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Exp. Mol. Med., 12 February 2025 | https://doi.org/10.1038/s12276-025-01408-1
A1AT dysregulation of metabolically stressed hepatocytes by Kupffer cells drives MASH and fibrosis
Jeong-Su Park 1,12, Jin Lee 2,12, Feng Wang 1,12, Hwan Ma 1,12, Zixiong Zhou 3, Yong-Sun Lee 4, Kwangyeon Oh 1, Haram Lee 5, Guoyan Sui 1, Sangkyu Lee 6, Yoon Mee Yang 7, Jang-Won Lee 8, Yong-Ha Ji 8, Chun-Woong Park 1, Hwan-Soo Yoo 1, Bang-Yeon Hwang 1, Sang-Bae Han 1, Nan Song 1, Soohwan Oh 5, Bumseok Kim 9, Ekihiro Seki 10,11, Jin Tae Hong 1,13,* and Yoon Seok Roh 1,13,*
1College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea.
2Department of Pathology, School of Medicine, University of California, San Diego, CA, USA.
3Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
4Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, South Korea.
5College of Pharmacy, Korea University, Sejong, South Korea.
6College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
7College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
8Research and Development Center, MediTake Co. Ltd., Suwon, South Korea.
9College of Veterinary Medicine and Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea.
10Karsh Division of Gastroenterology and Hepatology, Cedars–Sinai Medical Center, Los Angeles, CA, USA.
11Samuel Oschin Comprehensive Cancer Institute, Cedars–Sinai Medical Center, Los Angeles, CA, USA.
12These authors contributed equally: Jeong-Su Park, Jin Lee, Feng Wang, Hwan Ma.
13These authors jointly supervised this work: Jin Tae Hong, Yoon Seok Roh.
2Department of Pathology, School of Medicine, University of California, San Diego, CA, USA.
3Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
4Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, South Korea.
5College of Pharmacy, Korea University, Sejong, South Korea.
6College of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
7College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
8Research and Development Center, MediTake Co. Ltd., Suwon, South Korea.
9College of Veterinary Medicine and Biosafety Research Institute, Jeonbuk National University, Iksan, South Korea.
10Karsh Division of Gastroenterology and Hepatology, Cedars–Sinai Medical Center, Los Angeles, CA, USA.
11Samuel Oschin Comprehensive Cancer Institute, Cedars–Sinai Medical Center, Los Angeles, CA, USA.
12These authors contributed equally: Jeong-Su Park, Jin Lee, Feng Wang, Hwan Ma.
13These authors jointly supervised this work: Jin Tae Hong, Yoon Seok Roh.
*Corresponding authors: correspondence to Jin Tae Hong or Yoon Seok Roh
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is associated with the activation of Kupffer cells (KCs) and hepatic stellate cells, at which point a metabolically stressed hepatocyte becomes integral to the progression of the disease. We observed a significant reduction in the level of alpha-1-antitrypsin (A1AT), a hepatocyte-derived secreted factor, in both patients with MASH and mice fed a fast-food diet (FFD). KC-mediated hepatic inflammation, most notably IL-1β, led to the transcriptional inhibition of A1AT by HNF4α. In quintuple Serpina1a–e knockout mice, ablation of A1AT worsened MASH through increased activity of proteinase 3 (PR3), a proinflammatory protease produced by F4/80hi/CD11blow/TIM4−/CCR2+ monocyte-derived KCs (MoKCs). Conversely, A1AT restoration or PR3 inhibition mitigated MASH progression. A PR3-bound cytokine array identified IL-32 as a key factor associated with MASH. Combining IL-32 with SERPINA1, the gene encoding A1AT, synergistically predicted patients at risk of MASH through univariate logistic regression analysis. Furthermore, in vivo overexpression of IL-32γ alleviated MASH induced by FFD. However, additional knockout of A1AT increased PR3 activity, consequently abolishing the anti-MASH effects of IL-32γ. Blocking PR3-mediated IL-32γ cleavage via the V104A mutation sustained its protective actions, while the PR3-cleaved C-terminal fragment activated KCs. Additionally, after cleavage, the antifibrogenic effect of IL-32γ is lost, resulting in a failure to prevent the activation of hepatic stellate cells. This study highlights the critical role of hepatocyte-derived A1AT in the PR3/IL-32γ axis during MASH development. Strategies to correct A1AT dysregulation, such as A1AT supplementation or PR3 inhibition with sivelestat, may offer protection against the development and progression of MASH and fibrosis.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-13)
- 국내(교신)+국외 연구진
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