ANGPTL4 in Metabolic and Cardiovascular Disease

Abstract

Alterations in circulating lipids and ectopic lipid deposition impact on the risk of developing cardiovascular and metabolic diseases. Lipoprotein lipase (LPL) hydrolyzes fatty acids (FAs) from triglyceride (TAG)-rich lipoproteins including very low density lipoproteins (VLDLs) and chylomicrons, and regulates their distribution to peripheral tissues. Angiopoietin-like 4 (ANGPTL4) mediates the inhibition of LPL activity under different circumstances. Accumulating evidence associates ANGPTL4 directly with the risk of atherosclerosis and type 2 diabetes (T2D). This review focuses on recent findings on the role of ANGPTL4 in metabolic and cardiovascular diseases. We highlight human and murine studies that explore ANGPTL4 functions in different tissues and how these effect disease development through possible autocrine and paracrine forms of regulation.

Figure 1.. Lipid partitioning by angiopoietin like proteins (ANGPTLs).

ANGPTL4, ANGPTL3 and ANGPTL8 regulate triglyceride (TAG) clearance by inhibiting lipoprotein lipase (LPL), in a tissue-specific manner, under different nutritional conditions. While the levels of ANGPTL4 and ANGPTL8 are reciprocally regulated under fed and fasted conditions, the level of ANGPTL3 is stable regardless of nutritional status, but requires activation by ANGPTL8. Fasting induces ANGPTL4, which results in decreased LPL activity in white adipose tissues (WAT) and redirects circulating TAGs to heart and muscles for oxidation. In contrast, feeding induces ANGPTL8 resulting in the activation of ANGPTL3/8 mediated inhibition of LPL activity in heart and muscle and redirects circulating TAGs to WAT for storage. Overall, ANGPTLs regulate LPL activity and promote net storage of lipids during the fed state and utilization by peripheral tissues during fasting.

Figure 2.. ANGPTL4 Regulation of Insulin Sensitivity and Whole Glucose Metabolism

(1) ANGPTL4 is predominantly expressed in adipose tissues (AT) and its expression is under the regulation of PPARs and glucocorticoids in white AT (WAT). ANGPTL4 secreted from WAT regulates the hydrolysis of triglycerides (TAGs) from chylomicrons and VLDL particles by inhibiting LPL activity. (1+2) Whole body or AT specific depletion of ANGPTL4 results in increased LPL activity in WAT and brown AT (BAT), decreased circulating TAGs, and increased fatty acid (FA) uptake by AT. In addition, ANGPTL4 depletion increases lipolysis and FA oxidation in AT. Concomitantly, it also results in decreased TAG, diacylglycerol (DAG), and ceramide accumulation in liver and muscles, reduces membrane translocation of PKC proteins, and increases insulin sensitivity in these tissues. (2) Similarly, ANGPTL4 deficiency in BAT increases LPL activity, increases FA influx into BAT and improves thermogenesis in response to acute cold exposure, and improves glucose tolerance by preventing hepatic and muscle lipid deposition. (3) Finally, loss of ANGPTL4 alters gut microbiota composition, which may also improve insulin sensitivity and glucose tolerance. Overall, ANGPTL4 deficiency improves insulin sensitivity and glucose metabolism. EC, endothelial cell; PPARs, peroxisome proliferator-activated receptors; PKC, protein kinase C.

Figure 3.. The Janus Face Role of ANGPTL4 in Atherosclerosis.

Secreted ANGPTL4 from different tissues, including adipose tissues, binds to lipoprotein lipase (LPL) and inhibits its lipolytic activity, resulting in a decrease in the hydrolysis of triglycerides (TAGs) from triglyceride-rich lipoproteins [TRL (VLDL and chylomicrons)] in capillaries of storage (WAT) and metabolic tissues (Heart, muscle, BAT). Loss of ANGPTL4 in these tissues increases LPL activity and accelerates the catabolism of TRL, reducing circulating TAGs and LDL-C, which protects against the progression of atherosclerosis (1). In contrast ANGPTL4 plays a atheroprotective role in macrophages, preventing neutral lipid overloading, proinflammatory activation and apoptosis (2).