|
1
|
Caveolin-1 Alleviates Acetaminophen—Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis. Int J Mol Sci 2022; 23:ijms23147587. [PMID: 35886933 PMCID: PMC9317714 DOI: 10.3390/ijms23147587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/02/2022] [Accepted: 07/05/2022] [Indexed: 01/18/2023] Open
Abstract
Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.
Collapse
|
|
2
|
Oxidative Stress and Vascular Damage in the Context of Obesity: The Hidden Guest. Antioxidants (Basel) 2021; 10:antiox10030406. [PMID: 33800427 PMCID: PMC7999611 DOI: 10.3390/antiox10030406] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
Abstract
The vascular system plays a central role in the transport of cells, oxygen and nutrients between different regions of the body, depending on the needs, as well as of metabolic waste products for their elimination. While the structure of different components of the vascular system varies, these structures, especially those of main arteries and arterioles, can be affected by the presence of different cardiovascular risk factors, including obesity. This vascular remodeling is mainly characterized by a thickening of the media layer as a consequence of changes in smooth muscle cells or excessive fibrosis accumulation. These vascular changes associated with obesity can trigger functional alterations, with endothelial dysfunction and vascular stiffness being especially common features of obese vessels. These changes can also lead to impaired tissue perfusion that may affect multiple tissues and organs. In this review, we focus on the role played by perivascular adipose tissue, the activation of the renin-angiotensin-aldosterone system and endoplasmic reticulum stress in the vascular dysfunction associated with obesity. In addition, the participation of oxidative stress in this vascular damage, which can be produced in the perivascular adipose tissue as well as in other components of the vascular wall, is updated.
Collapse
|
|
3
|
Zheng J, Ding J, Liao M, Qiu Z, Yuan Q, Mai W, Dai Y, Zhang H, Wu H, Wang Y, Liao Y, Chen X, Cheng X. Immunotherapy against angiotensin II receptor ameliorated insulin resistance in a leptin receptor-dependent manner. FASEB J 2020; 35:e21157. [PMID: 33155736 DOI: 10.1096/fj.202000300r] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 10/15/2020] [Accepted: 10/19/2020] [Indexed: 12/13/2022]
Abstract
The angiotensin II type 1 receptor (AT1R) signaling pathway is reported to modulate glucose metabolism. Targeting AT1R, our group invented ATRQβ-001 vaccine, a novel immunotherapeutic strategy to block the activation of AT1R. Here, we evaluated the therapeutic efficacy of ATRQβ-001 vaccine in insulin resistance, and investigated the mechanism. Our results showed that ATRQβ-001 vaccine and specific monoclonal antibody against epitope ATR-001 (McAb-ATR) decreased fasting serum insulin concentration and improved glucose and insulin tolerance in ob/ob mice. These beneficial effects were verified in high-fat diet-induced obese mice. McAb-ATR activated insulin signaling in skeletal muscle and insulin-resistant C2C12 myotubes without affecting liver or white adipose tissue of ob/ob mice. Mechanistically, the favorable impact of McAb-ATR on insulin resistance was abolished in db/db mice and in C2C12 myotubes with leptin receptor knockdown. AT1R knockdown also eradicated the effects of McAb-ATR in C2C12 myotubes. Furthermore, McAb-ATR treatment was able to activate the leptin receptor-mediated JAK2/STAT3 signaling in skeletal muscle of ob/ob mice and C2C12 myotubes. Additionally, angiotensin II downregulated the leptin signaling in skeletal muscle of ob/ob and diet-induced obese mice. We demonstrated that ATRQβ-001 vaccine and McAb-ATR improved whole-body insulin resistance and regulated glucose metabolism in skeletal muscle in a leptin receptor-dependent manner. Our data suggest that immunotherapy targeting AT1R is a novel strategy for treating insulin resistance.
Collapse
Affiliation(s)
- Jiayu Zheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaxing Ding
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengyang Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihua Qiu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingchen Yuan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wuqian Mai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Dai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongrong Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailang Wu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingxuan Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhua Liao
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao Chen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Lab of Molecular Biological Targeted Therapies of the Ministry of Education, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
4
|
Increased Serum Angiotensin II Is a Risk Factor of Nonalcoholic Fatty Liver Disease: A Prospective Pilot Study. Gastroenterol Res Pract 2019; 2019:5647161. [PMID: 31827504 PMCID: PMC6881577 DOI: 10.1155/2019/5647161] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/03/2019] [Indexed: 01/18/2023] Open
Abstract
Background and Aims Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. In this prospective study, we aim to explore the role of angiotensin II (Ang II) and NLRP3 inflammasome in NAFLD patients. Methods We prospectively enrolled 96 patients in our hospital from September 2014 to February 2016. Patients were divided into two groups (NAFLD group and Control group), and the serum Ang II level, IL-1β, IL-18, and lipids were analyzed. Correlation and multivariable analyses were used in order to identify the potential risk factors of NAFLD. Results Although the two groups share a similar demographic background, the Ang II level of NAFLD group patients was significantly higher than that of the Control group (42.18 ± 12.37 vs. 36.69 ± 13.90, p = 0.014) when abdominal ultrasound was used for grouping. This finding was confirmed when a FibroScan Cap value was selected to divide participants into the NAFLD group and Control group (41.16 ± 13.06 vs. 34.85 ± 12.64, p = 0.040). Multivariable analysis showed that Ang II level is an independent risk factor of NAFLD whether abdominal ultrasound (OR = 1.056, p = 0.037) or FibroScan Cap value (OR = 1.069, p = 0.013) was deemed as the diagnostic standard. Furthermore, stepwise regression analysis was carried out between Ang II with other parameters and we discovered that Ang II had a linear correlation with IL-1β. Conclusion Ang II levels of NAFLD patients significantly increased, and elevated Ang II level is an independent risk factor of NAFLD. Our preliminary results also indicate that Ang II may promote the development of NAFLD by activating NLRP3 inflammasome.
Collapse
|
|
5
|
Dapper C, Schuster F, Stölting I, Vogt F, Castro e Souza LA, Alenina N, Bader M, Raasch W. The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:865-877. [DOI: 10.1007/s00210-019-01643-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
|
|
6
|
Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization. Sci Rep 2019; 9:1236. [PMID: 30718686 PMCID: PMC6362091 DOI: 10.1038/s41598-018-38399-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 12/20/2018] [Indexed: 01/08/2023] Open
Abstract
Telmisartan is a well-known anti-hypertensive drug acting as an angiotensin 2 receptor blocker (ARB), but it also possesses partial PPARγ agonistic activity and induces insulin sensitivity. In the present study, we investigated the effects of telmisartan on macrophage polarization in association with its browning capacity, because PPARγ plays a key role in M2 polarization and in the browning of white adipocytes. Telmisartan induced M2 marker expression in murine macrophages concentration dependently, which was confirmed by flow cytometry. Both PPARγ and PPARδ activations appear to be responsible for telmisartan-induced M2 polarization. Telmisartan-treated conditioned medium (Tel-CM) of RAW264.7 cells and of bone marrow derived macrophages (BMDM) induced the expressions of browning markers in fully differentiated white adipocytes with reduced lipid droplets, and increased oxygen consumption rate and mitochondrial biogenesis. Levels of catecholamines (CA) released into the conditioned medium as well as intracellular tyrosine hydroxylase (TH) mRNAs were found to be increased by telmisartan, and browning effects of Tel-CM were lessened by β3 receptor antagonist (L-748,337), suggesting CA secreted into CM play a role in Tel-CM-induced adipocyte browning. Acute administration of telmisartan (2 weeks, p.o.) to C57BL/6J mice increased the expressions of browning markers and M2 markers in white adipose tissues, whereas macrophage depletion by clodronate liposome pretreatment attenuated the telmisartan-induced expressions of browning markers. Together, telmisartan was observed to induce the browning of fully differentiated white adipocytes, at least in part, via PPAR activation-mediated M2 polarization.
