Mini Review Emerging roles of Lipasin as a critical lipid regulator Ren Zhang a,⇑ , Abdul B. Abou-Samra a,b a Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA b Department of Medicine, Hamad Medical Corporation, Doha, Qatar article info Article history: Received 29 January 2013 Available online 13 February 2013 Keywords: Gm6484 C19orf80 Triglycerides Lipasin RIFL ANGPTL8 abstract Patients with metabolic syndrome are at high risk for developing atherosclerotic cardiovascular diseases and diabetes. In addition to total cholesterol, LDL-C and HDL-C, elevated plasma triglycerides (TG) are increasingly recognized as an independent risk factor for cardiovascular diseases. Recently 3 groups inde- pendently reported the identification and characterization of a novel blood lipid regulator, Lipasin/RIFL/ ANGPTL8, which here is referred to as Lipasin for its lipoprotein lipase inhibition effect and for being a circulating factor denoted by ‘in’. Being highly enriched in the liver, Lipasin is a hepatocyte-derived cir- culating factor that regulates plasma TG levels. Lipasin is nutritionally regulated, as its mRNA levels in liver and fat as well as its protein level in serum are reduced by fasting. Mice deficient for Lipasin have lower serum TG levels; conversely, its adenovirus-mediated overexpression increases serum TG levels, in part, through promoting ANGPTL3 cleavage, releasing its N-terminal domain that inhibits lipoprotein lipase. Lipasin sequence variations are associated with LDL-C and HDL-C concentrations in humans. Being lipogenic, Lipasin is highly induced during adipogenesis. Levels of Lipasin and ANGPTL4 show opposite changes in response to fasting or cold environment. Lipasin, a novel but atypical ANGPTL family member, is emerging as a critical lipid regulator and a potential drug target. Ó 2013 Elsevier Inc. All rights reserved. 1. Introduction The prevalence of metabolic syndrome, a common metabolic disorder including glucose intolerance and dyslipidemia, has in- creased dramatically in the past two decades [1], largely due to the global obesity epidemic [2]. Patients with metabolic syndrome are at high risk of developing atherosclerotic cardiovascular dis- eases and diabetes, posing a major public health issue. Of note, in addition to total cholesterol, LDL-C and HDL-C [3], increasing epidemiological evidence indicates that plasma triglyceride (TG) level is an independent risk factor for cardiovascular diseases [4]. Plasma TGs are determined by the balance between their produc- tion and clearance, where the former involves chylomicrons (CMs) that are predominately synthesized in the intestine in the post- prandial state and VLDL that is synthesized in the liver in the fasted state, and the latter involves lipoprotein lipase (LPL) mediated clearance in peripheral tissues. Patients with hypertriglyceridemia have increased plasma levels of remnants from CMs and VLDL, which penetrate the arterial endothelium, are preferentially trapped within subendothelial space [5,6], and can lead to the development of atherosclerosis and coronary heart diseases [7]. Lowering TG levels pharmacologically therefore may provide an additional strategy for preventing cardiovascular diseases. Recently 3 groups almost simultaneously reported the identifi- cation and characterization of a novel blood lipid regulator, called Lipasin [8,9], RIFL [10] or ANGPTL8 [11]. The official symbols for this gene are Gm6484 (mouse) and C19orf80 (human). We here re- fer to this gene as Lipasin, which is a novel but atypical member of the angiopoietin-like protein family. Here we review the current knowledge about Lipasin regarding its expression, regulation, func- tion and mechanisms of action and discuss its potential roles in hu- man physiology and pathology. 2. The angiopoietin-like protein family (ANGPTLs) The ANGPTL protein family contains 7 typical members, ANG- PTL1–7, encoded by 7 different genes [12]. ANGPTLs have struc- tural homology to that of angiopoietins, hence the name angiopoietin like proteins. ANGPTLs are characterized by the pres- ence of a coiled-coil domain at the N-terminus, a fibrinogen like domain at the C-terminus and a signal peptide that is typical for se- creted proteins (Fig. 1). Indeed, ANGPTL 2, 3, 4 and 5 have been de- tected in the systemic circulation, suggesting that these ANGPTLs may function in an endocrine manner [12]. Although angiopoietins bind to TIE2 and TIE1 receptor tyrosine kinases, the signaling that regulates vascular remodeling, none of the 7 ANGPTLs binds to these receptors, suggesting that the physiological function of ANG- PTLs and angiopoietins are different (Table 1). Indeed, the roles of ANGPTL3 and ANGPTL4 in lipid regulation have received much 0006-291X/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbrc.2013.01.129 ⇑ Corresponding author. Fax: +1 313 577 5218. E-mail address: rzhang@med.wayne.edu (R. Zhang). Biochemical and Biophysical Research Communications 432 (2013) 401–405 Contents lists available at SciVerse ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc