WAT apoC-I secretion: role in delayed chylomicron clearance in vivo and ex vivo in WAT in obese subjects

Abstract

Reduced white adipose tissue (WAT) LPL activity delays plasma clearance of TG-rich lipoproteins (TRLs). We reported the secretion of apoC-I, an LPL inhibitor, from WAT ex vivo in women. Therefore we hypothesized that WAT-secreted apoC-I associates with reduced WAT LPL activity and TRL clearance. WAT apoC-I secretion averaged 86.9 ± 31.4 pmol/g/4 h and 74.1 ± 36.6 pmol/g/4 h in 28 women and 11 men with BMI ≥27 kg/m(2), respectively, with no sex differences. Following the ingestion of a (13)C-triolein-labeled high-fat meal, subjects with high WAT apoC-I secretion (above median) had delayed postprandial plasma clearance of dietary TRLs, assessed from plasma (13)C-triolein-labeled TGs and apoB48. They also had reduced hydrolysis and storage of synthetic (3)H-triolein-labeled ((3)H)-TRLs in WAT ex vivo (i.e., in situ LPL activity). Adjusting for WAT in situ LPL activity eliminated group differences in chylomicron clearance; while adjusting for plasma apoC-I, (3)H-NEFA uptake by WAT, or body composition did not. apoC-I inhibited in situ LPL activity in adipocytes in both a concentration- and time-dependent manner. There was no change in postprandial WAT apoC-I secretion. WAT apoC-I secretion may inhibit WAT LPL activity and promote delayed chylomicron clearance in overweight and obese subjects. We propose that reducing WAT apoC-I secretion ameliorates postprandial TRL clearance in humans.

Keywords: adipocytes; apolipoprotein C-I; cardiometabolic risk; fat storage; lipase/lipoprotein; lipolysis and fatty acid metabolism; obesity; triglyceride-rich lipoprotein; triglycerides; white adipose tissue.

Fig. 1.

Association of fasting plasma apoC-I with iAUC_6hrs of plasma TG (A), ¹³C-TG (B), ¹³C-NEFA (C), and chylomicrons (apoB48) (D), and with WAT in situ LPL activity measured as WAT ³H-lipids (E) and WAT apoC-I secretion (F) in women (N = 28, closed circles with dashed regression line) and men (N = 11, open circles with dotted regression lines). Solid regression line represents pooled data analysis.

Fig. 2.

Group differences in postprandial plasma clearance of TG (A), ¹³C-TG (B), ¹³C-NEFA (C), and chylomicrons (apoB48) (D) in subjects with low (N = 19) versus high (N = 20) WAT apoC-I secretion (except for (D) where N = 5 men in the high group for missing data). Women are represented as solid circles and men as open circles.

Fig. 3.

Group differences in in situ LPL activity measured as WAT ³H-lipids (A) and as medium ³H-NEFA (B) using ³H-TRL substrate (1.27 mmol/l TG) and ³H-NEFA uptake and incorporation into WAT ³H-lipids using ³H-NEFA:BSA substrate (C) in subjects with low (N = 16) versus high (N = 17) WAT apoC-I secretion for (A, B), and low (N = 13) versus high (N = 15) WAT apoC-I secretion for (C). Women are represented as solid circles and men as open circles.

Fig. 4.

Time-dependent effects of human VLDL-extracted apoC-I (15 μM) on ³H-TRL hydrolysis and incorporation as intracellular ³H-lipids (A), ³H-TRL hydrolysis and ³H-NEFA release into the medium (B), ³H-TRL accumulation in the medium (C), and concentration-dependent effect of human apoC-I on ³H-TRL hydrolysis and incorporation as intracellular ³H-lipids over 4-h in 3T3-L1 adipocytes (D).

Fig. 5.

Proposed model for the interaction of WAT-secreted apoC-I with TRL and LPL on the endothelial surface of WAT. Increased apoC-I secretion from WAT enriches TRL with apoC-I, which inhibits the activity of LPL on the endothelium of WAT and the hydrolysis of postprandial TRL without affecting the uptake of NEFA into WAT. This results in decreased clearance and incorporation of TRL into WAT lipids and increased postprandial plasma concentrations of TRLs (dashed arrow for inhibited and solid arrow for unaffected process).