Dual Role of Circulating Angiopoietin-Like 4 (ANGPTL4) in Promoting Hypertriglyceridemia and Lowering Proteinuria in Nephrotic Syndrome

In the Literature Dual Role of Circulating Angiopoietin-Like 4 (ANGPTL4) in Promoting Hypertriglyceridemia and Lowering Proteinuria in Nephrotic Syndrome Commentary on Clement LC, Mace´ C, Avila-Casado C, et al. Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med. 2014;20(1):37-46. H yperlipidemia is a hallmark of nephrotic syn- drome and is characterized by elevation of plasma cholesterol, triglyceride, low-density lipopro- tein (LDL), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and lipopro- tein(a) levels, as well as altered structure and function of high-density lipoprotein (HDL). 1-3 Recently in Na- ture Medicine, Clement et al 4 published a series of ex- periments that showed that elevation of circulating angiopoietin-like 4 (Angptl4 in rats; ANGPTL4 in hu- mans) appears to be the missing link that ties hyper- triglyceridemia to albuminuria in nephrotic syndrome. Nephrotic hyperlipidemia is due largely to the acquired deﬁciencies of lipoprotein lipase (LPL), 5-7 hepatic lipase, 8 the VLDL receptor, 5,9 the LDL receptor, 10-12 lecithin-cholesterol acyltransferase (LCAT), 13 and the HDL docking receptor (SRB1; en- coded by SCARB1) 14,15 ; upregulation of cholestery- lester transfer protein (CETP), 16,17 hepatic acyl coenzyme A cholesterol acyltransferase (ACAT, en- coded by ACAT1), 18,19 diglycerol acyltransferase, 20 and lipoprotein(a) 21 ; and altered composition of plasma lipoproteins interfering with their receptor binding and clearance. 22 Triglyceride-rich lipoproteins (VLDL and chylo- microns) deliver fatty acid to various tissues, inclu- ding myocytes for energy production and adipocytes for energy storage. Nascent VLDL particles are pro- duced in hepatocytes and released in the circulation, where they acquire apolipoproteins E and C (Apo-E and Apo-C) from cholesterol ester – rich HDL subfrac- tion 2 (HDL2). In the capillaries perfusing muscles and adipose tissues, VLDL binds to the endothelial sur- face by its Apo-E content and activates the adjacent LPL by its Apo-CII content. This leads to hydrolysis of 70% of VLDL’s triglyceride cargo by LPL, release of free fatty acid (FFA), and conversion of VLDL to IDL. Nascent chylomicrons are formed in the enter- ocytes and released in the circulation, where, like VLDL particles, they acquire Apo-E and Apo-C from HDL2. This is followed by LPL-mediated hydrolysis of 70% of their triglyceride contents and their con- version to chylomicron remnants (Fig 1). Two-thirds of the fatty acids released from VLDL and chylomicrons enter the adjacent myocytes or adipocytes, whereas the other FFAs enter the plasma pool bound to albumin and lipoproteins and are transported to distant sites, mainly the liver. After undergoing lipolysis by LPL, the IDL and chylomicron remnants, which contain Am J Kidney Dis. 2014; - ( - ): - - - 30% of their original triglyceride cargos, are released into the circulation. The remaining triglyceride con- tents of IDL normally are removed by CETP-mediated exchange of triglycerides for cholesterol ester with HDL2 and by hepatic lipase, leading to the formation of LDL, which ultimately is cleared by LDL receptor. The chylomicron remnants are removed by the liver by a large multifunctional receptor known as LDL receptor – related protein (LRP). As noted, LPL and hepatic lipase play a central part in triglyceride metabolism, and their acquired deﬁciencies in nephrotic syndrome are largely responsible for the associated hypertriglyceridemia. Until recently, the mechanism by which nephrotic syndrome causes LPL and hepatic lipase deﬁciencies was unknown. Recently, Clement et al 4 published a series of experiments that demonstrated the role of elevated FFA to albumin ratio as the mediator of elevation of circulating Angptl4, as well as the dual function of Angptl4 in inhibiting LPL and lowering proteinuria in nephrotic animals. Human ANGPTL4 is a glycoprotein (molecular weight, 45-65 kDa) that is constitutively expressed in the liver, adipose tissue, skeletal muscle, small intes- tine, and heart. ANGPTL4 expression is upregulated and its plasma level increases in response to fasting, high FFA levels, and hypoxia. 23 The effects of fasting and FFA on ANGPTL4 are mediated by peroxisome proliferator-activated receptors (PPARs). In addition, as a positive acute-phase protein, ANGPTL4 expres- sion in the liver, heart, muscle, and adipose tissue is increased during the acute-phase response. 24 By bind- ing to the active LPL dimers and converting LPL into inactive monomers, ANGPTL4 can impair clearance of triglyceride contents of VLDL and chylomicrons and cause hypertriglyceridemia. In addition to inhibiting LPL, ANGPTL4 may inhibit hepatic lipase, 23 which can increase plasma triglyceride levels further by impairing clearance of triglyceride contents of circulating IDL and HDL. The LPL-inhibitory effect of ANGPTL4 is miti- gated by glycosylphosphatidylinositol-anchored bind- ing protein 1 (GPIHBP1), which is the transporter and Address correspondence to Nosratola D. Vaziri, MD, MACP, University of California, Irvine, Division of Nephrology and Hypertension, 1001 Health Sciences Rd, Irvine, CA 92697. E-mail: ndvaziri@uci.edu O 2014 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2014.04.016