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Park JY, Lee J, Choi YH, Min KW, Han KA, Ahn KJ, Lim S, Kim YH, Ahn CW, Choi KM, Yoon KH. Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial. Diabetes Metab J 2024; 48:915-928. [PMID: 38650099 PMCID: PMC11449827 DOI: 10.4093/dmj.2023.0259] [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: 08/07/2023] [Accepted: 11/30/2023] [Indexed: 04/25/2024] Open
Abstract
BACKGRUOUND Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. METHODS The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. RESULTS After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were -1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. CONCLUSION Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.
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Affiliation(s)
- Ji-Yeon Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Joonyub Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoon-Hee Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- MedicalExcellence Inc., Seoul, Korea
| | - Kyung Wan Min
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Kyung Ah Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Kyu Jeung Ahn
- Division of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Soo Lim
- Division of Endocrinology and Metabolism, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Young-Hyun Kim
- Division of Endocrinology and Metabolism, Bundang Jesaeng Hospital, Seongnam, Korea
| | - Chul Woo Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Mook Choi
- Department of Endocrinology, Korea University Guro Hospital, Seoul, Korea
| | - Kun-Ho Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - the Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) study investigators
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- MedicalExcellence Inc., Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea
- Division of Endocrinology and Metabolism, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
- Division of Endocrinology and Metabolism, Bundang Jesaeng Hospital, Seongnam, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Department of Endocrinology, Korea University Guro Hospital, Seoul, Korea
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Fuior EV, Zvintzou E, Filippatos T, Giannatou K, Mparnia V, Simionescu M, Gafencu AV, Kypreos KE. Peroxisome Proliferator-Activated Receptor α in Lipoprotein Metabolism and Atherosclerotic Cardiovascular Disease. Biomedicines 2023; 11:2696. [PMID: 37893070 PMCID: PMC10604751 DOI: 10.3390/biomedicines11102696] [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: 08/23/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator of plasma lipid and lipoprotein metabolism, with pluripotent effects influencing the lipid and apolipoprotein cargo of both atherogenic and antiatherogenic lipoproteins and their functionality. Clinical evidence supports an important role of PPARα agonists (fibric acid derivatives) in the treatment of hypertriglyceridemia and/or low high-density lipoprotein (HDL) cholesterol levels, although the effects of clinical trials are contradictory and point to a reduction in the risk of nonfatal and fatal myocardial infarction events. In this manuscript, we provide an up-to-date critical review of the existing relevant literature.
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Affiliation(s)
- Elena Valeria Fuior
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
| | - Evangelia Zvintzou
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
| | - Theodosios Filippatos
- Internal Medicine Clinic, Department of Medicine, University of Crete, 71500 Heraklion, Greece;
| | - Katerina Giannatou
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
| | - Victoria Mparnia
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
| | - Maya Simionescu
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
| | - Anca Violeta Gafencu
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
| | - Kyriakos E. Kypreos
- Institute of Cellular Biology and Pathology, “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (E.V.F.); (E.Z.); (M.S.)
- Pharmacology Laboratory, Department of Medicine, University of Patras, 26500 Rio Achaias, Greece; (K.G.); (V.M.)
- Department of Life Sciences, School of Sciences, European University Cyprus, 2404 Nicosia, Cyprus
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3
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Heaven MR, Herren AW, Flint DL, Pacheco NL, Li J, Tang A, Khan F, Goldman JE, Phinney BS, Olsen ML. Metabolic Enzyme Alterations and Astrocyte Dysfunction in a Murine Model of Alexander Disease With Severe Reactive Gliosis. Mol Cell Proteomics 2022; 21:100180. [PMID: 34808356 PMCID: PMC8717607 DOI: 10.1016/j.mcpro.2021.100180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 11/30/2022] Open
Abstract
Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant fourfold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located, which was not observed in the GFAPTg;Gfap+/R236H mice.
