lipolysis, adipogenesis, thermogenesis, browning of adipocytes, and vascular tone regulation was also discussed by examining studies using pharmacological approaches or genetically modified animals for prostanoid receptors/synthase enzymes. Overall, the present review provides a perspective on the evidence from literature regarding the biological effects of prostanoids in adipose tissue. Among prostanoids, prostaglandin E2 (PGE2) is prominent in regards to its substantial role in both adipose tissue physiology and pathophysiology. Targeting prostanoids may serve as a potential therapeutic strategy for preventing or treating obesity and related diseases.
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Affiliation(s)
- Erkan Civelek
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Gulsev Ozen
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey.
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21
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Maciejewska-Markiewicz D, Drozd A, Palma J, Ryterska K, Hawryłkowicz V, Załęska P, Wunsh E, Kozłowska-Petriczko K, Stachowska E. Fatty Acids and Eicosanoids Change during High-Fiber Diet in NAFLD Patients-Randomized Control Trials (RCT). Nutrients 2022; 14:nu14204310. [PMID: 36296994 PMCID: PMC9608825 DOI: 10.3390/nu14204310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/08/2022] [Accepted: 10/12/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a wide spectrum condition characterized by excessive liver fat accumulation in people who do not abuse alcohol. There is no effective medical treatment for NAFLD; therefore, most important recommendations to reduce liver steatosis are diet and lifestyle, including proper physical activity. The aim of our study was to analyze the fatty acids and eicosanoids changes in the serum of patients who consumed high-fiber rolls for 8 weeks. MATERIALS AND METHODS The group of 28 Caucasian participants was randomly divided into two groups, those who received 24 g of fiber/day-from 2 buns of 12 g each (n = 14), and those who received 12 g of fiber/day-from 2 buns of 6 g (n = 14). At the beginning and on the last visit of the 8-week intervention, all patients underwent NAFLD evaluation, biochemical parameter measurements, and fatty acids and eicosanoids evaluation. RESULTS Patients who received 12 g of fiber had significantly reduced liver steatosis and body mass index. In the group who received 24 g of fiber/day, we observed a trend to liver steatosis reduction (p = 0.07) and significant decrease in aspartate aminotransferase (p = 0.03) and total cholesterol (p = 0.03). All changes in fatty acid and eicosanoids profile were similar. Fatty acids analysis revealed that extra fiber intake was associated with a significant increase in monounsaturated fatty acids and decrease in saturated fatty acids. Moreover, both groups showed increased concentration of gamma linoleic acid and docosahexaenoic acid. We also observed reduction in prostaglandin E2. CONCLUSIONS Our study revealed that a high amount of fiber in the diet is associated with a reduction in fatty liver, although this effect was more pronounced in patients in the lower fiber group. However, regardless of the amount of fiber consumed, we observed significant changes in the profile of FAs, which may reflect the positive changes in the lipids liver metabolism. Regardless of the amount of fiber consumed, patients decreased the amount of PGE2, which may indicate the lack of disease progression associated with the development of inflammation.
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Affiliation(s)
- Dominika Maciejewska-Markiewicz
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
| | - Arleta Drozd
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
- Correspondence: (A.D.); (J.P.)
| | - Joanna Palma
- Department of Biochemical Science, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
- Correspondence: (A.D.); (J.P.)
| | - Karina Ryterska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
| | - Viktoria Hawryłkowicz
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
| | - Patrycja Załęska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
| | - Ewa Wunsh
- Translational Medicine Group, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland
| | | | - Ewa Stachowska
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, Broniewskiego 24, 71-460 Szczecin, Poland
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22
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Fekry B, Ribas-Latre A, Drunen RV, Santos RB, Shivshankar S, Dai Y, Zhao Z, Yoo SH, Chen Z, Sun K, Sladek FM, Younes M, Eckel-Mahan K. Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis. FASEB J 2022; 36:e22482. [PMID: 35947136 PMCID: PMC10062014 DOI: 10.1096/fj.202101398r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 07/06/2022] [Accepted: 07/21/2022] [Indexed: 11/11/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.
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Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Rachel Van Drunen
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Rafael Bravo Santos
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Samay Shivshankar
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Yulin Dai
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.,Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, USA
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Zheng Chen
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Kai Sun
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, California, USA
| | - Mamoun Younes
- Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center, Houston, Texas, USA
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23
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Tian J, Du Y, Yu E, Lei C, Xia Y, Jiang P, Li H, Zhang K, Li Z, Gong W, Xie J, Wang G. Prostaglandin 2α Promotes Autophagy and Mitochondrial Energy Production in Fish Hepatocytes. Cells 2022; 11:1870. [PMID: 35740999 PMCID: PMC9220818 DOI: 10.3390/cells11121870] [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: 04/19/2022] [Revised: 05/23/2022] [Accepted: 06/02/2022] [Indexed: 12/10/2022] Open
Abstract
Fatty liver, characterized by excessive lipid droplet (LD) accumulation in hepatocytes, is a common physiological condition in humans and aquaculture species. Lipid mobilization is an important strategy for modulating the number and size of cellular LDs. Cyclooxygenase (COX)-mediated arachidonic acid derivatives are known to improve lipid catabolism in fish; however, the specific derivatives remain unknown. In the present study, we showed that serum starvation induced LD degradation via autophagy, lipolysis, and mitochondrial energy production in zebrafish hepatocytes, accompanied by activation of the COX pathway. The cellular concentration of PGF2α, but not other prostaglandins, was significantly increased. Administration of a COX inhibitor or interference with PGF2α synthase abolished serum deprivation-induced LD suppression, LD-lysosome colocalization, and expression of autophagic genes. Additionally, exogenous PGF2α suppressed the accumulation of LDs, promoted the accumulation of lysosomes with LD and the autophagy marker protein LC3A/B, and augmented the expression of autophagic genes. Moreover, PGF2α enhanced mitochondrial accumulation and ATP production, and increased the transcript levels of β-oxidation- and mitochondrial respiratory chain-related genes. Collectively, these findings demonstrate that the COX pathway is implicated in lipid degradation induced by energy deprivation, and that PGF2α is a key molecule triggering autophagy, lipolysis, and mitochondrial development in zebrafish hepatocytes.
