Endothelin-1 stimulates preadipocyte growth via the PKC, STAT3, AMPK, c-JUN, ERK, sphingosine kinase, and sphingomyelinase pathways

Author:

Siao An-Ci1,Lin Yen-Yue123,Shih Li-Jane34,Tsuei Yi-Wei2,Chuu Chih-Pin5,Kuo Yow-Chii6,Kao Yung-Hsi1

Affiliation:

1. Department of Life Sciences, National Central University, Taoyuan, Taiwan

2. Department of Emergency, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan

3. National Defense Medical Center, Taipei, Taiwan

4. Medical Laboratory, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan

5. Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan

6. Division of Gastroenterology, Landseed Hospital, Taoyuan, Taiwan

Abstract

Endothelin (ET)-1 regulates adipogenesis and the endocrine activity of fat cells. However, relatively little is known about the ET-1 signaling pathway in preadipocyte growth. We used 3T3-L1 preadipocytes to investigate the signaling pathways involved in ET-1 modulation of preadipocyte proliferation. As indicated by an increased number of cells and greater incorporation of bromodeoxyuridine (BrdU), the stimulation of preadipocyte growth by ET-1 depends on concentration and timing. The concentration of ET-1 that increased preadipocyte number by 51–67% was ~100 nM for ~24–48 h of treatment. ET-1 signaling time dependently stimulated phosphorylation of ERK, c-JUN, STAT3, AMPK, and PKCα/βII proteins but not AKT, JNK, or p38 MAPK. Treatment with an ETAR antagonist, such as BQ610, but not ETBR antagonist BQ788, blocked the ET-1-induced increase in cell proliferation and phosphorylated levels of ERK, c-JUN, STAT3, AMPK, and PKCα/βII proteins. In addition, pretreatment with specific inhibitors of ERK1/2 (U0126), JNK (SP600125), JAK2/STAT3 (AG490), AMPK (compound C), or PKC (Ro318220) prevented the ET-1-induced increase in cell proliferation and reduced the ET-1-stimulated phosphorylation of ERK1/2, c-JUN, STAT3, AMPK, and PKCα/β. Moreover, the SphK antagonist suppressed ET-1-induced cell proliferation and ERK, c-JUN, STAT3, AMPK, and PKC phosphorylation, and the SMase2 antagonist suppressed ET-1-induced cell proliferation. However, neither the p38 MAPK antagonist nor the CerS inhibitor altered the effect of ET-1. The results indicate that ETAR, JAK2/STAT3, ERK1/2, JNK/c-JUN, AMPK, PKC, SphK, and SMase2, but not ETBR, p38 MAPK, or CerS, are necessary for the ET-1 stimulation of preadipocyte proliferation.

Funder

Ministry of Science and Technology, Taiwan

Taoyuan Armed Forces General Hospital

National Central University and Landseed Hospital Joint Research Foundation

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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