PPARγ功能缺乏加速脂肪酸在肝脏的利用:炎症性脂肪因子诱导的类风湿性关节炎低血脂的基础

Yan Wang, Yu-Qing Ruan, Lian-Jun He, Meng-Ke Song, Opeyemi Joshua Olatunji, Xiu Wang* and Jian Zuo*, 
{"title":"PPARγ功能缺乏加速脂肪酸在肝脏的利用:炎症性脂肪因子诱导的类风湿性关节炎低血脂的基础","authors":"Yan Wang,&nbsp;Yu-Qing Ruan,&nbsp;Lian-Jun He,&nbsp;Meng-Ke Song,&nbsp;Opeyemi Joshua Olatunji,&nbsp;Xiu Wang* and Jian Zuo*,&nbsp;","doi":"10.1021/acsptsci.4c0047010.1021/acsptsci.4c00470","DOIUrl":null,"url":null,"abstract":"<p >Triglyceride (TG) and its derivatives tend to be decreased in rheumatoid arthritis (RA) patients’ blood when inflammation progresses. Aside from the role as a lipid buffer, white adipose tissue (WAT) contributes to this abnormality via adipokines, which regulate many metabolic signals. This work investigated adipokine-caused hepatic changes and their involvement in RA-related hypolipemia. Given their immune similarities with RA and pathological representativeness, adjuvant-induced arthritis (AIA) rats and antigen-induced arthritis (AA) mice were adopted. Adipokine levels in the liver were quantified, and their hepatic conditions were assessed by oxidative/enzymatic indicators. Besides kit-based metabolite quantification, fatty acid levels in blood were accurately determined by GC–MS. Metabolic differences between healthy and AIA rats were further characterized by UPLC-MS<sup>2</sup>. In vitro, preadipocytes were stimulated by RA/AIA blood serum or together with rosiglitazone, a PPARγ agonist. The medium was used to culture HepG2 cells. Some AIA rats were subjected to adipectomy or rosiglitazone therapies. Being WAT-released mediators, IL-1β, IL-6, MCP-1, adiponectin, and visfatin were apparently increased in AIA/AA rodent models’ liver, causing oxidative stress escalation, liver injuries, and fatty acid oxidation acceleration. This metabolic change was coincided to expression increase of CD36, FABP1, ATGL, and CPT-1A. PPARγ deficiency occurred both in vivo and in vitro under rheumatic conditions. RA serum reduced PPARγ expression and impaired its inhibition on NF-κB transcription activity in preadipocytes, which then led to excessive secretion of inflammatory adipokines. The corresponding medium down-regulated PPARγ and promoted expression of lipid catabolic enzymes in HepG2 cells. These effects were abrogated by rosiglitazone. Both the therapies impeded inflammatory secretion of WAT and fat catabolism of the liver. These data demonstrate that RA potentiates the capacity of WAT to secrete inflammatory adipokines. The resulting condition represses PPARγ expression and disrupts TG anabolism/catabolism balance in the liver. Because hepatocytes utilize more lipids but synthesize less, hypolipemia develops.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 12","pages":"3969–3983 3969–3983"},"PeriodicalIF":4.9000,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PPARγ Functional Deficiency Expedited Fatty Acid Utilization in the Liver: A Foundation of Inflammatory Adipokine-Induced Hypolipemia in Rheumatoid Arthritis\",\"authors\":\"Yan Wang,&nbsp;Yu-Qing Ruan,&nbsp;Lian-Jun He,&nbsp;Meng-Ke Song,&nbsp;Opeyemi Joshua Olatunji,&nbsp;Xiu Wang* and Jian Zuo*,&nbsp;\",\"doi\":\"10.1021/acsptsci.4c0047010.1021/acsptsci.4c00470\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Triglyceride (TG) and its derivatives tend to be decreased in rheumatoid arthritis (RA) patients’ blood when inflammation progresses. Aside from the role as a lipid buffer, white adipose tissue (WAT) contributes to this abnormality via adipokines, which regulate many metabolic signals. This work investigated adipokine-caused hepatic changes and their involvement in RA-related hypolipemia. Given their immune similarities with RA and pathological representativeness, adjuvant-induced arthritis (AIA) rats and antigen-induced arthritis (AA) mice were adopted. Adipokine levels in the liver were quantified, and their hepatic conditions were assessed by oxidative/enzymatic indicators. Besides kit-based metabolite quantification, fatty acid levels in blood were accurately determined by GC–MS. Metabolic differences between healthy and AIA rats were further characterized by UPLC-MS<sup>2</sup>. In vitro, preadipocytes were stimulated by RA/AIA blood serum or together with rosiglitazone, a PPARγ agonist. The medium was used to culture HepG2 cells. Some AIA rats were subjected to adipectomy or rosiglitazone therapies. Being WAT-released mediators, IL-1β, IL-6, MCP-1, adiponectin, and visfatin were apparently increased in AIA/AA rodent models’ liver, causing oxidative stress escalation, liver injuries, and fatty acid oxidation acceleration. This metabolic change was coincided to expression increase of CD36, FABP1, ATGL, and CPT-1A. PPARγ deficiency occurred both in vivo and in vitro under rheumatic conditions. RA serum reduced PPARγ expression and impaired its inhibition on NF-κB transcription activity in preadipocytes, which then led to excessive secretion of inflammatory adipokines. The corresponding medium down-regulated PPARγ and promoted expression of lipid catabolic enzymes in HepG2 cells. These effects were abrogated by rosiglitazone. Both the therapies impeded inflammatory secretion of WAT and fat catabolism of the liver. These data demonstrate that RA potentiates the capacity of WAT to secrete inflammatory adipokines. The resulting condition represses PPARγ expression and disrupts TG anabolism/catabolism balance in the liver. Because hepatocytes utilize more lipids but synthesize less, hypolipemia develops.</p>\",\"PeriodicalId\":36426,\"journal\":{\"name\":\"ACS Pharmacology and Translational Science\",\"volume\":\"7 12\",\"pages\":\"3969–3983 3969–3983\"},\"PeriodicalIF\":4.9000,\"publicationDate\":\"2024-11-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Pharmacology and Translational Science\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsptsci.4c00470\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Pharmacology and Translational Science","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsptsci.4c00470","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