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Affiliation(s)
| | - Anthony W Herren
- University of California at Davis Proteomics Core, Davis, California, USA
| | | | - Natasha L Pacheco
- Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jiangtao Li
- Graduate Program in Genetics, Bioinformatics, and Computational Biology, Virginia Tech, Blacksburg, Virginia, USA; School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA
| | - Alice Tang
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Fatima Khan
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - James E Goldman
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Brett S Phinney
- University of California at Davis Proteomics Core, Davis, California, USA
| | - Michelle L Olsen
- School of Neuroscience, Virginia Tech, Blacksburg, Virginia, USA.
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Vales-Villamarín C, de Dios O, Pérez-Nadador I, Gavela-Pérez T, Soriano-Guillén L, Garcés C. PPARγ2 Pro12Ala Polymorphism is Associated in Children With Traits Related to Susceptibility to Type 2 Diabetes. Front Pharmacol 2021; 12:763853. [PMID: 34887761 PMCID: PMC8650059 DOI: 10.3389/fphar.2021.763853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/10/2021] [Indexed: 12/16/2022] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. Pharmacological activators of PPARγ are being used as a treatment of obesity related disorders such as dyslipidaemia and type 2 diabetes, but questions remain open regarding the effects of PPARγ on traits related to the development of type 2 diabetes. In our study, we have analyzed the relationship of the common variant Pro12Ala in the human PPARγ2 gene with the presence of obesity and with insulin, HOMA and lipid profile in a representative sample of 6-to 8-year-old children free from the confounding factors associated with adults. We found that Ala12Ala genotype was significantly more frequent in females with obesity than in those without obesity, with Ala12Ala carriers having significantly higher weight and body mass index (BMI), however the association disappeared when adjusting by leptin concentrations. The Ala12Ala genotype was associated with significantly higher HDL-cholesterol and apoA-I levels in males but not in females, independently of BMI. In a recessive model, in females, leptin levels appeared higher in Ala12Ala carriers. Although no apparent differences were observed in any sex when analyzing insulin levels and HOMA among genotypes without adjusting, lower insulin levels and lower HOMA appeared associated with Ala12Ala carriers when adjusting for BMI and leptin levels. In summary, our data showed that leptin seems to be having an effect on the association between the PPARγ2 Pro12Ala and BMI. Besides, after controlling for BMI and leptin, a protective effect of the Ala12Ala variant of the PPARγ2 Pro12Ala polymorphism on insulin sensitivity is evident already in prepubertal children.
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Affiliation(s)
| | - Olaya de Dios
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | - Iris Pérez-Nadador
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
| | | | | | - Carmen Garcés
- Lipid Research Laboratory, IIS-Fundación Jiménez Díaz UAM, Madrid, Spain
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Yan H, Wu W, Chang X, Xia M, Ma S, Wang L, Gao J. Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism. Biol Sex Differ 2021; 12:1. [PMID: 33397443 PMCID: PMC7784274 DOI: 10.1186/s13293-020-00344-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 11/26/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Pioglitazone is a promising therapeutic method for nonalcoholic fatty liver disease (NAFLD) patients with or without type 2 diabetes. However, there is remarkable variability in treatment response. We analyzed our previous randomized controlled trial to examine the effects of gender and other factors on the efficacy of pioglitazone in treating Chinese nonalcoholic fatty liver disease (NAFLD) patients with abnormal glucose metabolism. METHODS This is a post hoc analysis of a previous randomized, parallel controlled, open-label clinical trial (RCT) with an original purpose of evaluating the efficacy of berberine and pioglitazone on NAFLD. The total population (n = 185) was randomly divided into three groups: lifestyle intervention (LSI), LSI + pioglitazone (PGZ) 15 mg qd, and LSI + berberine (BBR) 0.5 g tid, respectively, for 16 weeks. The study used proton magnetic resonance spectroscopy (1H-MRS) to assess liver fat content. RESULTS As compared with LSI, PGZ + LSI treatment further decreased liver fat content in women (- 15.24% ± 14.54% vs. - 8.76% ± 13.49%, p = 0.025), but less decreased liver fat content in men (- 9.95% ± 15.18% vs. - 12.64% ± 17.78%, p = 0.046). There was a significant interaction between gender and efficacy of pioglitazone before and after adjustment for age, smoking, drinking, baseline BMI, BMI change, treatment adherence, baseline liver fat content, and glucose metabolism. CONCLUSION The study recommends pioglitazone plus lifestyle intervention for Chinese NAFLD female patients with abnormal glucose metabolism. TRIAL REGISTRATION Role of Pioglitazone and Berberine in Treatment of Non-Alcoholic Fatty Liver Disease, NCT00633282 . Registered on 3 March 2008, https://register.clinicaltrials.gov .
