New insights into the suppression of inflammation and lipid accumulation by JAZF1
Atherosclerosis is one of the leading causes of disease and death worldwide. The identification of new therapeutic targets and agents is critical. JAZF1 is expressed in many tissues and is found at particularly high levels in adipose tissue (AT). JAZF1 suppresses inflammation (including IL-1β, IL-4,...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
KeAi Communications Co., Ltd.
2023-11-01
|
| Series: | Genes and Diseases |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304222003014 |
| _version_ | 1827267419053228032 |
|---|---|
| author | Wujun Chen Yingjie Zhong Yang Yuan Meng Zhu Wenchao Hu Ning Liu Dongming Xing |
| author_facet | Wujun Chen Yingjie Zhong Yang Yuan Meng Zhu Wenchao Hu Ning Liu Dongming Xing |
| author_sort | Wujun Chen |
| collection | DOAJ |
| description | Atherosclerosis is one of the leading causes of disease and death worldwide. The identification of new therapeutic targets and agents is critical. JAZF1 is expressed in many tissues and is found at particularly high levels in adipose tissue (AT). JAZF1 suppresses inflammation (including IL-1β, IL-4, IL-6, IL-8, IL-10, TNFα, IFN-γ, IAR-20, COL3A1, laminin, and MCP-1) by reducing NF-κB pathway activation and AT immune cell infiltration. JAZF1 reduces lipid accumulation by regulating the liver X receptor response element (LXRE) of the SREBP-1c promoter, the cAMP-response element (CRE) of HMGCR, and the TR4 axis. LXRE and CRE sites are present in many cytokine and lipid metabolism gene promoters, which suggests that JAZF1 regulates these genes through these sites. NF-κB is the center of the JAZF1-mediated inhibition of the inflammatory response. JAZF1 suppresses NF-κB expression by suppressing TAK1 expression. Interestingly, TAK1 inhibition also decreases lipid accumulation. A dual-targeting strategy of NF-κB and TAK1 could inhibit both inflammation and lipid accumulation. Dual-target compounds (including prodrugs) 1–5 exhibit nanomolar inhibition by targeting NF-κB and TAK1, EGFR, or COX-2. However, the NF-κB suppressing activity of these compounds is relatively low (IC50 > 300 nM). Compounds 6–14 suppress NF-κB expression with IC50 values ranging from 1.8 nM to 38.6 nM. HS-276 is a highly selective, orally bioavailable TAK1 inhibitor. Combined structural modifications of compounds using a prodrug strategy may enhance NF-κB inhibition. This review focused on the role and mechanism of JAZF1 in inflammation and lipid accumulation for the identification of new anti-atherosclerotic targets. |
| first_indexed | 2024-03-12T19:32:38Z |
| format | Article |
| id | doaj.art-877d9f42344646d3b72a8f14efc78c60 |
| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2025-03-22T04:33:26Z |
| publishDate | 2023-11-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-877d9f42344646d3b72a8f14efc78c602024-04-28T02:10:17ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422023-11-0110624572469New insights into the suppression of inflammation and lipid accumulation by JAZF1Wujun Chen0Yingjie Zhong1Yang Yuan2Meng Zhu3Wenchao Hu4Ning Liu5Dongming Xing6Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, ChinaCancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, ChinaCancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, ChinaCancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, ChinaCancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China; Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035, ChinaCancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China; Corresponding author. Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266071, China. Fax: 86-532-82991017.Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China; School of Life Sciences, Tsinghua University, Beijing 100084, China; Corresponding author. Cancer Institute, Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China.Atherosclerosis is one of the leading causes of disease and death worldwide. The identification of new therapeutic targets and agents is critical. JAZF1 is expressed in many tissues and is found at particularly high levels in adipose tissue (AT). JAZF1 suppresses inflammation (including IL-1β, IL-4, IL-6, IL-8, IL-10, TNFα, IFN-γ, IAR-20, COL3A1, laminin, and MCP-1) by reducing NF-κB pathway activation and AT immune cell infiltration. JAZF1 reduces lipid accumulation by regulating the liver X receptor response element (LXRE) of the SREBP-1c promoter, the cAMP-response element (CRE) of HMGCR, and the TR4 axis. LXRE and CRE sites are present in many cytokine and lipid metabolism gene promoters, which suggests that JAZF1 regulates these genes through these sites. NF-κB is the center of the JAZF1-mediated inhibition of the inflammatory response. JAZF1 suppresses NF-κB expression by suppressing TAK1 expression. Interestingly, TAK1 inhibition also decreases lipid accumulation. A dual-targeting strategy of NF-κB and TAK1 could inhibit both inflammation and lipid accumulation. Dual-target compounds (including prodrugs) 1–5 exhibit nanomolar inhibition by targeting NF-κB and TAK1, EGFR, or COX-2. However, the NF-κB suppressing activity of these compounds is relatively low (IC50 > 300 nM). Compounds 6–14 suppress NF-κB expression with IC50 values ranging from 1.8 nM to 38.6 nM. HS-276 is a highly selective, orally bioavailable TAK1 inhibitor. Combined structural modifications of compounds using a prodrug strategy may enhance NF-κB inhibition. This review focused on the role and mechanism of JAZF1 in inflammation and lipid accumulation for the identification of new anti-atherosclerotic targets.http://www.sciencedirect.com/science/article/pii/S2352304222003014AtherosclerosisCREJAZF1LXRENF-κBTAK1 |
| spellingShingle | Wujun Chen Yingjie Zhong Yang Yuan Meng Zhu Wenchao Hu Ning Liu Dongming Xing New insights into the suppression of inflammation and lipid accumulation by JAZF1 Genes and Diseases Atherosclerosis CRE JAZF1 LXRE NF-κB TAK1 |
| title | New insights into the suppression of inflammation and lipid accumulation by JAZF1 |
| title_full | New insights into the suppression of inflammation and lipid accumulation by JAZF1 |
| title_fullStr | New insights into the suppression of inflammation and lipid accumulation by JAZF1 |
| title_full_unstemmed | New insights into the suppression of inflammation and lipid accumulation by JAZF1 |
| title_short | New insights into the suppression of inflammation and lipid accumulation by JAZF1 |
| title_sort | new insights into the suppression of inflammation and lipid accumulation by jazf1 |
| topic | Atherosclerosis CRE JAZF1 LXRE NF-κB TAK1 |
| url | http://www.sciencedirect.com/science/article/pii/S2352304222003014 |
| work_keys_str_mv | AT wujunchen newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 AT yingjiezhong newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 AT yangyuan newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 AT mengzhu newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 AT wenchaohu newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 AT ningliu newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 AT dongmingxing newinsightsintothesuppressionofinflammationandlipidaccumulationbyjazf1 |