Collapse
|
|
7
|
Gustaityte V, Winkler M, Stoelting I, Raasch W. Influence of AT1 blockers on obesity and stress induced eating of cafeteria diet. J Endocrinol 2018; 240:JOE-18-0477.R1. [PMID: 30400045 DOI: 10.1530/joe-18-0477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 10/04/2018] [Indexed: 12/13/2022]
Abstract
Based on findings that treatment with AT1 receptor blocker (ARB) prevents diet-induced obesity and that the activity of the hypothalamic-pituitary-adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD) , thus contributing to alterations in eating behavior. Sprague Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8mg/kg/d) or vehicle. At weeks 2 and 12, rats were stressed over 5 consecutive days by restraint stress (RS, 4h) and by additional shaking at d5. Tail blood was sampled during RS to determine hormone levels. During the first period of RS, ACTH and corticosterone responses were diminished at d5 in CD- compared to chow-fed rats. Independently of feeding, TEL did not reduce stress hormones. Compared to food behavior before RS, the stress-induced CD eating increased in controls but remained unchanged in TEL-treated rats. After 12 weeks, TEL reduced weight gain and energy intake, particularly in CD-fed rats. Similar to the first RS period, corticosterone response was reduced in CD-fed rats at d5 during the second RS period. TEL did not further reduce stress hormones and did not lessen the CD eating upon RS. We conclude that CD feeding compensates for stress reactions. However, stress-induced CD eating was only reduced by TEL after short-term, but not after long-term drug treatment. Thus, the potency of ARBs to lower HPA activity only plays a minor role in reducing energy intake to prevent obesity.
Collapse
Affiliation(s)
- Viktorija Gustaityte
- V Gustaityte, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck, Lübeck, Germany
| | - Martina Winkler
- M Winkler, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck, Lübeck, Germany
| | - Ines Stoelting
- I Stoelting, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck, Lübeck, Germany
| | - Walter Raasch
- W Raasch, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck, Lübeck, Germany
| |
Collapse
|
|
8
|
Hussain SA, Utba RM, Assumaidaee AM. Effects of Azilsartan, Aliskiren or their Combination on High Fat Diet-induced Non-alcoholic Liver Disease Model in Rats. Med Arch 2018; 71:251-255. [PMID: 28974844 PMCID: PMC5585811 DOI: 10.5455/medarh.2017.71.251-255] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION In addition to its role in regulation of blood pressure, fluid and electrolyte homeostasis, the renin-angiotensin system (RAS) components were expressed in many other tissues suggesting potential roles in their functions. AIM The present study aims to evaluate the protective effect aliskiren, when used alone or in combination with azilsartan against high fat diet-induced liver disease in rats. MATERIAL AND METHODS Thirty-two Wistar male rats, weighing 150-200 gm were allocated evenly into four groups and treated as follow: group I, rats were fed a specially formulated high-fat diet for 8 weeks to induce non-alcoholic liver disease and considered as control group; groups II, III and IV, the rats were administered azilsartan (0.5 mg/kg), aliskiren (25 mg/kg) or their combination orally via gavage tube once daily, and maintained on high fat diet for 8 weeks. The possible treatment outcome was evaluated through measuring serum levels of glucose, insulin, lipid profile, TNF-α, IL-1β and liver enzymes. Additionally, the liver tissue contents of glycogen and lipids and histological changes were also evaluated. RESULT The results showed that azilsartan significantly improves the studied markers greater than aliskiren, and their combination o has no additive or synergistic effects on the activity of each one of them. CONCLUSION Both azilsartan and aliskiren protects the rats against high-fat diet induced NAFLD with predominant effects for the former, and their combination showed no beneficial synergistic or additive effects.
Collapse
Affiliation(s)
| | - Rabab Mohammed Utba
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq
| | | |
Collapse
|
|
9
|
Borém LMA, Neto JFR, Brandi IV, Lelis DF, Santos SHS. The role of the angiotensin II type I receptor blocker telmisartan in the treatment of non-alcoholic fatty liver disease: a brief review. Hypertens Res 2018; 41:394-405. [PMID: 29636553 PMCID: PMC7091617 DOI: 10.1038/s41440-018-0040-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 10/31/2017] [Accepted: 11/17/2017] [Indexed: 01/18/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently considered an important component of metabolic syndrome (MetS). The spectrum of NAFLD includes conditions that range from simple hepatic steatosis to non-alcoholic steatohepatitis. NAFLD is correlated with liver-related death and is predicted to be the most frequent indication for liver transplantation by 2030. Insulin resistance is directly correlated to the central mechanisms of hepatic steatosis in NAFLD patients, which is strongly correlated to the imbalance of the renin–angiotensin system, that is involved in lipid and glucose metabolism. Among the emerging treatment approaches for NAFLD is the anti-hypertensive agent telmisartan, which has positive effects on liver, lipid, and glucose metabolism, especially through its action on the renin–angiotensin system, by blocking the ACE/AngII/AT1 axis and increasing ACE2/Ang(1–7)/Mas axis activation. However, treatment with this drug is only recommended for patients with an established indication for anti-hypertensive therapy. Thus, there is an increased need for large randomized controlled trials with the aim of elucidating the effects of telmisartan on liver disease, especially NAFLD. From this perspective, the present review aims to provide a brief examination of the pathogenesis of NAFLD/NASH and the role of telmisartan on preventing liver disorders and thus to improve the discussion on potential therapies.
Collapse
Affiliation(s)
- Luciana M A Borém
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil.,Medicine Department, Faculdades Integradas Pitágoras, Montes Claros, Minas Gerais, Brazil
| | - João F R Neto
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Igor V Brandi
- Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil
| | - Deborah F Lelis
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil
| | - Sergio H S Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros (Unimontes), Montes Claros, Minas Gerais, Brazil. .,Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais (UFMG), Montes Claros, Minas Gerais, Brazil.
| |
Collapse
|
|
10
|
Zhou X, Ren L, Yu Z, Huang X, Li Y, Wang C. The antipsychotics sulpiride induces fatty liver in rats via phosphorylation of insulin receptor substrate-1 at Serine 307-mediated adipose tissue insulin resistance. Toxicol Appl Pharmacol 2018; 345:66-74. [PMID: 29551354 DOI: 10.1016/j.taap.2018.02.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/25/2018] [Accepted: 02/28/2018] [Indexed: 12/13/2022]
Abstract
Cumulative evidence has suggested that many antipsychotics cause metabolic abnormalities. Adipose tissue insulin resistance (Adipo-IR) contributes to the development and progress of metabolic abnormalities including fatty liver by inducing excessive free fatty acid release from adipose tissue. Sulpiride is an old antipsychotic still frequently used in many developing countries. However, its adverse metabolic effects remain poorly understood. Here, chronic administration of sulpiride (80 mg/kg, subcutaneously, once daily for 6 weeks) elevated fasting insulin concentration and the index of the homeostasis model assessment of insulin resistance in rats. More importantly, sulpiride increased hepatic triglyceride accumulation and Oil Red O-stained area, indicating the induction of fatty liver by sulpiride. Sulpiride also increased plasma non-esterified fatty acid concentrations at the baseline and during an oral glucose tolerance test, the Adipo-IR index, and adipocyte size. Adipose gene expression profile revealed that sulpiride decreased mRNA and protein expression of insulin receptor substrate (IRS)-1, but not IRS-2. Furthermore, sulpiride increased phosphorylation of both Ser307 in IRS-1 and Ser473 in Akt at baseline. Co-treatment with bromocriptine (a dopamine D2 receptor agonist) attenuated sulpiride-induced hyperprolactinemia, but it was without effect on insulin resistance and fatty liver. Therefore, the present results suggest that sulpiride induces fatty liver in rats via phosphorylation of IRS-1 at Ser307-mediated adipose tissue insulin resistance, in which dopamine D2 receptor is possibly not involved. Our findings may provide new insights into the mechanisms underlying the steatotic effect of the old antipsychotic.