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Affiliation(s)
- Jingjing Tian
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Yihui Du
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Ermeng Yu
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Caixia Lei
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Yun Xia
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Peng Jiang
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Hongyan Li
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Kai Zhang
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Zhifei Li
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Wangbao Gong
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Jun Xie
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
| | - Guangjun Wang
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China; (J.T.); (Y.D.); (E.Y.); (C.L.); (Y.X.); (P.J.); (H.L.); (K.Z.); (Z.L.); (W.G.)
- Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China
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Yin H, Shi A, Wu J. Platelet-Activating Factor Promotes the Development of Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2022; 15:2003-2030. [PMID: 35837578 PMCID: PMC9275506 DOI: 10.2147/dmso.s367483] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted clinicopathological syndrome characterised by excessive hepatic lipid accumulation that causes steatosis, excluding alcoholic factors. Platelet-activating factor (PAF), a biologically active lipid transmitter, induces platelet activation upon binding to the PAF receptor. Recent studies have found that PAF is associated with gamma-glutamyl transferase, which is an indicator of liver disease. Moreover, PAF can stimulate hepatic lipid synthesis and cause hypertriglyceridaemia. Furthermore, the knockdown of the PAF receptor gene in the animal models of NAFLD helped reduce the inflammatory response, improve glucose homeostasis and delay the development of NAFLD. These findings suggest that PAF is associated with NAFLD development. According to reports, patients with NAFLD or animal models have marked platelet activation abnormalities, mainly manifested as enhanced platelet adhesion and aggregation and altered blood rheology. Pharmacological interventions were accompanied by remission of abnormal platelet activation and significant improvement in liver function and lipids in the animal model of NAFLD. These confirm that platelet activation may accompany a critical importance in NAFLD development and progression. However, how PAFs are involved in the NAFLD signalling pathway needs further investigation. In this paper, we review the relevant literature in recent years and discuss the role played by PAF in NAFLD development. It is important to elucidate the pathogenesis of NAFLD and to find effective interventions for treatment.
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Affiliation(s)
- Hang Yin
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
| | - Anhua Shi
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
| | - Junzi Wu
- Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China
- Correspondence: Junzi Wu; Anhua Shi, Key Laboratory of Microcosmic Syndrome Differentiation, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China, Tel/Fax +86 187 8855 7524; +86 138 8885 0813, Email ;
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25
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Callegari IOM, Oliveira AG. The Role of LTB4 in Obesity-Induced Insulin Resistance Development: An Overview. Front Endocrinol (Lausanne) 2022; 13:848006. [PMID: 35392132 PMCID: PMC8981522 DOI: 10.3389/fendo.2022.848006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 03/01/2022] [Indexed: 01/10/2023] Open
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26
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Ayyash A, Holloway AC. Fluoxetine-induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15-deoxy-Δ 12,14 PGJ 2. J Appl Toxicol 2021; 42:1004-1015. [PMID: 34897744 DOI: 10.1002/jat.4272] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/17/2021] [Indexed: 12/11/2022]
Abstract
Major depressive disorder and other neuropsychiatric disorders are often managed with long-term use of antidepressant medication. Fluoxetine, an SSRI antidepressant, is widely used as a first-line treatment for neuropsychiatric disorders. However, fluoxetine has also been shown to increase the risk of metabolic diseases such as non-alcoholic fatty liver disease. Fluoxetine has been shown to increase hepatic lipid accumulation in vivo and in vitro. In addition, fluoxetine has been shown to alter the production of prostaglandins which have also been implicated in the development of non-alcoholic fatty liver disease. The goal of this study was to assess the effect of fluoxetine exposure on the prostaglandin biosynthetic pathway and lipid accumulation in a hepatic cell line (H4-II-E-C3 cells). Fluoxetine treatment increased mRNA expression of prostaglandin biosynthetic enzymes (Ptgs1, Ptgs2, and Ptgds), PPAR gamma (Pparg), and PPAR gamma downstream targets involved in fatty acid uptake (Cd36, Fatp2, and Fatp5) as well as production of 15-deoxy-Δ12,14 PGJ2 a PPAR gamma ligand. The effects of fluoxetine to induce lipid accumulation were attenuated with a PTGS1 specific inhibitor (SC-560), whereas inhibition of PTGS2 had no effect. Moreover, SC-560 attenuated 15-deoxy-Δ12,14 PGJ2 production and expression of PPAR gamma downstream target genes. Taken together these results suggest that fluoxetine-induced lipid abnormalities appear to be mediated via PTGS1 and its downstream product 15d-PGJ2 and suggest a novel therapeutic target to prevent some of the adverse effects of fluoxetine treatment.
