Sphingosine kinase 1 is involved in triglyceride breakdown by maintaining lysosomal integrity in brown adipocytes

Jun-Ichi Morishige; Kazuaki Yoshioka; Hiroki Nakata; Kazuhiro Ishimaru; Naoto Nagata; Tamotsu Tanaka; Yoh Takuwa; Hitoshi Ando

doi:10.1016/j.jlr.2023.100450

Sphingosine kinase 1 is involved in triglyceride breakdown by maintaining lysosomal integrity in brown adipocytes

J Lipid Res. 2023 Nov;64(11):100450. doi: 10.1016/j.jlr.2023.100450. Epub 2023 Sep 24.

Authors

Jun-Ichi Morishige¹, Kazuaki Yoshioka², Hiroki Nakata³, Kazuhiro Ishimaru², Naoto Nagata⁴, Tamotsu Tanaka⁵, Yoh Takuwa⁶, Hitoshi Ando⁷

Affiliations

¹ Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: morisige@med.kanazawa-u.ac.jp.
² Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
³ Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Komatsu, Japan.
⁴ Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
⁵ Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan.
⁶ Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: ytakuwa@med.kanazawa-u.ac.jp.
⁷ Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: h-ando@med.kanazawa-u.ac.jp.

Abstract

Sphingosine 1-phosphate (S1P) has been implicated in brown adipose tissue (BAT) formation and energy consumption; however, the mechanistic role of sphingolipids, including S1P, in BAT remains unclear. Here, we showed that, in mice, BAT activation by cold exposure upregulated mRNA and protein expression of the S1P-synthesizing enzyme sphingosine kinase 1 (SphK1) and S1P production in BAT. Treatment of wild-type brown adipocytes with exogenous S1P or S1P receptor subtype-selective agonists stimulated triglyceride (TG) breakdown only marginally, compared with noradrenaline. However, genetic deletion of Sphk1 resulted in hypothermia and diminished body weight loss upon cold exposure, suggesting that SphK1 is involved in thermogenesis through mechanisms different from receptor-mediated, extracellular action of S1P. In BAT of wild-type mice, SphK1 was localized largely in the lysosomes of brown adipocytes. In the brown adipocytes of Sphk1^-/- mice, the number of lysosomes was reduced and lysosomal function, including proteolytic activity, acid esterase activity, and motility, was impaired. Concordantly, nuclear translocation of transcription factor EB, a master transcriptional regulator of lysosome biogenesis, was reduced, leading to decreased mRNA expression of the lysosome-related genes in Sphk1^-/- BAT. Moreover, BAT of Sphk1^-/- mice showed greater TG accumulation with dominant larger lipid droplets in brown adipocytes. Inhibition of lysosomes with chloroquine resulted in a less extent of triglyceride accumulation in Sphk1^-/- brown adipocytes compared with wild-type brown adipocytes, suggesting a reduced lysosome-mediated TG breakdown in Sphk1^-/- mice. Our results indicate a novel role of SphK1 in lysosomal integrity, which is required for TG breakdown and thermogenesis in BAT.

Keywords: Adipose tissue; brown; lipase; lipid droplets; lipolysis; lysosome; sphingolipids; sphingosine kinase; sphingosine phosphate; thermogenesis; triglyceride.

Publication types

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

MeSH terms

Adipocytes, Brown* / metabolism
Adipose Tissue, Brown / metabolism
Animals
Lysophospholipids / metabolism
Mice
Phosphotransferases (Alcohol Group Acceptor) / metabolism
RNA, Messenger / metabolism
Signal Transduction*
Sphingosine / metabolism
Triglycerides / metabolism

Substances

sphingosine kinase
Phosphotransferases (Alcohol Group Acceptor)
sphingosine 1-phosphate
Sphingosine
RNA, Messenger
Lysophospholipids
Triglycerides