Quantitation of serum angiopoietin-like proteins 3 and 4 in a Finnish population sample

Abstract

Dysregulation of lipid metabolism is closely related with a number of pathological states including atherosclerosis, obesity, and insulin resistance. An extensive amount of data relates elevation of cholesterol and triglycerides (TG) in apolipoprotein (apo)B-containing particles such as VLDL and LDL to increased risk for atherosclerosis. Epidemiological and clinical studies have provided strong evidence that a low level of cholesterol in HDL is also a major risk factor for the development of atherosclerosis ( 4, 5 ). LPL is a key molecule involved in the hydrolysis of TG in VLDL and chylomicrons and in the clearance of these particles from circulation ( 6 ). In vitro observations as well as animal models have fi rmly established ANGPTL 3 and 4 as potent inhibitors of LPL ( 7,8 ). These studies are supported by genetic studies in humans that have associated mutations in these two proteins with circulating TG levels ( 9-11 ). Endothelial lipase (EL), a member of the triglyceride lipase gene family, has been demonstrated to infl uence the levels of HDL in circulation ( 12 ). Recently, it was shown that ANGPTL3 can inhibit EL and thereby increase the levels of HDL ( 13 ).Epidemiological studies clearly demonstrate that obesity has increased worldwide. Obesity increases the risk of diabetes, heart disease, fatty liver, and even some forms of cancer. It is therefore important to better understand the biological basis of obesity in order to aid its prevention and treatment. Several studies in mice have shown that ANGPTL4 can act as a powerful signal from adipose and other tissues to prevent fat storage and stimulate fat mobilization ( 14, 15 ). There is a large body of evidence demonstrating that ANGPTL 3 and 4 play major roles in rodent energy metabolism. However, there is limited information on the physiological roles of ANGPTL 3 and 4 in humans. The anthropometric and biochemical parameters of subjects were characterized in detail. ANGPTL 3 and 4 levels were determined using the developed ELISAs. The intraand inter-assay coeffi cients of variation for the assays were less than 15%. The average serum concentration of ANGPTL3 was 368 ± 168 ng/ml (mean ± SD) and for ANGPTL4 it was 18 ± 23 ng/ml (mean ± SD). ANGPTL4 serum levels displayed high variability between individuals ranging from 2 to 158 ng/ml. In post-heparin plasma, both ANGPTL 3 and 4 were increased. Low levels of ANGPTL3 were associated with decreased HDL-cholesterol and increased triglyceride levels. ANGPTL4 levels were positively correlated with FFAs ( P = 0.044) and waist-hip ratio ( P = 0.016). The developed ELISAs will be important tools to clarify the role of ANGPTL 3 and 4 in human energy metabolism and partitioning of triglycerides between sites of storage (adipose tissue) and oxidation (skeletal and cardiac muscle). Angiopoietin-like (ANGPTL) proteins 3 and 4 belong to a family of proteins that share a common modular structure consisting of an N-terminal signal sequence, a coiledcoil domain and a large fi brinogen/angiopoietin-like domain ( 1, 2 ...

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…Circulating ANGPTL4 levels were negatively associated with HDL‐c and positively associated with triglyceride in Americans 12. On the other hand, no correlation was seen between circulating ANGPTL4 levels with any of these aforementioned parameters in Finnish subjects 37. In the study, we did not observe any significant association between circulating ANGPTL4 levels and HDL‐c, LDL‐c, or triglyceride in nondiabetic participants.…”

Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

“…Inhibited LPL was found in a complex with ANGPTL4, and superstoichiometric ratios of ANGPTL4/LPL were required for complete inhibition. These findings may have considerable in vivo significance in light of recent data showing that, in humans, serum ANGPTL4 levels do not correlate with plasma triglyceride levels and that LPL travels bidirectionally across endothelial cells (24,25). These data have led to the suggestion that ANGPTL4 could inhibit LPL in the subendothelial space rather than on the endothelial surface (25).…”

“…ANGPTL4 could thus inhibit LPL in either the subendothelial space or on the surface of the capillary endothelium, and a number of recent studies support the former option. First, although ANGPTL4 is known to regulate LPL activity in vivo and in vitro, two studies in human populations found no correlation between serum ANGPTL4 and triglyceride levels (24,43). Full-length ANGPTL4 is known to interact with the extracellular matrix in the subendothelial space via its C-terminal domain (44).…”

Atypical angiopoietin-like protein that regulates ANGPTL3

“…S3D), suggesting that the substitution has modest effects on ANGPTL8 function. In contrast to ANGPTL8, adenovirus-mediated expression of ANGPTL3 at levels comparable to those present in human plasma (∼300 ng/mL) (27) did not elicit an increase in plasma TAG or NEFA (Fig. 3A).…”