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Affiliation(s)
- Ahmed Ayyash
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Alison C Holloway
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
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27
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Camacho-Muñoz D, Kiezel-Tsugunova M, Kiss O, Uddin M, Sundén M, Ryaboshapkina M, Lind L, Oscarsson J, Nicolaou A. Omega-3 carboxylic acids and fenofibrate differentially alter plasma lipid mediators in patients with non-alcoholic fatty liver disease. FASEB J 2021; 35:e21976. [PMID: 34618982 DOI: 10.1096/fj.202100380rrr] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 09/17/2021] [Accepted: 09/21/2021] [Indexed: 12/23/2022]
Abstract
Fibrates and omega-3 polyunsaturated acids are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study, we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid-lowering agents. Plasma from overweight patients with non-alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, participating in a randomized placebo-controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega-3 free carboxylic acids (OM-3CA) (200 mg or 4 g per day, respectively), were analyzed for eicosanoids and related PUFA species, N-acylethanolamines (NAE) and ceramides. OM-3CA reduced plasma concentrations of proinflammatory PGE2 , as well as PGE1 , PGD1 and thromboxane B2 but increased prostacyclin, and eicosapentaenoic acid- and docosahexaenoic acid-derived lipids of lipoxygenase and cytochrome P450 monooxygenase (CYP) (e.g., 17-HDHA, 18-HEPE, 19,20-DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP-derived eicosanoids (DHETs). Although OM-3CA increased plasma levels of the NAE docosahexaenoyl ethanolamine and docosapentaenoyl ethanolamine, and fenofibrate increased palmitoleoyl ethanolamine, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM-3CA in significantly reducing plasma ceramides, pro-inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM-3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM-3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction.
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Affiliation(s)
- Dolores Camacho-Muñoz
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Magdalena Kiezel-Tsugunova
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Orsolya Kiss
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Mohib Uddin
- AstraZeneca Gothenburg, Biopharmaceuticals R&D, Mӧlndal, Sweden
| | - Mattias Sundén
- Department of Economics, University of Gothenburg, Gothenburg, Sweden
| | | | - Lars Lind
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Jan Oscarsson
- AstraZeneca Gothenburg, Biopharmaceuticals R&D, Mӧlndal, Sweden
| | - Anna Nicolaou
- Laboratory for Lipidomics and Lipid Biology, Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.,Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
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28
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Xu D, Cai J, Wan ZK, Gao H, Sun Y. Pathophysiological role of prostaglandin E synthases in liver diseases. Prostaglandins Other Lipid Mediat 2021; 154:106552. [PMID: 33930567 DOI: 10.1016/j.prostaglandins.2021.106552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 04/11/2021] [Accepted: 04/23/2021] [Indexed: 12/20/2022]
Abstract
Prostaglandin E synthases (PGESs) convert cyclooxygenase (COX)-derived prostaglandin H2 (PGH2) into prostaglandin E2 (PGE2) and comprise at least three types of structurally and biologically distinct enzymes. Two of these, namely microsomal prostaglandin E synthase-1 (mPGES-1) and mPGES-2, are membrane-bound enzymes. mPGES-1 is an inflammation-inducible enzyme that converts PGH2 into PGE2. mPGES-2 is a bifunctional enzyme that generally forms a complex with haem in the presence of glutathione. This enzyme can metabolise PGH2 into malondialdehyde and can produce PGE2 after its separation from haem. In this review, we discuss the role of PGESs, particularly mPGES-1 and mPGES-2, in the pathogenesis of liver diseases. A better understanding of the roles of PGESs in liver disease may aid in the development of treatments for patients with liver diseases.
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Affiliation(s)
- Delong Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Jie Cai
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Zhi-Kang Wan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Hang Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Ying Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China.
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29
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Wang W, Zhong X, Guo J. Role of 2‑series prostaglandins in the pathogenesis of type 2 diabetes mellitus and non‑alcoholic fatty liver disease (Review). Int J Mol Med 2021; 47:114. [PMID: 33907839 PMCID: PMC8083810 DOI: 10.3892/ijmm.2021.4947] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
Nowadays, metabolic syndromes are emerging as global epidemics, whose incidence are increasing annually. However, the efficacy of therapy does not increase proportionately with the increased morbidity. Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are two common metabolic syndromes that are closely associated. The pathogenic mechanisms of T2DM and NAFLD have been studied, and it was revealed that insulin resistance, hyperglycemia, hepatic lipid accumulation and inflammation markedly contribute to the development of these two diseases. The 2-series prostaglandins (PGs), a subgroup of eicosanoids, including PGD2, PGE2, PGF2α and PGI2, are converted from arachidonic acid catalyzed by the rate-limiting enzymes cyclooxygenases (COXs). Considering their wide distribution in almost every tissue, 2-series PG pathways exert complex and interlinked effects in mediating pancreatic β-cell function and proliferation, insulin sensitivity, fat accumulation and lipolysis, as well as inflammatory processes. Previous studies have revealed that metabolic disturbances, such as hyperglycemia and hyperlipidemia, can be improved by treatment with COX inhibitors. At present, an accumulating number of studies have focused on the roles of 2-series PGs and their metabolites in the pathogenesis of metabolic syndromes, particularly T2DM and NAFLD. In the present review, the role of 2-series PGs in the highly intertwined pathogenic mechanisms of T2DM and NAFLD was discussed, and important therapeutic strategies based on targeting 2-series PG pathways in T2DM and NAFLD treatment were provided.
