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Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle.
Mol Cell Endocrinol. 2018 07 15; 470:26-33.MC

Abstract

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.

Authors+Show Affiliations

Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea.Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea.Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt; Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea; Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum 25240, Turkey. Electronic address: abdelaty44@hotmail.com.Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. Electronic address: jhjeong3@cau.ac.kr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29111387

Citation

Jung, Tae Woo, et al. "Hyperlipidemia-induced Hepassocin in the Liver Contributes to Insulin Resistance in Skeletal Muscle." Molecular and Cellular Endocrinology, vol. 470, 2018, pp. 26-33.
Jung TW, Chung YH, Kim HC, et al. Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle. Mol Cell Endocrinol. 2018;470:26-33.
Jung, T. W., Chung, Y. H., Kim, H. C., Abd El-Aty, A. M., & Jeong, J. H. (2018). Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle. Molecular and Cellular Endocrinology, 470, 26-33. https://doi.org/10.1016/j.mce.2017.10.014
Jung TW, et al. Hyperlipidemia-induced Hepassocin in the Liver Contributes to Insulin Resistance in Skeletal Muscle. Mol Cell Endocrinol. 2018 07 15;470:26-33. PubMed PMID: 29111387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle. AU - Jung,Tae Woo, AU - Chung,Yoon Hee, AU - Kim,Hyoung-Chun, AU - Abd El-Aty,A M, AU - Jeong,Ji Hoon, Y1 - 2017/10/28/ PY - 2017/06/24/received PY - 2017/10/24/revised PY - 2017/10/26/accepted PY - 2017/11/8/pubmed PY - 2019/3/23/medline PY - 2017/11/8/entrez KW - EGFR KW - ER stress KW - ERK1/2 KW - Hepassocin KW - Insulin resistance KW - JNK KW - p38 SP - 26 EP - 33 JF - Molecular and cellular endocrinology JO - Mol Cell Endocrinol VL - 470 N2 - 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. SN - 1872-8057 UR - https://www.unboundmedicine.com/medline/citation/29111387/Hyperlipidemia_induced_hepassocin_in_the_liver_contributes_to_insulin_resistance_in_skeletal_muscle_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0303-7207(17)30551-8 DB - PRIME DP - Unbound Medicine ER -