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Affiliation(s)
- Hongmei Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Weiyun Wu
- Department of Laboratory, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xinxia Chang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Sicheng Ma
- Shanghai Starriver Bilingual School, Shanghai, 201108, China
| | - Liu Wang
- Second Affiliated Hospital of Army Military Medical University, Chongqing, 400037, China.
| | - Jian Gao
- Department of Nutrition, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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6
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House JS, Motsinger-Reif AA. Fibrate pharmacogenomics: expanding past the genome. Pharmacogenomics 2020; 21:293-306. [PMID: 32180510 DOI: 10.2217/pgs-2019-0140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Fibrates are a medication class prescribed for decades as 'broad-spectrum' lipid-modifying agents used to lower blood triglyceride levels and raise high-density lipoprotein cholesterol levels. Such lipid changes are associated with a decrease in cardiovascular disease, and fibrates are commonly used to reduce risk of dangerous cardiovascular outcomes. As with most drugs, it is well established that response to fibrate treatment is variable, and this variation is heritable. This has motivated the investigation of pharmacogenomic determinants of response, and multiple studies have discovered a number of genes associated with fibrate response. Similar to other complex traits, the interrogation of single nucleotide polymorphisms using candidate gene or genome-wide approaches has not revealed a substantial portion of response variation. However, recent innovations in technological platforms and advances in statistical methodologies are revolutionizing the use and integration of other 'omes' in pharmacogenomics studies. Here, we detail successes, challenges, and recent advances in fibrate pharmacogenomics.
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Affiliation(s)
- John S House
- Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Department of Health & Human Services, Research Triangle Park, NC 27709, USA
| | - Alison A Motsinger-Reif
- Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Department of Health & Human Services, Research Triangle Park, NC 27709, USA
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Ghadieh HE, Muturi HT, Russo L, Marino CC, Ghanem SS, Khuder SS, Hanna JC, Jash S, Puri V, Heinrich G, Gatto-Weis C, Lee KY, Najjar SM. Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis. Hepatol Commun 2017; 2:35-47. [PMID: 29404511 PMCID: PMC5776867 DOI: 10.1002/hep4.1117] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/02/2017] [Accepted: 10/03/2017] [Indexed: 12/15/2022] Open
Abstract
Exenatide, a glucagon-like peptide-1 receptor agonist, induces insulin secretion. Its role in insulin clearance has not been adequately examined. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance to maintain insulin sensitivity. Feeding C57BL/6J mice a high-fat diet down-regulates hepatic Ceacam1 transcription to cause hyperinsulinemia, insulin resistance, and hepatic steatosis, as in Ceacam1 null mice (Cc1-/- ). Thus, we tested whether exenatide regulates Ceacam1 expression in high-fat diet-fed mice and whether this contributes to its insulin sensitizing effect. Exenatide (100 nM) induced the transcriptional activity of wild-type Ceacam1 promoter but not the constructs harboring block mutations of peroxisome proliferator-activated receptor response element and retinoid X receptor alpha, individually or collectively, in HepG2 human hepatoma cells. Chromatin immunoprecipitation analysis demonstrated binding of peroxisome proliferator-activated receptor gamma to Ceacam1 promoter in response to rosiglitazone and exenatide. Consistently, exenatide induced Ceacam1 messenger RNA expression within 12 hours in the absence but not in the presence of the glucagon-like peptide-1 receptor antagonist exendin 9-39. Exenatide (20 ng/g body weight once daily intraperitoneal injection in the last 30 days of feeding) restored hepatic Ceacam1 expression and insulin clearance to curb diet-induced metabolic abnormalities and steatohepatitis in wild-type but not Cc1-/- mice fed a high-fat diet for 2 months. Conclusion: Exenatide promotes insulin clearance in parallel with insulin secretion to prevent chronic hyperinsulinemia and the resulting hepatic steatosis, and this contributes to its insulin sensitizing effect. Our data further highlight the relevance of physiologic insulin metabolism in maintaining insulin sensitivity and normal lipid metabolism. (Hepatology Communications 2018;2:35-47).