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Affiliation(s)
- Weixuan Wang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
| | - Xin Zhong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, P.R. China
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30
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Aliabadi F, Ajami M, Pazoki–Toroudi H. Why does COVID‐19 pathology have several clinical forms? Bioessays 2020; 42:e2000198. [DOI: 10.1002/bies.202000198] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Fatemeh Aliabadi
- Physiology Research Center, Department of Medicine Iran University of Medical Sciences Tehran Iran
| | - Marjan Ajami
- Department of Food and Nutrition Policy and Planning Research, National Nutrition and Food Technology Research Institute Shahid Beheshti University of Medical Sciences Tehran Iran
| | - Hamidreza Pazoki–Toroudi
- Physiology Research Center, Department of Medicine Iran University of Medical Sciences Tehran Iran
- Department of Physiology, Department of Medicine Iran University of Medical Sciences Tehran Iran
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31
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Wu J, Wang Y, Zhou Y, Wang Y, Sun X, Zhao Y, Guan Y, Zhang Y, Wang W. PPARγ as an E3 Ubiquitin-Ligase Impedes Phosphate-Stat6 Stability and Promotes Prostaglandins E 2-Mediated Inhibition of IgE Production in Asthma. Front Immunol 2020; 11:1224. [PMID: 32636842 PMCID: PMC7317005 DOI: 10.3389/fimmu.2020.01224] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/15/2020] [Indexed: 12/18/2022] Open
Abstract
Increased serum IgE level is one of the features of allergic asthma. It is reported that IgE production can be enhanced by E-prostanoid 2 (EP2) receptor of prostaglandin E2 (PGE2); however, whether E-prostanoid 4 (EP4) receptor (encoded by Ptger4) has a unique or redundant role is still unclear. Here, we demonstrated the mice with B cell-specific deletion of the EP4 receptor (Ptger4fl/flMb1cre+/−) showed their serum levels of IgE were markedly increased. A much more severe airway allergic inflammation was observed in the absence of EP4 signal using the OVA-induced asthma model. Mechanistic studies demonstrated that the transcription levels of AID, GLTε, and PSTε in EP4-deficient B cells were found to be significantly increased, implying an enhanced IgE class switch. In addition, we saw higher levels of phosphorylated STAT6, a vital factor for IgE class switch. Biochemical analyses indicated that inhibitory effect of EP4 signal on IgE depended on the activation of the PI3K-AKT pathway. Further downstream, PPARγ expression was up-regulated. Independent of its activity as a transcription factor, PPARγ here primarily functioned as an E3 ubiquitin-ligase, which bound the phosphorylated STAT6 to initiate its degradation. In support of PPARγ as a key mediator downstream of the EP4 signal, PPARγ agonist induced the down-regulation of phospho-STAT6, whereas its antagonist was able to rescue the EP4-mediated inhibition of STAT6 activation and IgE production. Thus, our findings highlight a role for the PGE2-EP4-AKT-PPARγ-STAT6 signaling in IgE response, highlighting the therapeutic potential of combined application of EP4 and PPARγ agonists in asthma.
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Affiliation(s)
- Jia Wu
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yu Zhou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuqing Wang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Xiaowan Sun
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Ye Zhao
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Yu Zhang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China.,Institute of Biological Sciences, Jinzhou Medical University, Jinzhou, China
| | - Wei Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
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32
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Henkel J, Coleman CD, Schraplau A, Jöhrens K, Weiss TS, Jonas W, Schürmann A, Püschel GP. Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model. Sci Rep 2018; 8:16127. [PMID: 30382148 PMCID: PMC6208405 DOI: 10.1038/s41598-018-34633-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022] Open
Abstract
In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E2 (PGE2), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE2 synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE2 concentration that was completely abrogated in mPGES-1-deficient mice. PGE2 is known to inhibit TNF-α synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-α expression. Due to the impaired PGE2 production, TNF-α expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-α resulted in an enhanced IL-1β production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE2 production by mPGES-1 ablation enhanced the TNF-α-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.
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Affiliation(s)
- Janin Henkel
- University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal, Germany.