Collapse
Affiliation(s)
- Xia Zhou
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Liying Ren
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Zhiling Yu
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xiaoqian Huang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuhao Li
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000, Australia
| | - Chunxia Wang
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
| |
Collapse
|
|
11
|
Differential effects of hepatic cirrhosis on the intrinsic clearances of sorafenib and imatinib by CYPs in human liver. Eur J Pharm Sci 2018; 114:55-63. [DOI: 10.1016/j.ejps.2017.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 10/19/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023]
|
|
12
|
Molecular Mechanisms of Sodium-Sensitive Hypertension in the Metabolic Syndrome. Curr Hypertens Rep 2017; 19:60. [DOI: 10.1007/s11906-017-0759-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
|
|
13
|
Asada K, Aihara Y, Takaya H, Noguchi R, Namisaki T, Moriya K, Uejima M, Kitade M, Mashitani T, Takeda K, Kawaratani H, Okura Y, Kaji K, Douhara A, Sawada Y, Nishimura N, Seki K, Mitoro A, Yamao J, Yoshiji H. DNA methylation of angiotensin II receptor gene in nonalcoholic steatohepatitis-related liver fibrosis. World J Hepatol 2016; 8:1194-1199. [PMID: 27729955 PMCID: PMC5055588 DOI: 10.4254/wjh.v8.i28.1194] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 07/08/2016] [Accepted: 08/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To clarify whether Agtr1a methylation is involved in the development of nonalcoholic steatohepatitis (NASH)-related liver fibrosis in adult rats. METHODS A choline-deficient amino acid (CDAA) diet model was employed for methylation analysis of NASH-related liver fibrosis. Agtr1a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid (CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific PCR. Hepatic stellate cells (HSCs) were isolated by collagenase digestion of the liver, followed by centrifugation of the crude cell suspension through a density gradient. Agtr1a methylation and its gene expression were also analyzed during the activation of HSCs. RESULTS The mean levels of Agtr1a methylation in the livers of CDAA-fed rats (11.5% and 18.6% at 8 and 12 wk, respectively) tended to be higher (P = 0.06 and 0.09, respectively) than those in the livers of CSAA-fed rats (2.1% and 5.3% at 8 and 12 wk, respectively). Agtr1a was not methylated at all in quiescent HSCs, but was clearly methylated in activated HSCs (13.8%, P < 0.01). Interestingly, although Agtr1a was hypermethylated, the Agtr1a mRNA level increased up to 2.2-fold (P < 0.05) in activated HSCs compared with that in quiescent HSCs, suggesting that Agtr1a methylation did not silence its expression but instead had the potential to upregulate its expression. These findings indicate that Agtr1a methylation and its upregulation of gene expression are associated with the development of NASH-related liver fibrosis. CONCLUSION This is the first study to show that DNA methylation is potentially involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis.
Collapse
Affiliation(s)
- Kiyoshi Asada
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yosuke Aihara
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Hiroaki Takaya
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Ryuichi Noguchi
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Tadashi Namisaki
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kei Moriya
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Masakazu Uejima
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Mitsuteru Kitade
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Tsuyoshi Mashitani
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kosuke Takeda
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Hideto Kawaratani
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yasushi Okura
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kosuke Kaji
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Akitoshi Douhara
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yasuhiko Sawada
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Norihisa Nishimura
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kenichiro Seki
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Akira Mitoro
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Junichi Yamao
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Hitoshi Yoshiji
- Kiyoshi Asada, Yosuke Aihara, Hiroaki Takaya, Ryuichi Noguchi, Tadashi Namisaki, Kei Moriya, Masakazu Uejima, Mitsuteru Kitade, Tsuyoshi Mashitani, Kosuke Takeda, Hideto Kawaratani, Yasushi Okura, Kosuke Kaji, Akitoshi Douhara, Yasuhiko Sawada, Norihisa Nishimura, Kenichiro Seki, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| |
Collapse
|
|
14
|
|
|
15
|
Jacobs A, Warda A, Verbeek J, Cassiman D, Spincemaille P. An Overview of Mouse Models of Nonalcoholic Steatohepatitis: From Past to Present. ACTA ACUST UNITED AC 2016; 6:185-200. [DOI: 10.1002/cpmo.3] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Ans Jacobs
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
| | - Anne‐Sophie Warda
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
| | - Jef Verbeek
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center Maastricht The Netherlands
| | - David Cassiman
- Department of Hepatology, University Hospitals KU Leuven Leuven Belgium
- Metabolic Center, University Hospitals KU Leuven Leuven Belgium
| | - Pieter Spincemaille
- Department of Laboratory Medicine, University Hospitals KU Leuven Leuven Belgium
| |
Collapse
|
|
16
|
Abstract
Nonalcoholic fatty liver disease is the most common cause of liver disease in the United States. There are no drug therapies approved for the treatment of nonalcoholic steatohepatitis (NASH). Multiple different pathways are involved in the pathogenesis and each can be the target of the therapy. It is possible that more than 1 target is involved in disease development and progression. Multiple clinical trials with promising agents are underway. Because NASH is a slowly progressive disease and treatment likely to be of prolonged duration, acceptance and approval of any agent will require information on long-term clinical benefits and safety.
Collapse
Affiliation(s)
- Bilal Hameed
- Division of Gastroenterology, University of California San Francisco S357, 513 Parnassus Avenue, San Francisco, CA 94143-0538, USA.
| | - Norah Terrault
- Division of Gastroenterology, University of California San Francisco S357, 513 Parnassus Avenue, San Francisco, CA 94143-0538, USA
| |
Collapse
|
|
17
|
Michel MC, Brunner HR, Foster C, Huo Y. Angiotensin II type 1 receptor antagonists in animal models of vascular, cardiac, metabolic and renal disease. Pharmacol Ther 2016; 164:1-81. [PMID: 27130806 DOI: 10.1016/j.pharmthera.2016.03.019] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 02/07/2023]
Abstract
We have reviewed the effects of angiotensin II type 1 receptor antagonists (ARBs) in various animal models of hypertension, atherosclerosis, cardiac function, hypertrophy and fibrosis, glucose and lipid metabolism, and renal function and morphology. Those of azilsartan and telmisartan have been included comprehensively whereas those of other ARBs have been included systematically but without intention of completeness. ARBs as a class lower blood pressure in established hypertension and prevent hypertension development in all applicable animal models except those with a markedly suppressed renin-angiotensin system; blood pressure lowering even persists for a considerable time after discontinuation of treatment. This translates into a reduced mortality, particularly in models exhibiting marked hypertension. The retrieved data on vascular, cardiac and renal function and morphology as well as on glucose and lipid metabolism are discussed to address three main questions: 1. Can ARB effects on blood vessels, heart, kidney and metabolic function be explained by blood pressure lowering alone or are they additionally directly related to blockade of the renin-angiotensin system? 2. Are they shared by other inhibitors of the renin-angiotensin system, e.g. angiotensin converting enzyme inhibitors? 3. Are some effects specific for one or more compounds within the ARB class? Taken together these data profile ARBs as a drug class with unique properties that have beneficial effects far beyond those on blood pressure reduction and, in some cases distinct from those of angiotensin converting enzyme inhibitors. The clinical relevance of angiotensin receptor-independent effects of some ARBs remains to be determined.
