The adiponectin-PPARγ axis in hepatic stellate cells regulates liver fibrosis.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-09 DOI:10.1016/j.celrep.2024.115165

Shangang Zhao, Qingzhang Zhu, Wang-Hsin Lee, Jan-Bernd Funcke, Zhuzhen Zhang, May-Yun Wang, Qian Lin, Bianca Field, Xue-Nan Sun, Guannan Li, Mbolle Ekane, Toshiharu Onodera, Na Li, Yi Zhu, Christine M Kusminski, Terry D Hinds, Philipp E Scherer

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引用次数: 0

Abstract

Hepatic stellate cells (HSCs) are key drivers of local fibrosis. Adiponectin, conventionally thought of as an adipokine, is also expressed in quiescent HSCs. However, the impact of its local expression on the progression of liver fibrosis remains unclear. We recently generated a transgenic mouse line (Lrat-rtTA) that expresses the doxycycline-responsive transcriptional activator rtTA under the control of the HSC-specific lecithin retinol acyltransferase (Lrat) promoter, which enables us to specifically and inducibly overexpress or eliminate genes in these cells. The inducible elimination of HSCs protects mice from methionine/choline-deficient (MCD) diet-induced liver fibrosis, confirming their causal involvement in fibrosis development. We generated HSC-specific adiponectin overexpression and null models that demonstrate that HSC-specific adiponectin overexpression dramatically reduces liver fibrosis, whereas HSC-specific adiponectin elimination accelerates fibrosis progression. We identify a local adiponectin-peroxisome proliferator-activated receptor gamma (PPARγ) axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.

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肝星状细胞中的脂联素- ppar γ轴调节肝纤维化。

肝星状细胞（hsc）是局部纤维化的关键驱动因素。脂联素，通常被认为是一种脂肪因子，也在静止的hsc中表达。然而，其局部表达对肝纤维化进展的影响尚不清楚。我们最近培育了一种转基因小鼠系（Lrat-rtTA），它在hsc特异性卵磷脂视黄醇酰基转移酶（Lrat）启动子的控制下表达多西环素应答转录激活因子rtTA，这使我们能够特异性和诱导地过度表达或消除这些细胞中的基因。诱导消除hsc可以保护小鼠免受蛋氨酸/胆碱缺乏（MCD）饮食引起的肝纤维化，证实了它们在纤维化发展中的因果关系。我们建立了hsc特异性脂联素过表达和零模型，证明hsc特异性脂联素过表达显著减少肝纤维化，而hsc特异性脂联素消除加速纤维化进展。我们在hsc中发现了一个局部脂联素-过氧化物酶体增殖激活受体γ (PPARγ)轴，它对局部纤维化的进展有显著影响，独立于来自脂肪细胞的循环脂联素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.