| | - Charles Dominic Coleman
- University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal, Germany
| | - Anne Schraplau
- University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal, Germany
| | - Korinna Jöhrens
- Charité University Hospital Berlin, Institute of Pathology, Berlin, Germany
| | - Thomas Siegfried Weiss
- University Hospital Regensburg, University Children Hospital (KUNO) Regensburg, Regensburg, Germany
| | - Wenke Jonas
- German Institute of Human Nutrition, Department of Experimental Diabetology, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Annette Schürmann
- German Institute of Human Nutrition, Department of Experimental Diabetology, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Gerhard Paul Püschel
- University of Potsdam, Institute of Nutritional Science, Department of Nutritional Biochemistry, Nuthetal, Germany
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33
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Periodontitis causes abnormalities in the liver of rats. J Periodontol 2018; 90:295-305. [DOI: 10.1002/jper.18-0226] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/14/2018] [Accepted: 06/20/2018] [Indexed: 12/16/2022]
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34
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Pierre C, Guillebaud F, Airault C, Baril N, Barbouche R, Save E, Gaigé S, Bariohay B, Dallaporta M, Troadec JD. Invalidation of Microsomal Prostaglandin E Synthase-1 (mPGES-1) Reduces Diet-Induced Low-Grade Inflammation and Adiposity. Front Physiol 2018; 9:1358. [PMID: 30333759 PMCID: PMC6176076 DOI: 10.3389/fphys.2018.01358] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 09/07/2018] [Indexed: 01/04/2023] Open
Abstract
Chronic low-grade inflammation is known to be linked to obesity, and to occur in the early stages of the disease. This mechanism is complex and involves numerous organs, cells, and cytokines. In this context, inflammation of white adipose tissue seems to play a key role in the development of obesity. Because of its properties, prostaglandin E2 (PGE2), an emblematic inflammatory mediator, has been proposed as an actor linking inflammation and obesity. Indeed, PGE2 is involved in mechanisms that are dysregulated in obesity such as lipolysis and adipogenesis. Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which specifically catalyzes the final step of PGE2 biosynthesis. Interestingly, mPGES-1 invalidation dramatically alters the production of PGE2 during inflammation. In the present work, we sought to determine whether mPGES-1 could contribute to inflammation associated with obesity. To this end, we analyzed the energy metabolism of mPGES-1 deficient mice (mPGES-1-/-) and littermate controls, fed with a high-fat diet. Our data showed that mPGES-1-/- mice exhibited resistance to diet-induced obesity when compared to wild-type littermates. mPGES-1-/- mice fed with a high-fat diet, showed a lower body weight gain and a reduced adiposity, which were accompanied by a decrease in adipose tissues inflammation. We also observed an increase in energy expenditures in mPGES-1-/- mice fed with a high-fat diet without any changes in activity and browning process. Altogether, these data suggest that mPGES-1 inhibition may prevent diet-induced obesity.
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Affiliation(s)
- Clément Pierre
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France.,Biomeostasis CRO, La Penne-sur-Huveaune, France
| | - Florent Guillebaud
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
| | - Coraline Airault
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
| | - Nathalie Baril
- CNRS, Fédération de Recherche 3C FR 3512, Aix-Marseille Université, Marseille, France
| | - Rym Barbouche
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
| | - Etienne Save
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
| | - Stéphanie Gaigé
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
| | | | - Michel Dallaporta
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
| | - Jean-Denis Troadec
- Aix Marseille Université, CNRS, Laboratoire de Neurosciences Cognitives UMR 7291, Marseille, France
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35
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Application of a dye-based mitochondrion-thermometry to determine the receptor downstream of prostaglandin E 2 involved in the regulation of hepatocyte metabolism. Sci Rep 2018; 8:13065. [PMID: 30166566 PMCID: PMC6117307 DOI: 10.1038/s41598-018-31356-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 08/06/2018] [Indexed: 12/18/2022] Open
Abstract
Temperature distributions inside a living cell reflect the thermodynamics and functions of cellular components. We used a newly-developed method of mitochondrial thermometry based on Rhodamine B methyl ester, which equilibrates as a thermosensitive mixture of nonfluorescent and fluorescent resonance forms. Prostaglandin E2 (PGE2) is released from hepatic non-parenchymal Kupffer cells and acts as an inflammatory factor to impact various functions of hepatocytes. The activity of PGE2 on energy mechanism of hepatocytes has not been fully elucidated and in particular, which PGE2 receptor mediates the functions has been elusive. We identified EP4 as the major receptor of PGE2 via our mitochondrion-thermometry approach and then substantiated this receptor's role in hepatic metabolism. We discovered that PGE2 is able to decrease intracellular temperature of hepatocytes, via increasing some lipogenic genes' expressions, hampering lipolysis and mitochondrial β-oxidation, reducing intracellular ATP level and elevating cAMP level through EP4 receptor. The redox status of hepatocytes represented by FAD vs FAD + NADH ratio is influenced by PGE2 in an EP4 receptor-dependent manner. Collectively, these data demonstrate that PGE2 regulates metabolism of hepatocytes mainly through EP4 receptor.
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36
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Musso G, Cassader M, Paschetta E, Gambino R. Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. Gastroenterology 2018; 155:282-302.e8. [PMID: 29906416 DOI: 10.1053/j.gastro.2018.06.031] [Citation(s) in RCA: 236] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023]
Abstract
The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid species and metabolic pathways that contribute to the pathogenesis of NASH and potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids, and specialized pro-resolving lipid mediators. We discuss the concept that NASH is a disease that can resolve and the roles of lipid molecules in the resolution of inflammation and regression of fibrosis.
