한빛사논문
- 조회467
Kyung Eun Kim1†, Jaewoong Lee1†, Hyun Joo Shin1, Eun Ae Jeong1, Hye Min Jang1, Yu Jeong Ahn1, Hyeong Seok An1, Jong Youl Lee1, Meong Cheol Shin2, Soo Kyoung Kim3, Won Gi Yoo4, Won Ho Kim5, and Gu Seob Roh1*
1Department of Anatomy and Convergence Medical Science, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
2College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
3Department of Internal Medicine, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
4Department of Parasitology and Tropical Medicine, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 52727, Republic of Korea
5Division of Cardiovascular Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Cheongju, 28159, Republic of Korea
†These authors contributed equally.
*Correspondence should be addressed to: Gu Seob Roh, M.D., Ph.D.
Abstract
Background and Aims
In obesity and type 2 diabetes mellitus, leptin promotes insulin resistance and contributes to the progression of non-alcoholic steatohepatitis (NASH) via activation of hepatic stellate cells (HSCs). However, the pathogenic mechanisms that trigger HSC activation in leptin-deficient obesity are still unknown. This study aimed to determine how HSC-targeting lipocalin-2 (LCN2) mediates the transition from simple steatosis to NASH.
Approach and Results
Male wild-type (WT) and ob/ob mice were fed a high-fat diet (HFD) for 20 weeks to establish an animal model of NASH with fibrosis. Ob/ob mice were subject to caloric restriction or recombinant leptin treatment. Double knockout (DKO) mice lacking both leptin and lcn2 were also fed an HFD for 20 weeks. In addition, HFD-fed ob/ob mice were treated with gadolinium trichloride to deplete Kupffer cells. Human LX-2 cells and primary HSCs from ob/ob mice were used to investigate the effects of LCN2 on HSC activation. Serum and hepatic LCN2 expression levels were prominently increased in HFD-fed ob/ob mice compared with normal diet-fed ob/ob mice or HFD-fed WT mice, and these changes were closely linked to liver fibrosis and increased hepatic α-SMA/MMP9/STAT3 protein levels. HFD-fed DKO mice showed a marked reduction of α-SMA protein compared with HFD-fed ob/ob mice. In particular, the co-localization of LCN2 and α-SMA was increased in HSCs from HFD-fed ob/ob mice. In primary HSCs from ob/ob mice, exogenous LCN2 treatment-induced HSC activation and MMP9 secretion. By contrast, LCN2 receptor 24p3R deficiency or a STAT3 inhibitor reduced the activation and migration of primary HSCs.
Conclusions
LCN2 acts as a key mediator of HSC activation in leptin-deficient obesity via α-SMA/MMP9/STAT3 signaling, thereby exacerbating NASH.
논문정보
- Research article
- 2022년 05월 (BRIC 등록일 2022-05-27)
- 국내 연구진
- 의약학 > 인체시스템의학
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