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Affiliation(s)
- Hilda E Ghadieh
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Harrison T Muturi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine Ohio University Athens OH
| | - Lucia Russo
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Christopher C Marino
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Simona S Ghanem
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Saja S Khuder
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Julie C Hanna
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Sukanta Jash
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine Ohio University Athens OH
| | - Vishwajeet Puri
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine Ohio University Athens OH.,Diabetes Institute, Heritage College of Osteopathic Medicine Ohio University Athens OH
| | - Garrett Heinrich
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine Ohio University Athens OH.,Diabetes Institute, Heritage College of Osteopathic Medicine Ohio University Athens OH
| | - Cara Gatto-Weis
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH.,Department of Pathology, College of Medicine and Life Sciences University of Toledo Toledo OH
| | - Kevin Y Lee
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine Ohio University Athens OH
| | - Sonia M Najjar
- Center for Diabetes and Endocrine Research, College of Medicine and Life Sciences University of Toledo Toledo OH.,Department of Biomedical Sciences, Heritage College of Osteopathic Medicine Ohio University Athens OH.,Diabetes Institute, Heritage College of Osteopathic Medicine Ohio University Athens OH
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Gao XQ, Li YF, Jiang ZL. β 3-Adrenoceptor activation upregulates apolipoprotein A-I expression in HepG2 cells, which might further promote cholesterol efflux from macrophage foam cells. Drug Des Devel Ther 2017; 11:617-627. [PMID: 28424539 PMCID: PMC5344441 DOI: 10.2147/dddt.s130088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Objective The aim of this study was to explore the effects of β3-adrenoceptor (β3-AR) activation on HepG2 cells and its influence on cholesterol efflux from macrophage foam cells. Materials and methods HepG2 cells were cultured and treated with the β3-AR agonist, BRL37344, and antagonist, SR52390A, and the expression of apolipoprotein (Apo) A-I, ApoA-II, ApoB, and β3-AR in the supernatants and cells was determined. The expression of peroxisome proliferator-activated receptor (PPAR) γ and PPARα in the HepG2 cells was also assessed. Next, using the RAW264.7 macrophage foam cell model, we also assessed the influence of the HepG2 cell supernatants on lipid efflux. The cholesterol content of the foam cells was also measured, and the cholesterol efflux from the macrophages was examined by determining 3H-labeled cholesterol levels. Expression of ATP-binding cassette transporter (ABC) A1 and ABCG1 of the macrophage foam cells was also assessed. Results β3-AR activation increased ApoA-I expression in both the HepG2 cells and the supernatants; PPARγ expression was upregulated, but PPARα expression was not. Treatment with GW9662 abolished the increased expression of ApoA-I induced by the β3-AR agonist. The HepG2 cell supernatants decreased the lipid accumulation and increased the cholesterol efflux from the macrophage foam cells. ABCA1 expression, but not ABCG1 expression, increased in the macrophage foam cells treated with BRL37344-treated HepG2 cell supernatants. Conclusion Activation of β3-AR in HepG2 cells upregulates ApoA-I expression, which might further promote cholesterol efflux from macrophage foam cells. PPARγ might be required for the induction of ApoA-I expression.
