FSP27 is a potent player regulating lipid storage in liver as well as adipose tissue

Abstract

Obesity has increased dramatically worldwide and leads to numerous disorders including cardiovascular diseases, type 2 diabetes, dyslipidemia and cancers. These pathological states are closely associated with hyperinsulinemia or insulin resistance. Obesity itself is characterized by excessive triacylglycerol (TAG) storage as lipid droplets (LDs) in adipose tissue due to an increase in nutrient intake and insufficient energy expenditure. Excessive TAG storage in adipocytes causes adipose tissue inflammation and deregulation of adipokines, both of which induce systemic insulin resistance. At the same time, a hallmark of obesity is TAG accumulation in the liver and skeletal muscle, which is also important in inducing insulin resistance in these tissues. These findings underline the importance of lipid accumulation in insulin-sensitive organs in the development of insulin resistance and type 2 diabetes. Lipid droplets are comprised of a central core of neutral lipids containing TAG and cholesterol ester and surrounded by a phospholipid monolayer. This monolayer of LDs is decorated with a variety of proteins, which contribute to the formation of the droplets, the synthesis and hydrolysis of lipids, and the movement of theses lipids to specific intracellular and secretory pathways. The ability to store TAG in LDs is evolutionarily conserved in yeast, plants, invertebrates and vertebrates. In mammals, excess energy is primarily stored as TAG in LDs in adipose tissue. Especially white adipocytes are specifically differentiated cells for storing TAG as the large unilocular LDs that occupy most of the cell volume. The LD size can be in the 100 lm range. Such TAG storage in LDs serves a vital role as the body’s major stored energy supply. In the case of energy demand, such as starvation and exercise, TAG reserves are hydrolyzed by lipolysis to supply free fatty acid (FFA) to a variety of tissues. LDs are also recognized in non-adipose cells; however, non-adipocyte LDs are usually much smaller than those of adipocytes. Such TAG storage in liver, skeletal muscle and heart is thought to serve as a local energy supply. Recently, a fat-specific protein of 27 kDa (FSP27) was found to be the determining factor for LD size and critical for large unilocular LD formation in white adipocytes [1–3]. FSP27 was first identified in 1992 as a fat-specific protein whose expression was regulated by C/EBP, although its function in adipocytes remained elusive then [4]. Subsequently, FSP27 was reported to be a member of the CIDE family of proteins, comprised of CIDE-A, CIDEB and FSP27, which had homology with the amino-terminal domain of DFF-45 (45-kDa subunit of the DNA fragmentation factor) [5]. Later, CIDE-A was shown to be expressed in brown adipose tissue in mice and to inhibit energy expenditure [6]. CIDE-B is expressed mainly in the liver and kidney and is important for the maturation of VLDL as apolipoprotein B binding protein in the liver [7]. As for FSP27, functional analysis of FSP27 has robustly progressed since knockout (KO) mice were generated in 2008 [1, 3], although FSP27 was already found to be a LD Y. Tamori (&) Division of Metabolism and Endocrinology, Department of Internal Medicine, Chibune Hospital, 2-2-45 Tsukuda, Nishiyodogawa-ku, Osaka 555-0001, Japan e-mail: tamori@med.kobe-u.ac.jp