Suppression of IGF binding protein-3 by palmitate promotes hepatic inflammatory responses

FASEB J. 2016 Dec;30(12):4071-4082. doi: 10.1096/fj.201600427R. Epub 2016 Aug 23.

Abstract

IGF-binding protein-3 (IGFBP-3) is a liver-derived, anti-inflammatory molecule that is decreased in obesity, a key risk factor for nonalcoholic fatty liver disease (NAFLD). It was not known whether IGFBP-3 levels were altered in NAFLD, whether such alterations could be the result of lipotoxicity, and whether altered IGFBP-3 could affect pathways that are involved in hepatic and systemic inflammation. Serum IGFBP-3 was decreased in patients with NAFLD, whereas liver and circulating IL-8 levels were increased. Palmitate inhibited IGFBP-3 secretion by THP-1 macrophages and enhanced IL-8 expression. Exposure of palmitate-treated THP-1 macrophages to IGFBP-3-deficient conditioned medium led to a 20-fold increase in palmitate-induced IL-8 expression by hepatocytes. Conversely, overexpression of IGFBP-3 suppressed JNK and NF-κB activation and blocked palmitate-induced IL-8 expression in hepatocytes. Silencing IGFBP-3 in Huh7 cells enhanced JNK and NF-κB activity and increased palmitate-induced IL-8 secretion. These data indicate that IGFBP-3 serves as an anti-inflammatory brake in hepatocytes against JNK and NF-κB and limits their activation and downstream production of proinflammatory cytokines. Under lipotoxic conditions, palmitate inhibits hepatic macrophage secretion of IGFBP-3, thereby releasing the brake and enhancing palmitate-induced IL-8 synthesis and secretion.-Min, H.-K., Maruyama, H., Jang, B. K., Shimada, M., Mirshahi, F., Ren, S., Oh, Y., Puri, P., Sanyal, A. J. Suppression of IGF binding protein-3 by palmitate promotes hepatic inflammatory responses.

Keywords: IGFBP-3; NAFLD; interleukin-8; lipotoxicity; nonalcoholic steatohepatitis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Inflammatory Agents / pharmacology
  • Cytokines / metabolism
  • Gene Expression Regulation / drug effects*
  • Hepatitis / metabolism*
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • NF-kappa B / metabolism
  • Palmitates / metabolism
  • Palmitates / pharmacology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • NF-kappa B
  • Palmitates
  • Tumor Necrosis Factor-alpha