摘要

类风湿关节炎(RA)患者血液中甘油三酯(TG)及其衍生物在炎症进展时趋于降低。除了作为脂质缓冲剂的作用外,白色脂肪组织(WAT)还通过调节许多代谢信号的脂肪因子参与了这种异常。这项工作调查了脂肪因子引起的肝脏变化及其在ra相关的低血脂症中的作用。考虑到它们与RA的免疫相似性和病理代表性,我们采用了佐剂诱导关节炎(AIA)大鼠和抗原诱导关节炎(AA)小鼠。肝脏中的脂肪因子水平被量化,并通过氧化/酶指标评估其肝脏状况。除基于试剂盒的代谢物定量外,采用气相色谱-质谱法准确测定血液中脂肪酸水平。通过UPLC-MS2进一步表征健康大鼠和AIA大鼠之间的代谢差异。在体外,RA/AIA血清或与罗格列酮(一种PPARγ激动剂)联合刺激前脂肪细胞。用该培养基培养HepG2细胞。一些AIA大鼠进行了脂肪切除或罗格列酮治疗。作为wat释放介质,IL-1β、IL-6、MCP-1、脂联素和visfatin在AIA/AA模型小鼠肝脏中明显升高,引起氧化应激升级、肝脏损伤和脂肪酸氧化加速。这种代谢变化与CD36、FABP1、ATGL和CPT-1A的表达增加相一致。在风湿病条件下,体内和体外均发生PPARγ缺乏。RA血清降低PPARγ表达,破坏其对脂肪前细胞NF-κB转录活性的抑制,从而导致炎性脂肪因子的过度分泌。相应的培养基下调PPARγ,促进HepG2细胞脂质分解代谢酶的表达。罗格列酮消除了这些影响。这两种疗法都能抑制WAT的炎症分泌和肝脏的脂肪分解代谢。这些数据表明,RA增强了WAT分泌炎性脂肪因子的能力。由此产生的病症抑制PPARγ表达并破坏肝脏中TG合成代谢/分解代谢平衡。因为肝细胞利用更多的脂质而合成更少,所以出现了低脂血症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
PPARγ Functional Deficiency Expedited Fatty Acid Utilization in the Liver: A Foundation of Inflammatory Adipokine-Induced Hypolipemia in Rheumatoid Arthritis

Triglyceride (TG) and its derivatives tend to be decreased in rheumatoid arthritis (RA) patients’ blood when inflammation progresses. Aside from the role as a lipid buffer, white adipose tissue (WAT) contributes to this abnormality via adipokines, which regulate many metabolic signals. This work investigated adipokine-caused hepatic changes and their involvement in RA-related hypolipemia. Given their immune similarities with RA and pathological representativeness, adjuvant-induced arthritis (AIA) rats and antigen-induced arthritis (AA) mice were adopted. Adipokine levels in the liver were quantified, and their hepatic conditions were assessed by oxidative/enzymatic indicators. Besides kit-based metabolite quantification, fatty acid levels in blood were accurately determined by GC–MS. Metabolic differences between healthy and AIA rats were further characterized by UPLC-MS2. In vitro, preadipocytes were stimulated by RA/AIA blood serum or together with rosiglitazone, a PPARγ agonist. The medium was used to culture HepG2 cells. Some AIA rats were subjected to adipectomy or rosiglitazone therapies. Being WAT-released mediators, IL-1β, IL-6, MCP-1, adiponectin, and visfatin were apparently increased in AIA/AA rodent models’ liver, causing oxidative stress escalation, liver injuries, and fatty acid oxidation acceleration. This metabolic change was coincided to expression increase of CD36, FABP1, ATGL, and CPT-1A. PPARγ deficiency occurred both in vivo and in vitro under rheumatic conditions. RA serum reduced PPARγ expression and impaired its inhibition on NF-κB transcription activity in preadipocytes, which then led to excessive secretion of inflammatory adipokines. The corresponding medium down-regulated PPARγ and promoted expression of lipid catabolic enzymes in HepG2 cells. These effects were abrogated by rosiglitazone. Both the therapies impeded inflammatory secretion of WAT and fat catabolism of the liver. These data demonstrate that RA potentiates the capacity of WAT to secrete inflammatory adipokines. The resulting condition represses PPARγ expression and disrupts TG anabolism/catabolism balance in the liver. Because hepatocytes utilize more lipids but synthesize less, hypolipemia develops.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
ACS Pharmacology and Translational Science
ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)
CiteScore
10.00
自引率
3.30%
发文量
133
期刊介绍: ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.
期刊最新文献
Molecular and Immunological Properties of a Chimeric Glycosyl Hydrolase 18 Based on Immunoinformatics Approaches: A Design of a New Anti-Leishmania Vaccine. Recommended Opioid Receptor Tool Compounds: Comparative In Vitro for Receptor Selectivity Profiles and In Vivo for Pharmacological Antinociceptive Profiles. Sigma 1 Receptor and Its Pivotal Role in Neurological Disorders. A 3D Model of the Human Lung Airway for Evaluating Permeability of Inhaled Drugs. Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1