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Affiliation(s)
| | - Maurizio Cassader
- Department of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | | | - Roberto Gambino
- Department of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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37
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Araújo AC, Wheelock CE, Haeggström JZ. The Eicosanoids, Redox-Regulated Lipid Mediators in Immunometabolic Disorders. Antioxid Redox Signal 2018; 29:275-296. [PMID: 28978222 DOI: 10.1089/ars.2017.7332] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE The oxidation of arachidonic acid via cyclooxygenase (COX) and lipoxygenase (LOX) activity to produce eicosanoids during inflammation is a well-known biosynthetic pathway. These lipid mediators are involved in fever, pain, and thrombosis and are produced from multiple cells as well as cell/cell interactions, for example, immune cells and epithelial/endothelial cells. Metabolic disorders, including hyperlipidemia, hypertension, and diabetes, are linked with chronic low-grade inflammation, impacting the immune system and promoting a variety of chronic diseases. Recent Advances: Multiple studies have corroborated the important function of eicosanoids and their receptors in (non)-inflammatory cells in immunometabolic disorders (e.g., insulin resistance, obesity, and cardiovascular and nonalcoholic fatty liver diseases). In this context, LOX and COX products are involved in both pro- and anti-inflammatory responses. In addition, recent work has elucidated the potent function of specialized proresolving mediators (i.e., lipoxins and resolvins) in resolving inflammation, protecting organs, and stimulating tissue repair and remodeling. CRITICAL ISSUES Inhibiting/stimulating selected eicosanoid pathways may result in anti-inflammatory and proresolution responses leading to multiple beneficial effects, including the abrogation of reactive oxygen species production, increased speed of resolution, and overall improvement of diseases related to immunometabolic perturbations. FUTURE DIRECTIONS Despite many achievements, it is crucial to understand the molecular and cellular mechanisms underlying immunological/metabolic cross talk to offer substantial therapeutic promise. Antioxid. Redox Signal. 29, 275-296.
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Affiliation(s)
- Ana Carolina Araújo
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden
| | - Craig E Wheelock
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden
| | - Jesper Z Haeggström
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Stockholm, Sweden
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38
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Specialized Proresolving Mediators: Enhancing Nonalcoholic Steatohepatitis and Fibrosis Resolution. Trends Pharmacol Sci 2018; 39:387-401. [PMID: 29499974 DOI: 10.1016/j.tips.2018.01.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 01/06/2018] [Accepted: 01/09/2018] [Indexed: 12/13/2022]
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39
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de Castro GS, Calder PC. Non-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids. Clin Nutr 2018; 37:37-55. [DOI: 10.1016/j.clnu.2017.01.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 12/12/2016] [Accepted: 01/10/2017] [Indexed: 02/08/2023]
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40
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Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, Spalding D. Non-alcoholic fatty liver disease: A sign of systemic disease. Metabolism 2017; 72:94-108. [PMID: 28641788 DOI: 10.1016/j.metabol.2017.04.011] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 04/11/2017] [Accepted: 04/23/2017] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.
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Affiliation(s)
- Isabella Reccia
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Jayant Kumar
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Cherif Akladios
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Francesco Virdis
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Madhava Pai
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Nagy Habib
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
| | - Duncan Spalding
- Department of Surgery and Cancer Faculty of Medicine, Hammersmith Hospital, Imperial College London, UK.
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Tian JJ, Lei CX, Ji H, Jin A. Role of cyclooxygenase-mediated metabolites in lipid metabolism and expression of some immune-related genes in juvenile grass carp (Ctenopharyngodon idellus) fed arachidonic acid. FISH PHYSIOLOGY AND BIOCHEMISTRY 2017; 43:703-717. [PMID: 28012026 DOI: 10.1007/s10695-016-0326-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 12/11/2016] [Indexed: 06/06/2023]
Abstract
Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid (ARA) to prostaglandins, and COX-mediated metabolites play important roles in the regulation of lipid metabolism and immunity in mammals. However, such roles of COX in fish remain largely unknown. In this study, we designed three semi-purified diets, namely ARA-free (control), ARA, and ARA + acetylsalicylic acid (ASA; a COX inhibitor), and used them to feed grass carp (27.65 ± 3.05 g) for 8 weeks. The results showed that dietary ARA significantly increased the amount of ARA in the hepatopancreas, muscle, and kidney (P < 0.05), whereas this increase was reduced by dietary ASA. The hepatopancreatic prostaglandin E2 content increased in the ARA group, and this increase was inhibited by ASA (P < 0.05). ARA decreased the lipid content in the hepatopancreas, whereas ASA recovered lipid content to a significant level (P < 0.05). ARA significantly decreased the messenger RNA (mRNA) expression levels of fatty acid synthase and stearoyl-CoA desaturase in the hepatopancreas (P < 0.05). However, ASA did not rescue the mRNA expression of these genes (P > 0.05). Interestingly, ARA significantly enhanced the level of peroxisome proliferator-activated receptor α gene expression, and this increase was attenuated by ASA (P < 0.05). Finally, ARA significantly enhanced the mRNA expression of myeloid differentiation factor 88 (MyD88) in the kidney, and ASA attenuated the expression of toll-like receptor 22 and MyD88 (P < 0.05). In conclusion, our findings suggest that COX metabolites play important roles in the inhibition of lipid accumulation in the hepatopancreas of grass carp fed with ARA and that regulation of gene expression promotes lipid catabolism rather than lipogenic activities. Additionally, these eicosanoids might participate in the upregulation of immunity-related genes in the kidney.
