Fat-specific protein 27 undergoes ubiquitin-dependent degradation regulated by triacylglycerol synthesis and lipid droplet formation.
The fat-specific protein 27 (Fsp27), a protein localized to lipid droplets (LDs), plays an important role in controlling lipid storage and mitochondrial activity in adipocytes. Fsp27-null mice display increased energy expenditure and are resistant to high fat diet-induced obesity and diabetes. However, little is known about how the Fsp27 protein is regulated. Here, we show that Fsp27 stability is controlled by the ubiquitin-dependent proteasomal degradation pathway in adipocytes. The ubiquitination of Fsp27 is regulated by three lysine residues located in the C-terminal region. Substitution of these lysine residues with alanines greatly increased Fsp27 stability and enhanced lipid storage in adipocytes. Furthermore, Fsp27 was stabilized and rapidly accumulated following treatment with beta-agonists that induce lipolysis and fatty acid re-esterification in adipocytes. More importantly, Fsp27 stabilization was dependent on triacylglycerol synthesis and LD formation, because knockdown of diacylglycerol acyltransferase in adipocytes significantly reduced Fsp27 accumulation in adipocytes. Finally, we observed that increased Fsp27 during beta-agonist treatment preferentially associated with LDs. Taken together, our data revealed that Fsp27 can be stabilized by free fatty acid availability, triacylglycerol synthesis, and LD formation. The stabilization of Fsp27 when free fatty acids are abundant further enhances lipid storage, providing positive feedback to regulate lipid storage in adipocytes.
Nian
Zongqian
Z
Protein Science Laboratory of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Sun
Zhiqi
Z
Protein Science Laboratory of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Yu
Luxin
L
College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Toh
Shen Yon
SY
Institute of Molecular and Cell Biology, 138673 Singapore.
Sang
Jianli
J
College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Li
Peng
P
Protein Science Laboratory of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: li-peng@mail.tsinghua.edu.cn.
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D014280:Triglycerides / Q000737:chemistry* / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry*
D008055:Lipids; D011506:Proteins; D014280:Triglycerides; D025801:Ubiquitin; C525805:fat-specific protein 27, mouse; D049452:Green Fluorescent Proteins; D046988:Proteasome Endopeptidase Complex