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Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation‐related protein (ADRP)
Author(s) -
Lee Ting Fang,
Mak Ki M.,
Rackovsky Ori,
Lin YunLian,
Kwong Allison J.,
Loke Johnny C.,
Friedman Scott L.
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22063
Subject(s) - lipid droplet , hepatic stellate cell , downregulation and upregulation , gene knockdown , microbiology and biotechnology , chemistry , adipose tissue , biology , biochemistry , endocrinology , gene
Hepatic stellate cells (HSCs) store retinoids and triacylglycerols in cytoplasmic lipid droplets. Two prominent features of HSC activation in liver fibrosis are loss of lipid droplets along with increase of α‐smooth muscle actin (α‐SMA), but the link between these responses and HSC activation remains elusive. In non‐adipose cells, adipose differentiation‐related protein (ADRP) coats lipid droplets and regulates their formation and lipolysis; however its function in HSCs is unknown. Here, we observed, in human liver sections or primary HSC culture, ADRP localization to lipid droplets of HSCs, and reduced staining coincident with loss of lipid droplets in liver fibrosis and in culture‐activated HSCs, consistent with HSC activation. In the LX‐2 human immortalized HSCs, with scant lipid droplets and features of activated HSCs, we found that the upregulation of ADRP mRNA by palmitate is potentiated by retinol, accompanied by increased ADRP protein, generation of retinyl palmitate, and lipid droplet formation. ADRP induction also led to decreased expression of α‐SMA mRNA and its protein, while ADRP knockdown with small interfering RNA (siRNA) normalized α‐SMA expression. Furthermore, ADRP induction by retinol and palmitate resulted in decreased expression of collagen I and matrix metalloproteinase‐2 mRNA, fibrogenic genes associated with activated HSCs, while increasing matrix metalloproteinase‐1 mRNA; ADRP knockdown with siRNA reversed these changes. Tissue inhibitor of metalloproteinase‐1 was not affected. Thus, ADRP upregulation mediated by retinol and palmitate promotes downregulation of HSC activation and is functionally linked to the expression of fibrogenic genes. J. Cell. Physiol. 223:648–657, 2010. © 2010 Wiley‐Liss, Inc.