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Affiliation(s)
- Xia-Qing Gao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University.,Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Yan-Fang Li
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University.,Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, People's Republic of China
| | - Zhi-Li Jiang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University.,Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, People's Republic of China
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Abstract
Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.
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Affiliation(s)
- Barbara Gross
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Michal Pawlak
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, 02-109 Warsaw, Poland
| | - Philippe Lefebvre
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
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10
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Kubota T, Kubota N, Sato H, Inoue M, Kumagai H, Iwamura T, Takamoto I, Kobayashi T, Moroi M, Terauchi Y, Tobe K, Ueki K, Kadowaki T. Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways. Sci Rep 2016; 6:34707. [PMID: 27703271 PMCID: PMC5050439 DOI: 10.1038/srep34707] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/15/2016] [Indexed: 01/11/2023] Open
Abstract
The aim of this study is to elucidate to what degree adiponectin is involved in TZD-mediated amelioration of neointimal formation. We investigated the effect of 3- or 8-weeks' pioglitazone on cuff-induced neointimal formation in adiponectin-deficient (APN-KO) and wild-type (WT) mice. Pioglitazone for 3 weeks reduced neointimal formation in the WT mice with upregulation of the plasma adiponectin levels, but failed to reduce neointimal formation in the APN-KO mice, suggesting that pioglitazone suppressed neointimal formation by adiponectin-dependent mechanisms. Pioglitazone for 3 weeks suppressed vascular smooth muscle cell (VSMC) proliferation and increased AdipoR2 expression in the WT mice. In vitro, globular adiponectin activated AMPK through both AdipoR1 and AdipoR2, resulting in the inhibition of VSMC proliferation. Interestingly, 8-weeks' pioglitazone was reduced neointimal formation in APN-KO mice to degree similar to that seen in the WT mice, suggesting that pioglitazone can also suppress neointimal formation via a mechanism independent of adiponectin. Pioglitazone for 8 weeks completely abrogated the increased VSMC proliferation, along with a reduction of cyclin B1 and cyclin D1 expressions and cardiovascular risk profile in the APN-KO mice. In vitro, pioglitazone suppressed these expressions, leading to inhibition of VSMC proliferation. Pioglitazone suppresses neointimal formation via both adiponectin-dependent and adiponectin-independent mechanisms.
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Affiliation(s)
- Tetsuya Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.,Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.,Department of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan.,Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo 153-8515, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.,Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, 230-0045, Japan.,Department of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan.,Department of Clinical Nutrition Therapy, University of Tokyo, Tokyo 113-8655, Japan
| | - Hiroyuki Sato
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Mariko Inoue
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.,Department of Clinical Nutrition, National Institute of Health and Nutrition, Tokyo 162-8636, Japan
| | - Hiroki Kumagai
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Tomokatsu Iwamura
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Iseki Takamoto
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo 142-8501, Japan
| | - Masao Moroi
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo 153-8515, Japan
| | - Yasuo Terauchi
- Department of Diabetes and Endocrinology, Yokohama City University, School of Medicine, Kanagawa 236-0004, Japan
| | - Kazuyuki Tobe
- First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, 930-0194, Japan
| | - Kohjiro Ueki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
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Shipman KE, Strange RC, Ramachandran S. Use of fibrates in the metabolic syndrome: A review. World J Diabetes 2016; 7:74-88. [PMID: 26981181 PMCID: PMC4781903 DOI: 10.4239/wjd.v7.i5.74] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 10/30/2015] [Accepted: 01/21/2016] [Indexed: 02/06/2023] Open
Abstract
The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.