Collapse
Affiliation(s)
- Martin C Michel
- Dept. Pharmacology, Johannes Gutenberg University, Mainz, Germany; Dept. Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim, Ingelheim, Germany.
| | | | - Carolyn Foster
- Retiree from Dept. of Research Networking, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
| | - Yong Huo
- Dept. Cardiology & Heart Center, Peking University First Hospital, Beijing, PR China
| |
Collapse
|
|
18
|
Wannasiri S, Piyabhan P, Naowaboot J. Rhinacanthus nasutus leaf improves metabolic abnormalities in high-fat diet-induced obese mice. Asian Pac J Trop Biomed 2016. [DOI: 10.1016/j.apjtb.2015.10.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
|
|
19
|
Schuchard J, Winkler M, Stölting I, Schuster F, Vogt FM, Barkhausen J, Thorns C, Santos RA, Bader M, Raasch W. Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1-7)/Mas-dependent pathway. Br J Pharmacol 2015; 172:3764-78. [PMID: 25906670 DOI: 10.1111/bph.13172] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 03/24/2015] [Accepted: 04/04/2015] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND PURPOSE Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II . As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects. EXPERIMENTAL APPROACH We investigated the anti-obesity effects of transgenically overexpressed angiotensin-(1-7) in rats. We secondly examined whether weight loss due to telmisartan (8 mg·kg(-1) ·d(-1) ) in diet-induced obese Sprague Dawley (SD) rats can be blocked when the animals were co-treated with the Mas receptor antagonist A779 (24 or 72 μg·kg(-1) ·d(-1) ). KEY RESULTS In contrast to wild-type controls, transgenic rats overexpressing angiotensin-(1-7) had 1.) diminished body weight when they were regularly fed with chow; 2.) were protected from developing obesity although they were fed with cafeteria diet (CD); 3.) showed a reduced energy intake that was mainly related to a lower CD intake; 5.) remained responsive to leptin despite chronic CD feeding; 6.) had a higher, strain-dependent energy expenditure, and 7.) were protected from developing insulin resistance despite CD feeding. Telmisartan-induced weight loss in SD rats was partially antagonized after a high, but not a low dose of A779. CONCLUSIONS AND IMPLICATIONS Angiotensin-(1-7) regulated food intake and body weight and contributed to the weight loss after AT1 receptor blockade. Angiotensin-(1-7)-like agonists may be drug candidates for treating obesity.
Collapse
Affiliation(s)
- Johanna Schuchard
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | - Martina Winkler
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Ines Stölting
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Franziska Schuster
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Florian M Vogt
- Department for Radiology and Nuclear Medicine, University of Lübeck, Lübeck, Germany
| | - Jörg Barkhausen
- Department for Radiology and Nuclear Medicine, University of Lübeck, Lübeck, Germany
| | - Christoph Thorns
- Department of Pathology, University Clinic Schleswig-Holstein, Luebeck, Germany
| | - Robson A Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Michael Bader
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.,Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.,Center for Structural and Cell Biology in Medicine, Institute for Biology, University of Lübeck, Lübeck, Germany.,Charité - University Medicine Berlin, Berlin, Germany
| | - Walter Raasch
- Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany
| |
Collapse
|
|
20
|
Zhao Y, Pan Y, Yang Y, Batey R, Wang J, Li Y. Treatment of rats with Jiangzhi Capsule improves liquid fructose-induced fatty liver: modulation of hepatic expression of SREBP-1c and DGAT-2. J Transl Med 2015; 13:174. [PMID: 26031670 PMCID: PMC4467629 DOI: 10.1186/s12967-015-0529-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 05/12/2015] [Indexed: 12/25/2022] Open
Abstract
Background Jiangzhi Capsule is an Australian listed patented traditional Chinese medicine and has been used for management of lipid abnormalities over the past 10 years. To obtain a better understanding regarding Jiangzhi Capsule, the present study investigated the effects and underlying mechanisms of Jiangzhi Capsule on chronic fructose overconsumption-induced lipid abnormalities. Methods Male rats were treated with liquid fructose in their drinking water over 14 weeks. Jiangzhi Capsule was co-administered (once daily, by oral gavage) during the last 7 weeks. Indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by real-time PCR, Western blot and/or immunohistochemistry. Results Treatment with Jiangzhi Capsule (100 mg/kg) attenuated fructose-induced excessive triglyceride accumulation and Oil Red O-stained area in the liver. This effect was accompanied by amelioration of hyperinsulinemia. There was no significant difference in intakes of fructose and chow, and body weight between fructose control and fructose Jiangzhi Capsule-treated groups. Mechanistically, Jiangzhi Capsule downregulated fructose-stimulated hepatic overexpression of sterol regulatory element binding protein (SREBP)-1/1c at the mRNA and protein levels. Accordingly, the SREBP-1c downstream genes, acetyl-CoA carboxylase-1 and stearoyl-CoA desaturase-1, were also inhibited. In addition, acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver was also inhibited after Jiangzhi Capsule treatment. In contrast, Jiangzhi Capsule affected neither carbohydrate response element binding protein, peroxisome proliferator-activated receptor (PPAR)-gamma and DGAT-1, nor PPAR-alpha and its target genes. Conclusions These findings demonstrate the anti-steatotic action of Jiangzhi Capsule in fructose-fed rats, and modulation of hepatic SREBP-1c and DGAT-2 involved in hepatic de novo synthesis of fatty acids and triglyceride, respectively. Our findings provide an evidence-based and mechanistic understanding of Jiangzhi Capsule supporting its application for the prevention and/or treatment of fatty liver and its associated disorders in clinical practice. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0529-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Yuanyang Zhao
- Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
| | - Yongquan Pan
- The Laboratory Animal Center, Chongqing Medical University, Chongqing, China.
| | - Yifan Yang
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, NSW, Australia.
| | - Robert Batey
- Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, NSW, Australia.
| | - Jianwei Wang
- Laboratory of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China.
| | - Yuhao Li
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Sydney, NSW, Australia.
| |
Collapse
|
|
21
|
Abstract
Angiotensin II receptor blockers (ARBs, collectively called sartans) are widely used compounds therapeutically effective in cardiovascular disorders, renal disease, the metabolic syndrome, and diabetes. It has been more recently recognized that ARBs are neuroprotective and have potential therapeutic use in many brain disorders. ARBs ameliorate inflammatory and apoptotic responses to glutamate, interleukin 1β and bacterial endotoxin in cultured neurons, astrocytes, microglial, and endothelial cerebrovascular cells. When administered systemically, ARBs enter the brain, protecting cerebral blood flow, maintaining blood brain barrier function and decreasing cerebral hemorrhage, excessive brain inflammation and neuronal injury in animal models of stroke, traumatic brain injury, Alzheimer's and Parkinson's disease and other brain conditions. Epidemiological analyses reported that ARBs reduced the progression of Alzheimer's disease, and clinical studies suggested amelioration of cognitive loss following stroke and aging. ARBs are pharmacologically heterogeneous; their effects are not only the result of Ang II type 1(AT1) receptor blockade but also of additional mechanisms selective for only some compounds of the class. These include peroxisome proliferator-activated receptor gamma activation and other still poorly defined mechanisms. However, the complete pharmacological spectrum and therapeutic efficacy of individual ARBs have never been systematically compared, and the neuroprotective efficacy of these compounds has not been rigorously determined in controlled clinical studies. The accumulation of pre-clinical evidence should promote further epidemiological and controlled clinical studies. Repurposing ARBs for the treatment of brain disorders, currently without effective therapy, may be of immediate and major translational value.
