한빛사논문
- 조회102
경북대학교 약학대학
Ojha, Uttam1; Kim, Somi2; Rhee, Chang Yun1; You, Jihye1; Choi, Yoon Ha2; Yoon, Soo-Hyun1; Park, Soo Young3; Lee, Yu Rim3; Kim, Jong Kyoung2; Bae, Suk-Chul4; Lee, You Mie1
1Vessel-Organ Interaction Research Center, VOICE (MRC), Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea
2Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Gyeongbuk 37673, Republic of Korea
3Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
4Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 28644, Republic of Korea
Correspondence You Mie Lee
Abstract
Background and aims: Liver fibrosis represents a global health burden, given the paucity of approved antifibrotic therapies. Liver sinusoidal endothelial cells (LSECs) play a major gatekeeping role in hepatic homeostasis and liver disease pathophysiology. In early tumorigenesis, runt-related transcription factor 3 (RUNX3) functions as a sentinel; however, its function in liver fibrosis in LSECs remains unclear. This study aimed to investigate the role of RUNX3 as an important regulator of the gatekeeping functions of LSECs and explore novel angiocrine regulators of liver fibrosis.
Approach and results: Mice with endothelial Runx3 deficiency develop gradual and spontaneous liver fibrosis secondary to LSEC dysfunction, thereby more prone to liver injury. Mechanistic studies in human immortalized LSECs and mouse primary LSECs revealed that IL-6/JAK/STAT-3 pathway activation was associated with LSEC dysfunction in the absence of RUNX3. Single-cell RNA sequencing and quantitative RT-PCR revealed that leucine-rich alpha-2-glycoprotein 1 (LRG1) was highly expressed in RUNX3-deficient and dysfunctional LSECs. In in vitro and coculture experiments, RUNX3-depleted LSECs secreted LRG1, which activated hepatic stellate cells via TGFBR1-SMAD2/3 signaling in a paracrine manner. Furthermore, circulating LRG1 levels were elevated in mouse models of liver fibrosis and in patients with fatty liver and cirrhosis.
Conclusions: RUNX3 deficiency in the endothelium induces LSEC dysfunction, LRG1 secretion, and liver fibrosis progression. Therefore, endothelial RUNX3 is a crucial gatekeeping factor in LSECs, and profibrotic angiocrine LRG1 may be a novel target for combating liver fibrosis.
논문정보
- Research article
- 2024년 07월 (BRIC 등록일 2024-07-31)
- 국내 연구진
- 생명과학 > 노화/암생물학
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