Regulation of hepatocyte growth factor expression by NF-κB and PPARγ in adipose tissue

Jun Yin, Jong Han Lee, Jin Zhang, Zhanguo Gao, Vsevolod Y. Polotsky, Jianping Ye

Research output: Contribution to journalArticle

Abstract

Hepatocyte growth factor (HGF) is expressed as an angiogenic factor in adipose tissue. However, the molecular mechanism of Hgf expression remains largely unknown in the tissue. We addressed the issue by studying Hgf expression in adipocytes and macrophages. Hgf was expressed more in the stromal-vascular fraction than the adipocyte fraction. The expression was fivefold more in macrophages than the stromal-vascular faction and was reduced by 50% after macrophage deletion in adipose tissue. The expression was reduced by differentiation in adipocytes and by tumor necrosis factor-α or lipopolysaccharide treatment in macrophages. The expression was suppressed by nuclear factor (NF)-κB in C57BL/6 mice with NF-κB p65 overexpression under the aP2 gene promoter (aP2-p65 mice) but enhanced by inactivation of NF-κB p65 in mouse embryonic fibroblasts. The Hgf gene promoter was suppressed by p65 overexpression, which blocked peroxisome proliferator-activated receptor-γ (PPARγ) interaction with RNA polymerase II. The p65 activity was abolished by knockdown of histone deacetylase 3. Hgf expression was upregulated by hypoxia in vitro and in vivo. Compared with vascular endothelial growth factor (Vegf), which was predominately expressed in mature adipocytes, Hgf was mainly expressed in nonadipocytes, suggesting that Hgf and Vegf may have different cell sources in adipose tissue. In mechanism, Hgf expression is inhibited by NF-κB through suppression of PPARγ function in the Hgf gene promoter. Both Hgf and Vegf are induced by hypoxia. The study provides a molecular mechanism for the difference of inflammation and hypoxia in the regulation of angiogenic factors.

Original languageEnglish (US)
Pages (from-to)E929-E936
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume306
Issue number8
DOIs
StatePublished - Apr 15 2014

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Keywords

  • Adipose tissue hypoxia
  • Inflammation
  • Macrophage infiltration
  • Mice with nuclear factor-κB p65 overexpression under the Ap2 gene promoter
  • Nuclear factor-κB
  • Peroxisome proliferator-activated receptorγ
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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