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Shavva VS, Mogilenko DA, Bogomolova AM, Nikitin AA, Dizhe EB, Efremov AM, Oleinikova GN, Perevozchikov AP, Orlov SV. PPARγ Represses Apolipoprotein A-I Gene but Impedes TNFα-Mediated ApoA-I Downregulation in HepG2 Cells. J Cell Biochem 2016; 117:2010-22. [DOI: 10.1002/jcb.25498] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 01/25/2016] [Indexed: 11/06/2022]
Affiliation(s)
- Vladimir S. Shavva
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
- Department of Embryology; St. Petersburg State University; St. Petersburg Russia
| | - Denis A. Mogilenko
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
- Department of Embryology; St. Petersburg State University; St. Petersburg Russia
| | | | - Artemy A. Nikitin
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
- Department of Biochemistry; St. Petersburg State University; St. Petersburg Russia
| | - Ella B. Dizhe
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
| | - Alexander M. Efremov
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
- Department of Embryology; St. Petersburg State University; St. Petersburg Russia
| | - Galina N. Oleinikova
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
| | - Andrej P. Perevozchikov
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
- Department of Embryology; St. Petersburg State University; St. Petersburg Russia
| | - Sergey V. Orlov
- Department of Biochemistry; Institute of Experimental Medicine; Russian Academy of Medical Sciences; St. Petersburg Russia
- Department of Embryology; St. Petersburg State University; St. Petersburg Russia
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Abstract
Atherosclerosis is a chronic inflammatory disease with deposition of excessive cholesterol in the arterial intima. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that can activate or inhibit the expression of many target genes by forming a heterodimer complex with the retinoid X receptor. Activation of PPARα plays an important role in the metabolism of multiple lipids, including high-density lipoprotein, cholesterol, low-density lipoprotein, triglyceride, phospholipid, bile acids, and fatty acids. Increased PPARα activity also mitigates atherosclerosis by blocking macrophage foam cell formation, vascular inflammation, vascular smooth muscle cell proliferation and migration, plaque instability, and thrombogenicity. Clinical use of synthetic PPARα agonist fibrate improved dyslipidemia and attenuated atherosclerosis-related disease risk. This review summarizes PPARα in lipid and lipoprotein metabolism and atherosclerosis, and also highlights its potential therapeutic benefits.
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Du Y, Wang L, Si S, Yang Y, Hong B. A novel compound 4010B-30 upregulates apolipoprotein A-I gene expression through activation of PPARγ in HepG2 cells. Atherosclerosis 2015; 239:589-98. [DOI: 10.1016/j.atherosclerosis.2015.02.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 02/10/2015] [Accepted: 02/15/2015] [Indexed: 01/31/2023]
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High-density lipoproteins in the prevention of cardiovascular disease: changing the paradigm. Clin Pharmacol Ther 2014; 96:48-56. [PMID: 24713591 DOI: 10.1038/clpt.2014.79] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/03/2014] [Indexed: 01/04/2023]
Abstract
High-density-lipoprotein cholesterol (HDL-C) has been identified in population studies as an independent inverse predictor of cardiovascular events. Although the causal nature of this association has been questioned, HDL and its major protein, apolipoprotein (apo)A1, have been shown to prevent and reverse atherosclerosis in animal models. In addition, HDL and apoA1 have several putatively atheroprotective functions, such as the ability to promote efflux of cholesterol from macrophages in the artery wall, inhibit vascular inflammation, and enhance endothelial function. Therefore, HDL-C and apoA1 have been investigated as therapeutic targets for coronary heart disease. However, recent clinical trials with drugs that raise HDL-C, such as niacin and inhibitors of cholesteryl ester transfer protein, have been disappointing. Here, we review the current state of the science regarding HDL as a therapeutic target.