Collapse
Affiliation(s)
- Sonia Villapol
- Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia, USA
| | - Juan M Saavedra
- Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, District of Columbia, USA.
| |
Collapse
|
|
22
|
Müller-Fielitz H, Hübel N, Mildner M, Vogt FM, Barkhausen J, Raasch W. Chronic blockade of angiotensin AT₁ receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats. Br J Pharmacol 2014; 171:746-60. [PMID: 24490862 DOI: 10.1111/bph.12510] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Revised: 10/18/2013] [Accepted: 10/26/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE AT₁ receptor antagonists decrease body weight gain in models of murine obesity. However, fewer data are available concerning the anti-obesity effects of these antagonists, given as a treatment after obesity had been established. EXPERIMENTAL APPROACH In spontaneously hypertensive rats, obesity was established by cafeteria diet (CD) feeding for 19 weeks. Rats were then were treated with telmisartan (8 mg·kg⁻¹·d⁻¹) or amlodipine (10 mg·kg⁻¹·d⁻¹; serving as blood pressure control) or telmisartan + amlodipine (2 + 10 mg·kg⁻¹·d⁻¹; to control for dose-dependency) for 17 weeks. Rats receiving only chow (C(chow)) or CD-fed rats treated with vehicle (C(CD)) served as controls. KEY RESULTS The CD feeding induced obesity, hyperphagia, hyperlipidaemia, and leptin and insulin resistance. Telmisartan reduced the CD-induced increase in body weight and abdominal fat mass. Whereas energy intake was higher rather than lower, the respiratory ratio was lower. After telmisartan, leptin-induced energy intake was reduced and respiratory ratio was increased compared with C(CD) rats. Telmisartan also decreased plasma levels of triglycerides, free fatty acids and low-density lipoprotein. Amlodipine alone or the combination telmisartan + amlodipine did not affect body weight and eating behaviour. Telmisartan, but not amlodipine and telmisartan + amlodipine, improved glucose utilization. The decrease in BP reduction was almost the same in all treatment groups. CONCLUSIONS AND IMPLICATIONS Telmisartan exerted anti-obesity effects and restored leptin sensitivity, given as a treatment to rats with obesity. Such effects required high doses of telmisartan and were independent of the decrease in blood pressure.
Collapse
Affiliation(s)
- Helge Müller-Fielitz
- Institute of Experimental and Clinical Pharmacology and Toxicology, partner site Hamburg/Kiel/Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany
| | | | | | | | | | | |
Collapse
|
|
23
|
Liu L, Yang M, Lin X, Li Y, Liu C, Yang Y, Yamahara J, Wang J, Li Y. Modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to Salacia oblonga root-elicited improvement of fructose-induced fatty liver in rats. JOURNAL OF ETHNOPHARMACOLOGY 2013; 150:1045-1052. [PMID: 24157375 DOI: 10.1016/j.jep.2013.10.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 07/04/2013] [Accepted: 10/10/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Salacia oblonga root (SOR) is a traditionally herbal medicine for obesity and diabetes, which are closely associated with fatty liver. To investigate the molecular mechanisms of SOR in the treatment of dietary-induced fatty liver. MATERIALS AND METHODS Male rats were co-administered with fructose in drinking water and vehicle or the aqueous-ethanolic extract of SOR (by gavage, once daily) for 10 weeks. Biochemical variables were determined enzymatically or by ELISA. Gene expression was analyzed by Real-Time PCR and/or Western blot. RESULTS SOR treatment (20mg/kg) diminished fructose-induced fatty liver indicated by decreases in excess triglyceride accumulation and the increased vacuolization and Oil Red O staining area in the livers of rats. Importantly, Hepatic gene expression profile revealed that SOR suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein (SREBP)-1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes, such as fatty acid synthase, acetyl-CoA carboxylase-1 and stearoyl-CoA desaturase-1, was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element binding protein and mRNA of its target gene liver pyruvate kinase were not altered. Additionally, SOR also did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha, as well as their target genes, such as carnitine palmitoyltransferase-1a, acyl-CoA oxidase and CD36. CONCLUSIONS These results suggest that modulation of hepatic sterol regulatory element-binding protein-1c-mediated gene expression contributes to SOR-elicited improvement of fructose-induced fatty liver in rats. Our findings provide a better understanding of SOR in the treatment of obesity and diabetes.
Collapse
Affiliation(s)
- Lei Liu
- Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Rüster C, Wolf G. The role of the renin-angiotensin-aldosterone system in obesity-related renal diseases. Semin Nephrol 2013; 33:44-53. [PMID: 23374893 DOI: 10.1016/j.semnephrol.2012.12.002] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Obesity is an independent risk factor for the development and progression of chronic kidney disease and one of the emerging reasons for end-stage renal disease owing to its dramatic increase worldwide. Among the potential underlying pathophysiologic mechanisms, activation of the renin-angiotensin-aldosterone-system (RAAS) plays a central role. Increased angiotensin II (AngII) levels also are central in hypertension, dyslipidemia, and insulin resistance, which, taken together with obesity, represent the metabolic syndrome. Increased AngII levels contribute to hyperfiltration, glomerulomegaly, and subsequent focal glomerulosclerosis by altering renal hemodynamics via afferent arteriolar dilation, together with efferent renal arteriolar vasoconstriction as well as by its endocrine and paracrine properties linking the intrarenal and the systemic RAAS, adipose tissue dysfunction, as well as insulin resistance and hypertension. The imbalance between increased AngII levels and the angiotensin converting enzyme 2/Ang (1-7)/Mas receptor axis additionally contributes to renal injury in obesity and its concomitant metabolic disturbances. As shown in several large trials and experimental studies, treatment of obesity by weight loss is associated with an improvement of kidney disease because it also is beneficial in dyslipidemia, hypertension, and diabetes. The most promising data have been seen by RAAS blockade, pointing to the central position of RAAS within obesity, kidney disease, and the metabolic syndrome.
Collapse
Affiliation(s)
- Christiane Rüster
- Department of Internal Medicine III, University Hospital Jena, Jena, Germany
| | | |
Collapse
|
|
25
|
Zídek V, Mlejnek P, Simáková M, Silhavy J, Landa V, Kazdová L, Pravenec M, Kurtz TW. Tissue-specific peroxisome proliferator activated receptor gamma expression and metabolic effects of telmisartan. Am J Hypertens 2013; 26:829-35. [PMID: 23426788 DOI: 10.1093/ajh/hpt019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The angiotensin receptor blocker telmisartan has unique chemical properties that enable it to partially activate the peroxisome proliferator activated receptor gamma (PPARG) as well as block angiotensin II type 1 receptors. METHODS To directly test whether some of the metabolic effects of telmisartan require the presence of PPARG, we studied mice in which the gene (Pparg) for PPARG had been deleted in fat or in muscle. RESULTS We found that knockout of Pparg in fat tissue greatly impaired the ability of telmisartan to increase adiponectin levels and to enhance sensitivity to insulin-stimulated glucose incorporation into adipose tissue lipids. In contrast, muscle-specific Pparg knockout had relatively little or no impact on the ability of telmisartan to increase adiponectin levels or affect glucose metabolism either in fat or muscle. These findings provide compelling evidence that the ability of telmisartan to increase adiponectin levels and stimulate glucose use in adipose tissue may depend on the presence of PPARG in fat. CONCLUSIONS We conclude that PPARG in adipose tissue is required for at least several of the metabolic actions of telmisartan.
