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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #426917
Research Project: Regulatory Aspects of Nutritional Metabolism

Location: Children's Nutrition Research Center

Title: The adiponectin-PPAR axis in hepatic stellate cells regulates liver fibrosis

Author
item ZHAO, SHANGANG - University Of Texas Health Science Center
item ZHU, QINGZHANG - University Of Texas Southwestern Medical Center
item LEE, WANG-HSIN - University Of Kentucky
item FUNCKE, JAN-BERND - University Of Texas Southwestern Medical Center
item ZHANG, ZHUZHEN - University Of Texas Southwestern Medical Center
item WANG, MAY-YUN - University Of Texas Southwestern Medical Center
item LIN, QIAN - University Of Texas Southwestern Medical Center
item FIELD, BIANCA - University Of Texas Southwestern Medical Center
item SUN, XUE-NAN - University Of Texas Southwestern Medical Center
item LI, GUANNAN - University Of Texas Health Science Center
item EKANE, MBOLLE - University Of Texas Health Science Center
item ONODERA, TOSHIHARU - University Of Texas Southwestern Medical Center
item LI, NA - University Of Texas Southwestern Medical Center
item ZHU, YI - Children'S Nutrition Research Center (CNRC)
item KUSMINSKI, CHRISTINE - University Of Texas Southwestern Medical Center
item HINDS, TERRY - University Of Kentucky
item SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2024
Publication Date: 1/9/2025
Citation: Zhao, S., Zhu, Q., Lee, W., Funcke, J., Zhang, Z., Wang, M., Lin, Q., Field, B., Sun, X., Li, G., Ekane, M., Onodera, T., Li, N., Zhu, Y., Kusminski, C.M., Hinds, T.D., Scherer, P.E. 2025. The adiponectin-PPAR axis in hepatic stellate cells regulates liver fibrosis. Cell Reports. 44. Article 115165. https://doi.org/10.1016/j.celrep.2024.115165.
DOI: https://doi.org/10.1016/j.celrep.2024.115165

Interpretive Summary: Scientists found that a protein called adiponectin, made by special liver cells, helps prevent liver scarring. When they increased adiponectin in mice, it protected their livers from damage, but removing it made scarring worse. This discovery could lead to new treatments for liver disease by boosting this natural "shield" against scarring.

Technical 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 (PPAR') axis in HSCs that exerts a marked influence on the progression of local fibrosis, independent of circulating adiponectin derived from adipocytes.