Inhibition of lipid droplet formation by Ser/Thr protein phosphatase PPM1D inhibitor, SL-176

Rui Kamada; Nozomi Kimura; Fumihiko Yoshimura; Keiji Tanino; Kazuyasu Sakaguchi

doi:10.1371/journal.pone.0212682

Inhibition of lipid droplet formation by Ser/Thr protein phosphatase PPM1D inhibitor, SL-176

PLoS One. 2019 Feb 27;14(2):e0212682. doi: 10.1371/journal.pone.0212682. eCollection 2019.

Authors

Rui Kamada¹, Nozomi Kimura¹, Fumihiko Yoshimura², Keiji Tanino³, Kazuyasu Sakaguchi¹

Affiliations

¹ Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
² School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
³ Laboratory of Organic Chemistry II, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.

Abstract

Obesity is a worldwide public health problem, which is associated with various severe diseases including diabetes, hypertension, atherosclerosis, and cancer. Recent studies have revealed that combination treatment of several different compounds using low doses is effective to reduce side effects. Thus, there is a need to develop an efficient inhibitor for reducing lipid droplets with a divergent target/pathway. Ser/Thr protein phosphatase PPM1D is involved in cellular metabolic processes and is a promising target for anti-obesity treatment. We have previously developed a potent and specific PPM1D inhibitor, SL-176. In this study, we demonstrated that significant reduction of lipid droplet formation in adipocytes by the PPM1D specific inhibitor, SL-176. Using Oil-red O staining and fluorescent imaging of lipid droplet, we found that treatment of SL-176 significantly suppressed lipid droplet formation of 3T3-L1 cells both in amount and in size. SL-176 also repressed mRNA and protein expression of PPARγ and C/EBPα, adipogenic markers, at nontoxic conditions. Thus, SL-176 is a unique and potent inhibitor of lipid droplet formation that acts via PPM1D, a novel target toward inhibiting adipocyte differentiation.

Publication types

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

MeSH terms

3T3-L1 Cells
Adipocytes / cytology
Adipocytes / drug effects*
Adipocytes / physiology
Adipogenesis / drug effects
Animals
Anti-Obesity Agents / pharmacology*
Anti-Obesity Agents / therapeutic use
Cell Differentiation / drug effects
Drug Evaluation, Preclinical
Lipid Droplets / drug effects*
Mice
Naphthalenes / pharmacology*
Naphthalenes / therapeutic use
Obesity / drug therapy
Organosilicon Compounds / pharmacology*
Organosilicon Compounds / therapeutic use
Protein Phosphatase 2C / antagonists & inhibitors*
Protein Phosphatase 2C / metabolism

Substances

Anti-Obesity Agents
Naphthalenes
Organosilicon Compounds
SL-176
Ppm1d protein, mouse
Protein Phosphatase 2C

Grants and funding

This work was supported in part by Grant-in-Aid for Young Scientists (B) (No. 17K1756507) (to R.K.) from JSPS-Japan, Toyota RIKEN, Japan (to R.K.), Japan Foundation for Applied Enzymology (to K.S.), JP15H05842 in Middle Molecular Strategy and JP18H01970 (to K.T.). This work was also supported in part through Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), found by MEXT under “Support Program for Implementation of New Equipment Sharing System”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.