Collapse
Affiliation(s)
- Václav Zídek
- Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Oleanolic Acid diminishes liquid fructose-induced Fatty liver in rats: role of modulation of hepatic sterol regulatory element-binding protein-1c-mediated expression of genes responsible for de novo Fatty Acid synthesis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:534084. [PMID: 23737835 PMCID: PMC3659486 DOI: 10.1155/2013/534084] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 03/29/2013] [Accepted: 04/07/2013] [Indexed: 01/01/2023]
Abstract
Oleanolic acid (OA), contained in more than 1620 plants and as an aglycone precursor for naturally occurred and synthesized triterpenoid saponins, is used in China for liver disorders in humans. However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that treatment of rats with OA (25 mg/kg/day, gavage, once daily) over 10 weeks diminished liquid fructose-induced excess hepatic triglyceride accumulation without effect on total energy intake. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in OA-treated rats. Hepatic gene expression profile demonstrated that OA suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein-(SREBP-) 1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes responsible for fatty acid synthesis was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element-binding protein and its target genes liver pyruvate kinase and microsomal triglyceride transfer protein were not altered. Additionally, OA did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha and their target genes. It is concluded that modulation of hepatic SREBP-1c-mediated expression of the genes responsible for de novo fatty acid synthesis plays a pivotal role in OA-elicited diminishment of fructose-induced fatty liver in rats.
Collapse
|
|
27
|
Michel MC, Foster C, Brunner HR, Liu L. A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev 2013; 65:809-48. [PMID: 23487168 DOI: 10.1124/pr.112.007278] [Citation(s) in RCA: 218] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy. Eight ARBs are clinically available [azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan]. Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites. On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism. The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier. Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action. Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article. Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed.
Collapse
Affiliation(s)
- Martin C Michel
- Department of Clinical Development & Medical Affairs, Boehringer Ingelheim, 55216 Ingelheim, Germany.
| | | | | | | |
Collapse
|
|
28
|
Improvement of liquid fructose-induced adipose tissue insulin resistance by ginger treatment in rats is associated with suppression of adipose macrophage-related proinflammatory cytokines. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:590376. [PMID: 23533500 PMCID: PMC3594984 DOI: 10.1155/2013/590376] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Revised: 12/25/2012] [Accepted: 01/12/2013] [Indexed: 02/06/2023]
Abstract
Adipose tissue insulin resistance (Adipo-IR) results in excessive release of free fatty acids from adipose tissue, which plays a key role in the development of “lipotoxicity.” Therefore, amelioration of Adipo-IR may benefit the treatment of other metabolic abnormalities. Here we found that treatment with the alcoholic extract of ginger (50 mg/kg/day, by oral gavage) for five weeks attenuated liquid fructose-induced hyperinsulinemia and an increase in the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. More importantly, ginger reversed the increases in the Adipo-IR index and plasma nonesterified fatty acid concentrations during the oral glucose tolerance test assessment. Adipose gene/protein expression profiles revealed that ginger treatment suppressed CD68 and F4/80, two important macrophage accumulation markers. Consistently, the macrophage-associated cytokines tissue necrosis factor alpha and interleukin-6 were also downregulated. In contrast, insulin receptor substrate (IRS)-1, but not IRS-2, was upregulated. Moreover, monocyte chemotactic protein (MCP)-1 and its receptor chemokine (C-C motif) receptor-2 were also suppressed. Thus these results suggest that amelioration of fructose-induced Adipo-IR by ginger treatment in rats is associated with suppression of adipose macrophage-related proinflammatory cytokines.
Collapse
|
|
29
|
Salama RM, Schaalan MF, Ibrahim ME, Khalifa AE, Elkoussi AA. Effectiveness of Telmisartan as an Adjunct to Metformin in Treating Type II Diabetes Mellitus in Rats. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/ojemd.2013.33026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
30
|
Paschos P, Tziomalos K. Nonalcoholic fatty liver disease and the renin-angiotensin system: Implications for treatment. World J Hepatol 2012; 4:327-331. [PMID: 23355909 PMCID: PMC3554795 DOI: 10.4254/wjh.v4.i12.327] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 10/18/2012] [Accepted: 11/17/2012] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest liver disease in Western countries. Treatment of NAFLD is currently based on lifestyle measures and no effective pharmacologic treatment is available so far. Emerging evidence, mainly from animal studies, suggests that the renin-angiotensin-aldosterone system may be of major importance in the pathogenesis of NAFLD and indicates that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) as a potentially useful therapeutic approach. However, data from human studies are limited and contradictory. In addition, there are few randomized controlled trials (RCTs) on the effects of ACE-I or ARB in patients with NAFLD and most data are from retrospective studies, pilot prospective studies and post hoc analyses of clinical trials. Accordingly, more and larger RCTs are needed to directly assess the effectiveness of ACE-I and ARBs in NAFLD.
Collapse
Affiliation(s)
- Paschalis Paschos
- Paschalis Paschos, Konstantinos Tziomalos, First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
| | | |
Collapse
|
|
31
|
Treatment with ginger ameliorates fructose-induced Fatty liver and hypertriglyceridemia in rats: modulation of the hepatic carbohydrate response element-binding protein-mediated pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012. [PMID: 23193424 PMCID: PMC3502023 DOI: 10.1155/2012/570948] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Ginger has been demonstrated to improve lipid derangements. However, its underlying triglyceride-lowering mechanisms remain unclear. Fructose overconsumption is associated with increase in hepatic de novo lipogenesis, thereby resulting in lipid derangements. Here we found that coadministration of the alcoholic extract of ginger (50 mg/kg/day, oral gavage, once daily) over 5 weeks reversed liquid fructose-induced increase in plasma triglyceride and glucose concentrations and hepatic triglyceride content in rats. Plasma nonesterified fatty acid concentration was also decreased. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in ginger-treated rats. However, ginger treatment did not affect chow intake and body weight. Further, ginger treatment suppressed fructose-stimulated overexpression of carbohydrate response element-binding protein (ChREBP) at the mRNA and protein levels in the liver. Consequently, hepatic expression of the ChREBP-targeted lipogenic genes responsible for fatty acid biosynthesis was also downregulated. In contrast, expression of neither peroxisome proliferator-activated receptor- (PPAR-) alpha and its downstream genes, nor PPAR-gamma and sterol regulatory element-binding protein 1c was altered. Thus the present findings suggest that in rats, amelioration of fructose-induced fatty liver and hypertriglyceridemia by ginger treatment involves modulation of the hepatic ChREBP-mediated pathway.