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Affiliation(s)
- Jing-Jing Tian
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
| | - Cai-Xia Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
| | - Hong Ji
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China.
| | - Ai Jin
- College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, People's Republic of China
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42
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Martín-Sanz P, Casado M, Boscá L. Cyclooxygenase 2 in liver dysfunction and carcinogenesis: Facts and perspectives. World J Gastroenterol 2017; 23:3572-3580. [PMID: 28611510 PMCID: PMC5449414 DOI: 10.3748/wjg.v23.i20.3572] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 03/03/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
The biosynthesis of prostaglandins and thromboxanes has been a focus of interest in the management of many liver diseases. Cyclooxygenases are the enzymes involved in the first step of the biosynthesis of these lipid mediators and selective inhibitors for these isoenzymes as well as pharmacological analogues of prostaglandins have been developed and are currently applied therapeutically. Here we discuss the implications of these enzymes in the onset of metabolic and lipid disorders in the liver and their potential role in the progression of the diseases towards fibrosis and hepatocellular carcinogenesis.
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Henkel J, Coleman CD, Schraplau A, Jöhrens K, Weber D, Castro JP, Hugo M, Schulz TJ, Krämer S, Schürmann A, Püschel GP. Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol. Mol Med 2017; 23:70-82. [PMID: 28332698 PMCID: PMC5429885 DOI: 10.2119/molmed.2016.00203] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 03/15/2017] [Indexed: 12/27/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g. high-fat diets) or overweight and insulin resistance (e.g. methionine-choline-deficient diets) or they are based on monogenetic defects (e.g. ob/ob mice). In the current study, a western-type diet containing soybean oil with high n 6-PUFA and 0.75% cholesterol (SOD+Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast a soybean oil-containing western-type diet without cholesterol (SOD) induced only mild steatosis but neither hepatic inflammation nor fibrosis, weight gain or insulin resistance. Another high-fat diet mainly consisting of lard and supplemented with fructose in drinking water (LAD+Fru) resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD+Cho but livers were devoid of inflammation and fibrosis. Although both LAD+Fru- and SOD+Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD+Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. Summarizing, dietary cholesterol in SOD+Cho diet may trigger hepatic inflammation and fibrosis. SOD+Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
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Affiliation(s)
- Janin Henkel
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Charles Dominic Coleman
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Anne Schraplau
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Korinna Jöhrens
- Institute of Pathology, Charité University Hospital Berlin, Berlin, Germany
| | - Daniela Weber
- Department of Molecular Toxicology, German Institute of Human Nutrition, Nuthetal, Germany
- NutriAct – Competence Cluster Nutrition Research Berlin-Potsdam, Nuthetal, Germany
| | - José Pedro Castro
- German Center for Diabetes Research, München-Neuherberg, Germany
- Department of Molecular Toxicology, German Institute of Human Nutrition, Nuthetal, Germany
- Faculty of Medicine, Department of Biomedicine, University of Porto, Porto, Portugal
- Aging and Stress Group, Institute for Innovation and Health Research, Porto, Portugal
| | - Martin Hugo
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Tim Julius Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Nuthetal, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
| | - Stephanie Krämer
- Animal Facility, German Institute of Human Nutrition, Nuthetal, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition, Nuthetal, Germany
- German Center for Diabetes Research, München-Neuherberg, Germany
| | - Gerhard Paul Püschel
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
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Dietary Arachidonic Acid Has a Time-Dependent Differential Impact on Adipogenesis Modulated via COX and LOX Pathways in Grass Carp Ctenopharyngodon idellus. Lipids 2016; 51:1325-1338. [DOI: 10.1007/s11745-016-4205-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 10/10/2016] [Indexed: 02/07/2023]
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45
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Abruzzese GA, Heber MF, Ferreira SR, Velez LM, Reynoso R, Pignataro OP, Motta AB. Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism. J Endocrinol 2016; 230:67-79. [PMID: 27179108 DOI: 10.1530/joe-15-0471] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 05/13/2016] [Indexed: 12/22/2022]
Abstract
Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats were hyperandrogenized with testosterone. At pubertal age, the prenatally hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid oxidation pathway, oxidant/antioxidant balance and proinflammatory status. We also evaluated the general metabolic status through growth rate curve, basal glucose and insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile. Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty oxidation pathways were altered. The PH groups also showed impaired oxidant/antioxidant balance, a decrease in the proinflammatory pathway (measured by prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance of circulating lipids and increased risk of metabolic syndrome. We conclude that prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of liver alterations, imbalance in lipid metabolism and increased risk of developing metabolic syndrome. The anovulatory phenotype showed more alterations in liver lipogenesis and a more impaired balance of insulin and glucose metabolism, being more susceptible to the development of steatosis.
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Affiliation(s)
- Giselle Adriana Abruzzese
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Maria Florencia Heber
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Silvana Rocio Ferreira
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Leandro Martin Velez
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Roxana Reynoso
- Laboratorio de EndocrinologíaDepartamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Omar Pedro Pignataro
- Laboratorio de Endocrinología Molecular y Transducción de SeñalesInstituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
| | - Alicia Beatriz Motta
- Laboratorio de Fisio-patología OváricaCentro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina
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46
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Manowsky J, Camargo RG, Kipp AP, Henkel J, Püschel GP. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes. Am J Physiol Endocrinol Metab 2016; 310:E938-46. [PMID: 27094035 DOI: 10.1152/ajpendo.00427.2015] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 04/14/2016] [Indexed: 01/09/2023]
Abstract
Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues.
