Journal
FASEB JOURNAL
Volume 30, Issue 12, Pages 4071-4082Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201600427R
Keywords
NAFLD; nonalcoholic steatohepatitis; lipotoxicity; interleukin-8; IGFBP-3
Categories
Funding
- U.S. National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases) [DK081450, T32 DK07150]
- U.S. National Institutes of Health (National Institute on Alcohol Abuse and Alcoholism) [AA020758]
- Grants-in-Aid for Scientific Research [16K01406] Funding Source: KAKEN
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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-1macrophages and enhanced IL-8 expression. Exposure of palmitate-treated THP-1macrophages to IGFBP-3-deficient conditioned medium led to a 20-fold increase in palmitate-induced IL-8 expression by hepato-cytes. Conversely, overexpression of IGFBP-3 suppressed JNK and NF-kappa B activation and blocked palmitate-induced IL-8 expression in hepatocytes. Silencing IGFBP-3 in Huh7 cells enhanced JNK and NF-kappa B 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-kappa B 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.
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