Hepassocin (HPS) has recently been identified as a novel hepatokine that causes hepatic steatosis. However, the role of HPS in the development of
insulin resistance in skeletal muscle under
obesity remains unclear. The effect of
hyperlipidemia on hepatic HPS expression was evaluated in primary hepatocytes and liver of mice. HPS-mediated signal pathways were explored using small interfering (si) RNAs of specific genes or inhibitors. We found that treatment of primary hepatocytes with
palmitate could induce HPS expression through C/EBPβ-mediated transcriptional activation. Furthermore, increased HPS expression was observed in the liver of high fat diet (HFD)-fed or
tunicamycin-treated mice. Pretreatment with
4-phenylbutyrate (4-BPA) (an endoplasmic reticulum (ER) stress inhibitor) and suppression of p38 by
siRNA abrogated the effect of
palmitate on HPS expression in primary hepatocytes. Treatment of differentiated C2C12 cells with recombinant HPS caused
c-Jun N-terminal kinase (JNK) phosphorylation and impairment of
insulin sensitivity in a dose-dependent manner.
siRNA-mediated suppression of JNK reduced the effect of HPS on
insulin signaling. Furthermore, the suppression of
epidermal growth factor receptor (EGFR) by
siRNA mitigated both HPS-induced JNK phosphorylation and
insulin resistance. In addition, HPS did not affect
inflammation and ER stress in differentiated C2C12 cells. In conclusion, we elucidated that ER stress induced by
palmitate could increase the expression of HPS in hepatocytes and further contribute to the development of
insulin resistance in skeletal muscle via EGFR/JNK-mediated pathway. Taken together, we suggest that HPS could be a therapeutic target for
obesity-linked
insulin resistance.