Collapse
|
|
32
|
Putnam K, Batifoulier-Yiannikouris F, Bharadwaj KG, Lewis E, Karounos M, Daugherty A, Cassis LA. Deficiency of angiotensin type 1a receptors in adipocytes reduces differentiation and promotes hypertrophy of adipocytes in lean mice. Endocrinology 2012; 153:4677-86. [PMID: 22919058 PMCID: PMC3512029 DOI: 10.1210/en.2012-1352] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Adipocytes express angiotensin receptors, but the direct effects of angiotensin II (AngII) stimulating this cell type are undefined. Adipocytes express angiotensin type 1a receptor (AT1aR) and AT2R, both of which have been implicated in obesity. In this study, we determined the effects of adipocyte AT1aR deficiency on adipocyte differentiation and the development of obesity in mice fed low-fat (LF) or high-fat (HF) diets. Mice expressing Cre recombinase under the control of the aP2 promoter were bred with AT1aR-floxed mice to generate mice with adipocyte AT1aR deficiency (AT1aR(aP2)). AT1aR mRNA abundance was reduced significantly in both white and brown adipose tissue from AT1aR(aP2) mice compared with nontransgenic littermates (AT1aR(fl/fl)). Adipocyte AT1aR deficiency did not influence body weight, glucose tolerance, or blood pressure in mice fed either LF or high-fat diets. However, LF-fed AT1aR(aP2) mice exhibited striking adipocyte hypertrophy even though total fat mass was not different between genotypes. Stromal vascular cells from AT1aR(aP2) mice differentiated to a lesser extent to adipocytes compared with controls. Conversely, incubation of 3T3-L1 adipocytes with AngII increased Oil Red O staining and increased mRNA abundance of peroxisome proliferator-activated receptor γ (PPARγ) via AT1R stimulation. These results suggest that reductions in adipocyte differentiation in LF-fed AT1aR(aP2) mice resulted in increased lipid storage and hypertrophy of remaining adipocytes. These results demonstrate that AngII regulates adipocyte differentiation and morphology through the adipocyte AT1aR in lean mice.
Collapse
Affiliation(s)
- Kelly Putnam
- Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536-0200, USA
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Wang J, Rong X, Li W, Yang Y, Yamahara J, Li Y. Rhodiola crenulata root ameliorates derangements of glucose and lipid metabolism in a rat model of the metabolic syndrome and type 2 diabetes. JOURNAL OF ETHNOPHARMACOLOGY 2012; 142:782-788. [PMID: 22683493 DOI: 10.1016/j.jep.2012.05.063] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 05/07/2012] [Accepted: 05/29/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Rhodiola species are traditionally used as tonics and stimulants to treat asthenia, suggesting their possible regulatory effect on energy metabolism. Clinical trials have demonstrated their glucose-lowering effect in type 2 diabetes. AIM OF THE STUDY To examine the effects of Rhodiola on glucose and lipid metabolism in the metabolic syndrome and type 2 diabetes. MATERIALS AND METHODS Zucker diabetic fatty (ZDF) rats were treated with Rhodiola crenulata root (RCR) powder (100 and 500 mg/kg, by gavage, once daily for 4 weeks). In addition, the effects of RCR on sucrose-induced acute hyperglycemia in mice and olive oil-induced hypertriglyceridemia in rats were also examined. Biochemical variables were determined enzymatically or by ELISA. RESULTS In ZDF rats, RCR treatment decreased the increased plasma insulin and triglyceride concentrations at baseline, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and excessive hepatic triglyceride accumulation. This treatment also inhibited abnormal increases in plasma glucose and insulin concentrations during oral glucose tolerance test. Furthermore, RCR reversed the increased adipose insulin resistance index, and accelerated the decline of plasma concentrations of non-esterified fatty acids after exogenous glucose stimulation. However, RCR minimally affected sucrose-induced acute hyperglycemia in mice and olive oil-induced acute hypertriglyceridemia in rats. CONCLUSIONS The present results demonstrate that RCR treatment improves metabolic derangements in animal model of the metabolic syndrome and type 2 diabetes. Our findings may provide new pharmacological basis of therapeutics for the adaptogenic plants to treat metabolic derangements-associated disorders, such as asthenia.
Collapse
Affiliation(s)
- Jianwei Wang
- Faculty of Basic Medical Sciences, Chongqing Medical University, China
| | | | | | | | | | | |
Collapse
|
|
34
|
Wang J, Rong X, Li W, Yamahara J, Li Y. Salacia oblonga ameliorates hypertriglyceridemia and excessive ectopic fat accumulation in laying hens. JOURNAL OF ETHNOPHARMACOLOGY 2012; 142:221-227. [PMID: 22561158 DOI: 10.1016/j.jep.2012.04.048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 03/17/2012] [Accepted: 04/25/2012] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Salacia oblonga root (SOR) is an Ayurvedic medicine for obesity and diabetes, those are associated with glucose and lipid metabolism. AIM OF THE STUDY SOR has been demonstrated previously to improve glucose and lipid metabolism in animal models of obesity and diabetes and to be a peroxisome proliferator-activated receptor-alpha activator. However, the anti-obesogenic and anti-diabetic mechanisms of SOR are still not largely understood. Here, we investigated the effects of SOR on lipid metabolism using laying hen, a unique animal model with a very high rate of triglyceride synthesis in the liver. MATERIALS AND METHODS Laying hens and preadolescent pullets were treated with the layer ration containing 0%, 0.5%, or 1% SOR water extract for 4 weeks. Biochemical variables were determined enzymatically. RESULTS Laying hens showed much higher fasted triglyceride concentrations (increased by 5-13 folds) in plasma, liver, skeletal muscle and heart than pullets. 1% SOR extract treatment inhibited body weight increase without affecting food intake. Importantly, this treatment substantially attenuated hypertriglyceridemia and inhibited increases in triglyceride contents in the non-adipose tissues. However, SOR extract did not induce change in plasma glucose concentration. Moreover, SOR extract did not alter all variables in pullets. CONCLUSIONS These results demonstrate that SOR ameliorates hypertriglyceridemia and excessive ectopic fat accumulation in laying hens. These findings suggest that the triglyceride-lowering property is one of the primary effects of SOR, possibly via hepatic mechanisms.
Collapse
Affiliation(s)
- Jianwei Wang
- Division of Metabolism, Faculty of Basic Medical Sciences, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong District, Chongqing 400016, China
| | | | | | | | | |
Collapse
|
|
35
|
Younis F, Oron Y, Limor R, Stern N, Rosenthal T. Prophylactic treatment with telmisartan induces tissue-specific gene modulation favoring normal glucose homeostasis in Cohen-Rosenthal diabetic hypertensive rats. Metabolism 2012; 61:164-74. [PMID: 21820685 DOI: 10.1016/j.metabol.2011.06.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 05/31/2011] [Accepted: 06/09/2011] [Indexed: 01/22/2023]
Abstract
The objectives were to assess the potential of long-term prophylactic administration of telmisartan, an angiotensin II receptor antagonist and a partial peroxisome proliferator activator receptor (PPAR)γ agonist, in preventing the development of hypertension and hyperglycemia and to demonstrate the alteration in gene expression associated with the development of hyperglycemia and insulin resistance in Cohen-Rosenthal diabetic hypertensive rat, a unique model of hypertension and type 2 diabetes mellitus comorbidity. Cohen-Rosenthal diabetic hypertensive rats were continuously treated with telmisartan (3 mg/[kg d]) starting at age 6 to 8 weeks before developing hypertension or diabetes. Weight changes, blood pressure, blood insulin, adiponectin, glucose tolerance, and insulin sensitivity were monitored. Fat, liver, and muscle messenger RNAs were examined for the expression of genes potentially involved in the onset of insulin resistance. In addition to the expected antihypertensive effect of prophylactic telmisartan, diabetes was blunted, evidenced at the end of the study by a significantly lower glucose level. This was accompanied by improved glucose tolerance, increased sensitivity to insulin, reduction in fasting insulin levels and homeostasis model assessment index, as well as an increase in serum adiponectin. Telmisartan also prevented the increase in serum triglycerides and the associated appearance of lipid droplets in the liver. Diabetes induced tissue-specific changes in messenger RNAs expression of the following selected genes, which were restored by telmisartan treatment: PPARγ, PPARδ, PPARγ coactivator 1α, adiponectin, adiponectin receptor 1, adiponectin receptor 2, phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, adenosine monophosphate kinase, and glucose translocator 4. Telmisartan blunted the development of hypertension, insulin resistance, and diabetes in prediabetic Cohen-Rosenthal diabetic hypertensive rats through pleiotropic activity, involving specific gene regulation of target organs.
