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Suppression of IGF binding protein‐3 by palmitate promotes hepatic inflammatory responses
Author(s) -
Min HaeKi,
Maruyama Hitoshi,
Jang Byoung Kuk,
Shimada Masahiko,
Mirshahi Faridoddin,
Ren Shunlin,
Oh Youngman,
Puri Puneet,
Sanyal Arun J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201600427r
Subject(s) - proinflammatory cytokine , endocrinology , medicine , nonalcoholic fatty liver disease , inflammation , secretion , tumor necrosis factor alpha , chemistry , hepatic stellate cell , gene silencing , biology , fatty liver , biochemistry , disease , gene
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 hepatocytes. Conversely, overexpressionof IGFBP‐3 suppressedJNK and NF‐κBactivation andblockedpalmitate‐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. FASEB J. 30, 4071–4082 (2016). www.fasebj.org