Full Text | PDF

Share on tweeters Share on facebook Share on linkedin Share on googleplus

Theranostics 2020; 10(25):11416-11427. doi:10.7150/thno.49770 This issue Cite

Research Paper

Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis

Min Yan Shi1*, In Hyuk Bang1*, Chang Yeob Han2*, Dae Ho Lee3, Byung-Hyun Park1✉, Eun Ju Bae2✉

1. Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk 54896, Republic of Korea.
2. College of Pharmacy, Chonbuk National University, Jeonju, Jeonbuk 54896, Republic of Korea.
3. Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon 21565, Republic of Korea.
*These authors equally contributed to this work.

✉ Corresponding authors: Byung-Hyun Park, E-mail: bhparkac.kr; Phone: +82-63-270-3139; Eun Ju Bae, E-mail: ejbae7ac.kr; Phone: +82-63-219-5650.

Citation:
Shi MY, Bang IH, Han CY, Lee DH, Park BH, Bae EJ. Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis. Theranostics 2020; 10(25):11416-11427. doi:10.7150/thno.49770. https://www.thno.org/v10p11416.htm
Other styles

File import instruction

Abstract

Graphic abstract

Rationale: Statin, the most widely used medication in lowering cholesterol, is also associated with increased risk of type 2 diabetes, but its molecular basis remains unclear.

Methods: Mice were injected intraperitoneally with statins alone or in combination with sirtuin (Sirt) 6 activator, and blood glucose levels were measured. Liver tissues from patients with statin use were analyzed for the expression of Sirt6.

Results: Statin treatment up-regulated the hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which was prevented by Sirt6 overexpression. Mechanistically, statin directly repressed Sirt6 expression by induction of microRNA (miR)-495, a novel inhibitor of Sirt6. Pathway analysis for predicted target genes of miR-495 recognized forkhead box protein (Fox)O1 as a key downstream signaling of Sirt6. Statin treatment increased the acetylation and protein stability of FoxO1, which was suppressed by Sirt6 overexpression. Inhibiting miR-495 recovered Sirt6 levels, blocking the ability of statin to increase FoxO1 mediated gluconeogenesis, and thus confirming the role of the miR-495/Sirt6/FoxO1 pathway in controlling gluconeogenesis. Moreover, the Sirt6 activator MDL801 prevented gluconeogenesis and hyperglycemia induced by statin in mice. Equally noteworthy was that human liver tissues obtained from statin users showed a significant decrease in Sirt6 protein levels compared to those of non-users.

Conclusion: Statin induces miR-495 to suppress Sirt6 expression, which leads to enhancement of FoxO1-mediated hepatic gluconeogenesis. Thus, Sirt6 activation may offer a promising strategy for preventing statin-induced hyperglycemia.

Keywords: Sirt6, statin, gluconeogenesis, miR-495, FoxO1

Citation styles

APA
Shi, M.Y., Bang, I.H., Han, C.Y., Lee, D.H., Park, B.H., Bae, E.J. (2020). Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis. Theranostics, 10(25), 11416-11427. https://doi.org/10.7150/thno.49770.

ACS
Shi, M.Y.; Bang, I.H.; Han, C.Y.; Lee, D.H.; Park, B.H.; Bae, E.J. Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis. Theranostics 2020, 10 (25), 11416-11427. DOI: 10.7150/thno.49770.

NLM
Shi MY, Bang IH, Han CY, Lee DH, Park BH, Bae EJ. Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis. Theranostics 2020; 10(25):11416-11427. doi:10.7150/thno.49770. https://www.thno.org/v10p11416.htm

CSE
Shi MY, Bang IH, Han CY, Lee DH, Park BH, Bae EJ. 2020. Statin suppresses sirtuin 6 through miR-495, increasing FoxO1-dependent hepatic gluconeogenesis. Theranostics. 10(25):11416-11427.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image

©2024 Ivyspring International Publisher. Terms of use