Increased oxidative stress impairs adipose tissue function in sphingomyelin synthase 1 null mice

Masato Yano; Tadashi Yamamoto; Naotaka Nishimura; Tomomi Gotoh; Ken Watanabe; Kazutaka Ikeda; Yohei Garan; Ryo Taguchi; Koichi Node; Toshiro Okazaki; Yuichi Oike

doi:10.1371/journal.pone.0061380

Increased oxidative stress impairs adipose tissue function in sphingomyelin synthase 1 null mice

PLoS One. 2013 Apr 12;8(4):e61380. doi: 10.1371/journal.pone.0061380. Print 2013.

Authors

Masato Yano¹, Tadashi Yamamoto, Naotaka Nishimura, Tomomi Gotoh, Ken Watanabe, Kazutaka Ikeda, Yohei Garan, Ryo Taguchi, Koichi Node, Toshiro Okazaki, Yuichi Oike

Affiliation

¹ Department of Molecular Genetics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. myano@gpo.kumamoto-u.ac.jp

Abstract

Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we found that SMS1 null mice showed lipodystrophic phenotype. Mutant mice showed up-regulation of plasma triglyceride concentrations accompanied by reduction of white adipose tissue (WAT) as they aged. Lipoprotein lipase (LPL) activity was severely reduced in mutant mice. In vivo analysis indicated that fatty acid uptake in WAT but not in liver decreased in SMS1 null compared to wild-type mice. In vitro analysis using cultured cell revealed that SMS1 depletion reduced fatty acid uptake. Proteins extracted from WAT of mutant mice were severely modified by oxidative stress, and up-regulation of mRNAs related to apoptosis, redox adjustment, mitochondrial stress response and mitochondrial biogenesis was observed. ATP content of WAT was reduced in SMS1 null mice. Blue native gel analysis indicated that accumulation of mitochondrial respiratory chain complexes was reduced. These results suggest that WAT of SMS1 null mice is severely damaged by oxidative stress and barely functional. Indeed, mutant mice treated with the anti-oxidant N-acetyl cysteine (NAC) showed partial recovery of lipodystrophic phenotypes together with normalized plasma triglyceride concentrations. Altogether, our data suggest that SMS1 is crucial to control oxidative stress in order to maintain WAT function.

Publication types

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

MeSH terms

Acetylcysteine / pharmacology
Acetylcysteine / therapeutic use
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism
Adipose Tissue, White / pathology*
Adipose Tissue, White / physiopathology*
Animals
Antioxidants / pharmacology
Antioxidants / therapeutic use
Fatty Acids / metabolism
Hyperlipidemias / complications
Hyperlipidemias / drug therapy
Hyperlipidemias / metabolism
Hyperlipidemias / pathology
Lipodystrophy / complications
Lipodystrophy / drug therapy
Lipodystrophy / enzymology
Lipodystrophy / pathology
Lipoprotein Lipase / metabolism
Mice
Mice, Knockout
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondrial Turnover / drug effects
Oxidative Stress* / drug effects
Phenotype
Transferases (Other Substituted Phosphate Groups) / deficiency*
Transferases (Other Substituted Phosphate Groups) / metabolism

Substances

Antioxidants
Fatty Acids
Sgms1 protein, mouse
Transferases (Other Substituted Phosphate Groups)
Lipoprotein Lipase
Acetylcysteine

Grants and funding

This work was supported by grants-in-aid 19790215 (to MY) and 23590340 (to MY), and 22116009 (to YO) from the Ministry of Education, Science, Technology, Sports and Culture of Japan, by a grant-in-aid 22659156 (to YO) from the Japan Society for the Promotion of Science, and by grants-in-aid from the Takeda Science Foundation (to MY) and Inamori Foundation (to MY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.