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Kotla S, Singh NK, Heckle MR, Tigyi GJ, Rao GN. The transcription factor CREB enhances interleukin-17A production and inflammation in a mouse model of atherosclerosis. Sci Signal 2013; 6:ra83. [PMID: 24045154 DOI: 10.1126/scisignal.2004214] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The enzyme 15-lipoxygenase (15-LO) plays a role in atherogenesis (also known as atherosclerosis), but the underlying mechanisms are unclear. We found that 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], the major 15-LO-dependent metabolite of arachidonic acid, stimulated the production of reactive oxygen species (ROS) by monocytes through the xanthine oxidase-mediated activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS production led to the Syk-, Pyk2-, and mitogen-activated protein kinase (MAPK)-dependent production of the proinflammatory cytokine interleukin-17A (IL-17A) in a manner that required the transcription factor CREB (cyclic adenosine monophosphate response element-binding protein). In addition, this pathway was required for the 15(S)-HETE-dependent migration and adhesion of monocytes to endothelial cells. Consistent with these observations, we found that peritoneal macrophages from apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet (a mouse model of atherosclerosis) exhibited increased xanthine oxidase and NADPH oxidase activities; ROS production; phosphorylation of Syk, Pyk2, MAPK, and CREB; and IL-17A production compared to those from similarly fed ApoE-/-:12/15-LO-/- mice. These events correlated with increased lipid deposits and numbers of monocytes and macrophages in the aortic arches of ApoE-/- mice, which resulted in atherosclerotic plaque formation. Together, these observations suggest that 15(S)-HETE exacerbates atherogenesis by enhancing CREB-dependent IL-17A production and inflammation.
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Affiliation(s)
- Sivareddy Kotla
- Department of Physiology, University of Tennessee Health Science Center, 894 Union Avenue, Memphis, TN 38163, USA
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McEneny J, McPherson PA, McGinty A, Hull SS, McCance DR, Young IS. Pioglitazone protects HDL(2&3) against oxidation in overweight and obese men. Ann Clin Biochem 2012; 50:20-4. [PMID: 23148280 DOI: 10.1258/acb.2012.012019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND The worldwide epidemic of obesity is a major public health concern and is persuasively linked to the rising prevalence of diabetes and cardiovascular disease. Obesity is often associated with an abnormal lipoprotein profile, which may be partly negated by pioglitazone intervention, as this can influence the composition and oxidation characteristics of low-density lipoprotein (LDL). However, as pioglitazone's impact on these parameters within high-density lipoprotein (HDL), specifically HDL(2&3), is absent from the literature, this study was performed to address this shortcoming. METHODS Twenty men were randomized to placebo or pioglitazone (30 mg/day) for 12 weeks. HDL(2&3) were isolated by rapid-ultracentrifugation. HDL(2&3)-cholesterol and phospholipid content were assessed by enzymatic assays and apolipoprotein AI (apoAI) content by single-radial immunodiffusion. HDL(2&3) oxidation characteristics were assessed by monitoring conjugated diene production and paraoxonase-1 activity by spectrophotometric assays. RESULTS Compared with the placebo group, pioglitazone influenced the composition and oxidation potential of HDL(2&3). Specifically, total cholesterol (P < 0.05), phospholipid (P < 0.001) and apoAI (P < 0.001) were enriched within HDL(2). Furthermore, the resistance of HDL(2&3) to oxidation (P < 0.05) and the activity of paroxonase-1 were also increased (P < 0.001). CONCLUSIONS Overall, these findings indicate that pioglitazone treatment induced antiatherogenic changes within HDL(2&3), which may help reduce the incidence of premature cardiovascular disease linked with obesity.
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Affiliation(s)
- Jane McEneny
- Centre for Public Health, Queen's University Belfast, Nutrition & Metabolism Group, Grosvenor Road, Belfast BT12 6BJ, UK.
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Du Y, Yang Y, Jiang W, Wang L, Jia XJ, Si SY, Chen XF, Hong B. Substituted benzamides containing azaspiro rings as upregulators of apolipoprotein A-I transcription. Molecules 2012; 17:7379-86. [PMID: 22699570 PMCID: PMC6268513 DOI: 10.3390/molecules17067379] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 06/08/2012] [Accepted: 06/11/2012] [Indexed: 01/18/2023] Open
Abstract
Apolipoprotein A-I (Apo A-I) is the principal protein component of high density lipoprotein (HDL), which is generally considered as a potential therapeutic target against atherosclerosis. The understanding of the Apo A-I regulation mechanism has fuelled the development of novel HDL targeted therapeutic approaches. To identify novel agents that can upregulate Apo A-I expression, we performed a cell-based reporter assay to screen 25,600 small molecules. Based on the dataset obtained from screening, a series of novel analogs of substituted benzamides containing azaspiro rings were assessed for their ability to induce the transcription of the Apo A-I gene, and the structure-activity relationship (SAR) around these analogs was also proposed. The results indicated that the trifluoromethyl substituted benzamide containing an azaspiro ring is a promising backbone for designing Apo A-I transcriptional upregulator and could be viable leads for development of new drugs to prevent and treat atherosclerosis in the future.
