Angptl3 Deficiency Is Associated With Increased Insulin Sensitivity, Lipoprotein Lipase Activity, and Decreased Serum Free Fatty Acids

Abstract

Objective-Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism. Approach and Results-We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age-and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects. Conclusions-These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism. Key Words: ANGPTL3 protein, human ◼ ANGPTL4 protein, human ◼ endothelial lipase, human ◼ familial combined hypolipidemia ◼ fatty acids, nonesterified ◼ hepatic lipase, human ◼ lipoprotein lipase

Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism

“…In particular, we found that, compared with noncarriers, homozygotes, but not heterozygotes, displayed a 3-fold higher postheparin LPL activity. Moreover, we also observed that the homozygotes had reduced fasting plasma levels of FFAs and lower homeostasis model assessment of insulin resistance compared with control subjects (17). Based on these findings, it is reasonable to postulate that complete ANGPTL3 deficiency would cause accelerated postprandial clearance of TRLs, an effect that might be potentially implicated in FHBL2 hypolipidemia.…”

“…It has been proposed that low LDL might be due to reduced VLDL to LDL conversion (14), even though an increased clearance rate of LDL particles has been observed in homozygous individuals (13). Reduced HDL has been explained by elevated endothelial lipase activity in the absence of ANGPTL3 (16), but the direct in vivo demonstration of this mechanism in FHBL2 subjects is lacking (17). Therefore, the full effect of ANGPTL3 on lipoprotein metabolism is likely to be very complex and is not yet fully understood.…”

Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis

“…It seem interesting to consider this observation in the light of results by Romeo et al ( 28 ) that reported in a population study higher prevalence of nonsynonymous (probably inactivating) variations in the ANGPTL3 genes among subjects in the lowest quartile of blood glucose levels. Moreover, we recently reported that FHBL2 homozygotes showed lower plasma levels of insulin and lower degree of insulin-resistance as estimated HOMA-IR index ( 36 ). If further confi rmed in additional investigations, these fi ndings could highlight a more comprehensive role of ANGPTL3 in regulating not only lipid but also glucose metabolism.…”

Tissue expression and predicted protein structures of the bovine ANGPTL3 and association of novel SNPs with growth and meat quality traits

“…Many studies in humans, mice and livestock have shown that ANGPTL3 is involved in the regulation of lipid, glucose metabolism and energy balance (Kadomatsu et al, 2011;Arca et al, 2013;Robciuc et al, 2013). Accumulating evidence indicates that some genes closely related to ANGPTL3, especially LXRα, ANGPTL4 and ANGPTL6, function as a new class of lipid and energy metabolism modulator (Kadomatsu et al, 2011).…”

“…Romeo et al (2009) also noted that a genetic variation of ANGPTL3 was associated with the lowest quartile of blood glucose levels. Therefore, ANGPTL3 appears to have an important role in lipoprotein, FFA and glucose metabolism (Robciuc et al, 2013).…”