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Affiliation(s)
- Julia Manowsky
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany;
| | - Rodolfo Gonzalez Camargo
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany; Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil; and
| | - Anna P Kipp
- German Institute for Human Nutrition, Nuthetal, Germany
| | - Janin Henkel
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany
| | - Gerhard P Püschel
- University of Potsdam, Institute of Nutritional Science, Nutritional Biochemistry, Nuthetal, Germany
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47
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Martins IJ. Anti-Aging Genes Improve Appetite Regulation and Reverse Cell Senescence and Apoptosis in Global Populations. ACTA ACUST UNITED AC 2016. [DOI: 10.4236/aar.2016.51002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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48
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Nobili V, Alisi A, Musso G, Scorletti E, Calder PC, Byrne CD. Omega-3 fatty acids: Mechanisms of benefit and therapeutic effects in pediatric and adult NAFLD. Crit Rev Clin Lab Sci 2015; 53:106-20. [PMID: 26463349 DOI: 10.3109/10408363.2015.1092106] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common liver disease in industrialized countries, and it is estimated that it will become the most frequent indication for liver transplantation in the next decade. NAFLD may be associated with moderate (i.e. steatosis) to severe (i.e. steatohepatitis and fibrosis) liver damage and affects all age groups. Furthermore, subjects with NAFLD may be at a greater risk of other obesity-related complications later in life, and people with obesity and obesity-related complications (e.g. metabolic syndrome, type 2 diabetes and cardiovascular disease) are at increased risk of developing NAFLD. To date, there is no licensed treatment for NAFLD and therapy has been mainly centered on weight loss and increased physical activity. Unfortunately, it is often difficult for patients to adhere to the advised lifestyle changes. Therefore, based on the known pathogenesis of NAFLD, several clinical trials with different nutritional supplementation and prescribed drugs have been undertaken or are currently underway. Experimental evidence has emerged about the health benefits of omega-3 fatty acids, a group of polyunsaturated fatty acids that are important for a number of health-related functions. Omega-3 fatty acids are present in some foods (oils, nuts and seeds) that also contain omega-6 fatty acids, and the best sources of exclusively omega-3 fatty acids are oily fish, krill oil and algae. In this review, we provide a brief overview of the pathogenesis of NAFLD, and we also discuss the molecular and clinical evidence for the benefits of different omega-3 fatty acid preparations in NAFLD.
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Affiliation(s)
| | - Anna Alisi
- b Liver Research Unit, "Bambino Gesù" Children's Hospital and IRCCS , Rome , Italy
| | - Giovanni Musso
- c Gradenigo Hospital, University of Turin , Turin , Italy
| | - Eleonora Scorletti
- d Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton , Southampton , UK , and.,e National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, University of Southampton , Southampton , UK
| | - Philip C Calder
- d Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton , Southampton , UK , and.,e National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, University of Southampton , Southampton , UK
| | - Christopher D Byrne
- d Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton , Southampton , UK , and.,e National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, University of Southampton , Southampton , UK
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Nasrallah R, Hassouneh R, Hébert RL. PGE2, Kidney Disease, and Cardiovascular Risk: Beyond Hypertension and Diabetes. J Am Soc Nephrol 2015; 27:666-76. [PMID: 26319242 DOI: 10.1681/asn.2015050528] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
An important measure of cardiovascular health is obtained by evaluating the global cardiovascular risk, which comprises a number of factors, including hypertension and type 2 diabetes, the leading causes of illness and death in the world, as well as the metabolic syndrome. Altered immunity, inflammation, and oxidative stress underlie many of the changes associated with cardiovascular disease, diabetes, and the metabolic syndrome, and recent efforts have begun to elucidate the contribution of PGE2 in these events. This review summarizes the role of PGE2 in kidney disease outcomes that accelerate cardiovascular disease, highlights the role of cyclooxygenase-2/microsomal PGE synthase 1/PGE2 signaling in hypertension and diabetes, and outlines the contribution of PGE2 to other aspects of the metabolic syndrome, particularly abdominal adiposity, dyslipidemia, and atherogenesis. A clearer understanding of the role of PGE2 could lead to new avenues to improve therapeutic options and disease management strategies.
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Affiliation(s)
- Rania Nasrallah
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Ramzi Hassouneh
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Richard L Hébert
- Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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50
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Roles of lipid-modulating enzymes diacylglycerol kinase and cyclooxygenase under pathophysiological conditions. Anat Sci Int 2014; 90:22-32. [PMID: 25471593 DOI: 10.1007/s12565-014-0265-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Accepted: 11/17/2014] [Indexed: 10/24/2022]
Abstract
Lipid not only represents a constituent of the plasma membrane, but also plays a pivotal role in intracellular signaling. Lipid-mediated signaling system is strictly regulated by several enzymes, which act at various steps of the lipid metabolism. Under pathological conditions, prolonged or insufficient activation of this system results in dysregulated signaling, leading to diseases such as cancer or metabolic syndrome. Of the lipid-modulating enzymes, diacylglycerol kinase (DGK) and cyclooxygenase (COX) are intimately involved in the signaling system. DGK consists of a family of enzymes that phosphorylate a second messenger diacylglycerol (DG) to produce phosphatidic acid (PA). Both DG and PA are known to activate signaling molecules such as protein kinase C. COX catalyzes the committed step in prostanoid biosynthesis, which involves the metabolism of arachidonic acid to produce prostaglandins. Previous studies have shown that the DGK and COX are engaged in a number of pathological conditions. This review summarizes the functional implications of these two enzymes in ischemia, liver regeneration, vascular events, diabetes, cancer and inflammation.
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