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Affiliation(s)
| | | | | | | | | | | | - Xiao-Fang Chen
- Authors to whom correspondence should be addressed; (X.-F.C.); (B.H.); Tel.: +86-10-8315-5803 (X.-F.C.); Fax: +86-10-6301-7302 (X.-F.C.); Tel.: +86-10-6302-8003 (B.H.); Fax: +86-10-6301-7302 (B.H.)
| | - Bin Hong
- Authors to whom correspondence should be addressed; (X.-F.C.); (B.H.); Tel.: +86-10-8315-5803 (X.-F.C.); Fax: +86-10-6301-7302 (X.-F.C.); Tel.: +86-10-6302-8003 (B.H.); Fax: +86-10-6301-7302 (B.H.)
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Zhang LH, Kamanna VS, Ganji SH, Xiong XM, Kashyap ML. Niacin increases HDL biogenesis by enhancing DR4-dependent transcription of ABCA1 and lipidation of apolipoprotein A-I in HepG2 cells. J Lipid Res 2012; 53:941-950. [PMID: 22389325 DOI: 10.1194/jlr.m020917] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The lipidation of apoA-I in liver greatly influences HDL biogenesis and plasma HDL levels by stabilizing the secreted apoA-I. Niacin is the most effective lipid-regulating agent clinically available to raise HDL. This study was undertaken to identify regulatory mechanisms of niacin action in hepatic lipidation of apoA-I, a critical event involved in HDL biogenesis. In cultured human hepatocytes (HepG2), niacin increased: association of apoA-I with phospholipids and cholesterol by 46% and 23% respectively, formation of lipid-poor single apoA-I molecule-containing particles up to ~2.4-fold, and pre β 1 and α migrating HDL particles. Niacin dose-dependently stimulated the cell efflux of phospholipid and cholesterol and increased transcription of ABCA1 gene and ABCA1 protein. Mutated DR4, a binding site for nuclear factor liver X receptor alpha (LXR α ) in the ABCA1 promoter, abolished niacin stimulatory effect. Further, knocking down LXR α or ABCA1 by RNA interference eliminated niacin-stimulated apoA-I lipidation. Niacin treatment did not change apoA-I gene expression. The present data indicate that niacin increases apoA-I lipidation by enhancing lipid efflux through a DR4-dependent transcription of ABCA1 gene in HepG2 cells. A stimulatory role of niacin in early hepatic formation of HDL particles suggests a new mechanism that contributes to niacin action to increase the stability of newly synthesized circulating HDL.
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Affiliation(s)
- Lin-Hua Zhang
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
| | - Vaijinath S Kamanna
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA
| | - Shobha H Ganji
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA
| | - Xi-Ming Xiong
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA
| | - Moti L Kashyap
- Atherosclerosis Research Center, Veterans Affairs Healthcare System, Long Beach, CA; and the Department of Medicine, University of California, Irvine, CA; Department of Medicine, University of California, Irvine, CA.
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Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364:127-35. [PMID: 21226578 PMCID: PMC3030449 DOI: 10.1056/nejmoa1001689] [Citation(s) in RCA: 1557] [Impact Index Per Article: 111.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden. METHODS We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants. RESULTS The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. CONCLUSIONS Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).
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Affiliation(s)
- Amit V Khera
- Cardiovascular Institute, University of Pennsylvania, Philadelphia, USA
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Johns BR, Reaven GM. PPAR-γ agonists, insulin resistance and dyslipidemia: not a simple relationship. ACTA ACUST UNITED AC 2010. [DOI: 10.2217/clp.10.36] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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