TY - JOUR
T1 - Adipokine C1q/Tumor Necrosis Factor- Related Protein 3 (CTRP3) Attenuates Intestinal Inflammation Via Sirtuin 1/NF-κB Signaling
AU - Yu, Huimin
AU - Zhang, Zixin
AU - Li, Gangping
AU - Feng, Yan
AU - Xian, Lingling
AU - Bakhsh, Fatemeh
AU - Xu, Dongqing
AU - Xu, Cheng
AU - Vong, Tyrus
AU - Wu, Bin
AU - Selaru, Florin M.
AU - Wan, Fengyi
AU - Donowitz, Mark
AU - Wong, G. William
N1 - Funding Information:
Huimin Yu, MD, PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Resources: Lead; Software: Supporting; Supervision: Lead; Validation: Lead; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead), Zixin Zhang, MS (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Software: Lead; Visualization: Lead; Writing – original draft: Supporting), Gangping Li, MD, PhD (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Software: Lead; Visualization: Lead), Yan Feng, MD, PhD (Conceptualization: Supporting; Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting; Software: Supporting; Visualization: Supporting; Writing – review & editing: Supporting), Lingling Xian, MD, PhD (Conceptualization: Supporting; Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting; Software: Supporting; Visualization: Supporting; Writing – review & editing: Supporting), Fatemeh Bakhsh, PhD (Investigation: Supporting), Dongqing Xu, PhD (Investigation: Supporting), Cheng Xu, PhD (Resources: Supporting), Tyrus Vong, BS (Data curation: Supporting; Resources: Supporting), Bin Wu, PhD (Methodology: Supporting), Florin M. Selaru, MD (Resources: Supporting; Writing – review & editing: Supporting), Fengyi Wan, PhD (Formal analysis: Supporting; Methodology: Supporting; Resources: Supporting Writing – review & editing: Supporting), Mark Donowitz, MD (Formal analysis: Supporting; Resources: Supporting; Writing – review & editing: Supporting), G. William Wong, PhD (Formal analysis: Supporting; Resources: Supporting; Writing – review & editing: Supporting) Funding This work was supported by the Johns Hopkins Discovery Fund Challenge Award (to HY), the Johns Hopkins Gastroenterology Division Pilot Award (to HY), the National Institutes of Health grant DK084171 (to GWW), and the National Institutes of Health grant P30DK089502 (to the Johns Hopkins Digestive Disease Center).
Funding Information:
Funding This work was supported by the Johns Hopkins Discovery Fund Challenge Award (to HY), the Johns Hopkins Gastroenterology Division Pilot Award (to HY), the National Institutes of Health grant DK084171 (to GWW), and the National Institutes of Health grant P30DK089502 (to the Johns Hopkins Digestive Disease Center).
Publisher Copyright:
© 2023 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - Background & Aims: The adipokine CTRP3 has anti-inflammatory effects in several nonintestinal disorders. Although serum CTRP3 is reduced in patients with inflammatory bowel disease (IBD), its function in IBD has not been established. Here, we elucidate the function of CTRP3 in intestinal inflammation. Methods: CTRP3 knockout (KO) and overexpressing transgenic (Tg) mice, along with their corresponding wild-type littermates, were treated with dextran sulfate sodium for 6–10 days. Colitis phenotypes and histologic data were analyzed. CTRP3-mediated signaling was examined in murine and human intestinal mucosa and mouse intestinal organoids derived from CTRP3 KO and Tg mice. Results: CTRP3 KO mice developed more severe colitis, whereas CTRP3 Tg mice developed less severe colitis than wild-type littermates. The deletion of CTRP3 correlated with decreased levels of Sirtuin-1 (SIRT1), a histone deacetylase, and increased levels of phosphorylated/acetylated NF-κB subunit p65 and proinflammatory cytokines tumor necrosis factor-α and interleukin-6. Results from CTRP3 Tg mice were inverse to those from CTRP3 KO mice. The addition of SIRT1 activator resveratrol to KO intestinal organoids and SIRT1 inhibitor Ex-527 to Tg intestinal organoids suggest that SIRT1 is a downstream effector of CTRP3-related inflammatory changes. In patients with IBD, a similar CTRP3/SIRT1/NF-κB relationship was observed. Conclusions: CTRP3 expression levels correlate negatively with intestinal inflammation in acute mouse colitis models and patients with IBD. CTRP3 may attenuate intestinal inflammation via SIRT1/NF-κB signaling. The manipulation of CTRP3 signaling, including through the use of SIRT1 activators, may offer translational potential in the treatment of IBD.
AB - Background & Aims: The adipokine CTRP3 has anti-inflammatory effects in several nonintestinal disorders. Although serum CTRP3 is reduced in patients with inflammatory bowel disease (IBD), its function in IBD has not been established. Here, we elucidate the function of CTRP3 in intestinal inflammation. Methods: CTRP3 knockout (KO) and overexpressing transgenic (Tg) mice, along with their corresponding wild-type littermates, were treated with dextran sulfate sodium for 6–10 days. Colitis phenotypes and histologic data were analyzed. CTRP3-mediated signaling was examined in murine and human intestinal mucosa and mouse intestinal organoids derived from CTRP3 KO and Tg mice. Results: CTRP3 KO mice developed more severe colitis, whereas CTRP3 Tg mice developed less severe colitis than wild-type littermates. The deletion of CTRP3 correlated with decreased levels of Sirtuin-1 (SIRT1), a histone deacetylase, and increased levels of phosphorylated/acetylated NF-κB subunit p65 and proinflammatory cytokines tumor necrosis factor-α and interleukin-6. Results from CTRP3 Tg mice were inverse to those from CTRP3 KO mice. The addition of SIRT1 activator resveratrol to KO intestinal organoids and SIRT1 inhibitor Ex-527 to Tg intestinal organoids suggest that SIRT1 is a downstream effector of CTRP3-related inflammatory changes. In patients with IBD, a similar CTRP3/SIRT1/NF-κB relationship was observed. Conclusions: CTRP3 expression levels correlate negatively with intestinal inflammation in acute mouse colitis models and patients with IBD. CTRP3 may attenuate intestinal inflammation via SIRT1/NF-κB signaling. The manipulation of CTRP3 signaling, including through the use of SIRT1 activators, may offer translational potential in the treatment of IBD.
KW - Adipokine CTRP3
KW - IBD
KW - Intestinal Inflammation
KW - Intestinal organoids
KW - SIRT1/NF-κB Signaling
UR - http://www.scopus.com/inward/record.url?scp=85150254218&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85150254218&partnerID=8YFLogxK
U2 - 10.1016/j.jcmgh.2022.12.013
DO - 10.1016/j.jcmgh.2022.12.013
M3 - Article
C2 - 36592863
AN - SCOPUS:85150254218
SN - 2352-345X
VL - 15
SP - 1000
EP - 1015
JO - CMGH
JF - CMGH
IS - 4
ER -