Collapse
Affiliation(s)
- Firas Younis
- Department of Physiology and Pharmacology, Hypertension Research Unit, Sackler School of Medicine, Tel Aviv University 69978, Tel Aviv, Israel
| | | | | | | | | |
Collapse
|
|
36
|
Kumar R, Yong QC, Thomas CM, Baker KM. Intracardiac intracellular angiotensin system in diabetes. Am J Physiol Regul Integr Comp Physiol 2011; 302:R510-7. [PMID: 22170614 DOI: 10.1152/ajpregu.00512.2011] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies.
Collapse
Affiliation(s)
- Rajesh Kumar
- Division of Molecular Cardiology, Texas A&M Health Science Center, College of Medicine, Temple, TX 76504, USA
| | | | | | | |
Collapse
|
|
37
|
Zhao M, Li Y, Wang J, Ebihara K, Rong X, Hosoda K, Tomita T, Nakao K. Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats. Diabetes Obes Metab 2011; 13:1123-9. [PMID: 21749604 DOI: 10.1111/j.1463-1326.2011.01471.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats. METHODS Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR. RESULTS In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression. CONCLUSIONS These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.
Collapse
Affiliation(s)
- M Zhao
- Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Xu X, Yin X, Feng W, Li G, Wang D, Tu L. Telmisartan protects against insulin resistance by attenuating inflammatory response in rats. ACTA ACUST UNITED AC 2011; 31:317-323. [DOI: 10.1007/s11596-011-0374-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2010] [Indexed: 12/29/2022]
|
|
39
|
Sahebkar A. Metabolic improvement by telmisartan beyond angiotensin receptor blockade: role of adipokines. ARQUIVOS BRASILEIROS DE ENDOCRINOLOGIA E METABOLOGIA 2011; 55:353-354. [PMID: 21881820 DOI: 10.1590/s0004-27302011000500010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
|
|
40
|
Ma LJ, Corsa BA, Zhou J, Yang H, Li H, Tang YW, Babaev VR, Major AS, Linton MF, Fazio S, Hunley TE, Kon V, Fogo AB. Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity. Am J Physiol Renal Physiol 2011; 300:F1203-13. [PMID: 21367915 DOI: 10.1152/ajprenal.00468.2010] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The mechanisms for increased risk of chronic kidney disease (CKD) in obesity remain unclear. The renin-angiotensin system is implicated in the pathogenesis of both adiposity and CKD. We investigated whether the angiotensin type 1 (AT(1)) receptor, composed of dominant AT(1a) and less expressed AT(1b) in wild-type (WT) mice, modulates development and progression of kidney injury in a high-fat diet (HFD)-induced obesity model. WT mice had increased body weight, body fat, and insulin levels and decreased adiponectin levels after 24 wk of a high-fat diet. Identically fed AT(1a) knockout (AT1aKO) mice gained weight similarly to WT mice, but had lower body fat and higher plasma cholesterol. Both obese AT1aKO and obese WT mice had increased visceral fat and kidney macrophage infiltration, with more proinflammatory M1 macrophage markers as well as increased mesangial expansion and tubular vacuolization, compared with lean mice. These abnormalities were heightened in the obese AT1aKO mice, with downregulated M2 macrophage markers and increased macrophage AT(1b) receptor. Treatment with an AT(1) receptor blocker, which affects both AT(1a) and AT(1b), abolished renal macrophage infiltration with inhibition of renal M1 and upregulation of M2 macrophage markers in obese WT mice. Our data suggest obesity accelerates kidney injury, linked to augmented inflammation in adipose and kidney tissues and a proinflammatory shift in macrophage and M1/M2 balance.
Collapse
Affiliation(s)
- Li-Jun Ma
- Department of Pathology, Vanderbilt Univ. Medical Center, Nashville, TN 37232-2561, USA.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Lardizabal JA, Deedwania PC. The role of renin-angiotensin agents in altering the natural history of type 2 diabetes mellitus. Curr Cardiol Rep 2010; 12:464-71. [PMID: 20809236 PMCID: PMC2939350 DOI: 10.1007/s11886-010-0138-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease (CVD) morbidity and mortality worldwide. Renin-angiotensin system (RAS) blockers have been indispensable in diminishing the macrovascular and microvascular complications of diabetes. In addition, cumulative evidence from retrospective studies pointed toward a beneficial effect of RAS agents in preventing the development and progression of T2DM. This disease-modifying potential of RAS blockers has been substantiated by recent prospective trials. Contemporary concepts regarding the natural history of T2DM and the pathophysiologic processes involved have increased our understanding of the mechanisms underlying the therapeutic potential of these agents in diabetes management. In addition to their established roles in the primary prevention of CVD in patients with diabetes, RAS blockers might be considered a suitable therapeutic choice for preventing the development of frank diabetes in high-risk patients.
Collapse
Affiliation(s)
- Joel A Lardizabal
- Department of Medicine, University of California in San Francisco (Fresno-MEP), 155 North Fresno Street, Fresno, CA 93701, USA.
| | | |
Collapse
|
|
42
|
Foryst-Ludwig A, Hartge M, Clemenz M, Sprang C, Hess K, Marx N, Unger T, Kintscher U. PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice. Cardiovasc Diabetol 2010; 9:64. [PMID: 20955583 PMCID: PMC2984486 DOI: 10.1186/1475-2840-9-64] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2010] [Accepted: 10/18/2010] [Indexed: 12/13/2022] Open
Abstract
Background Inflammation of adipose tissue (AT) has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD) develop systemic insulin resistance (IR) and glucose intolerance (GI) associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti-inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model) in mice. Methods In order to investigate the molecular mechanisms underlying early development of systemic insulin resistance and glucose intolerance male C57BL/6J mice were fed with high fat diet (HFD) for 10-weeks in parallel to the pharmacological intervention with rosiglitazone, telmisartan, or vehicle. Results Both rosiglitazone and telmisartan were able to reduce T-lymphocyte infiltration into AT analyzed by quantitative analysis of the T-cell marker CD3gamma and the chemokine SDF1alpha. Subsequently, both PPARgamma agonists were able to attenuate macrophage infiltration into AT, measured by the reduction of MCP1 and F4/80 expression. In parallel to the reduction of AT-inflammation, ligand-activated PPARgamma improved diet-induced IR and GI. Conclusion Together the present study demonstrates a close connection between PPARgamma-mediated anti-inflammation in AT and systemic improvement of glucose metabolism identifying T-lymphocytes as one cellular mediator of PPARgamma´s action.
Collapse
Affiliation(s)
- Anna Foryst-Ludwig
- Center for Cardiovascular Research, Institute of Pharmacology Charité-Universitätsmedizin Berlin, Germany
| | | | | | | | | | | | | | | |
Collapse
|