Plasma carboxyl ester lipase activity modulates apolipoprotein B–containing lipoprotein metabolism in a transgenic mouse model

Abstract

Pancreatic carboxyl ester lipase (CEL) is in the plasma of many mammals, including humans and rats, but not mice. In vitro, CEL hydrolyzes cholesterol esters (CE) of apoB-containing lipoproteins (apoB-Lp). To study the effect of CEL on metabolism of apoB-Lp and atherosclerosis in vivo, apoEknockout (EKO) mice, which have high plasma levels of apoB-Lp and are prone to atherosclerosis, were made to secrete CEL into plasma by introducing a transgene containing a liver-specific promoter and rat CEL cDNA. Plasma CEL activity in EKO-CEL mice was comparable to that found in rats. Evidence of modification of apoB-Lp by plasma CEL in vivo was an increase in the free cholesterol:CE ratio of apoB-Lp from mice on chow or a Western-type diet. In addition, plasma total cholesterol levels were elevated in EKO-CEL mice, with the elevation found exclusively in the apoBLp fraction. Associated with the increase in steady-state apoB-Lp levels was an increase in the plasma half life of very low density lipoproteins (VLDL) in EKO-CEL mice, measured by the clearance rate of injected VLDL. Interestingly, in spite of the increase of apoB-lipoproteins, the atherosclerotic lesion did not differ between EKO and EKO-CEL mice on a Western-type diet. In summary, our results demonstrate that plasma CEL modulates apoB-Lp metabolism in vivo, resulting in reduced VLDL clearance and elevated plasma cholesterol levels.

Absence of Diabetes and Pancreatic Exocrine Dysfunction in a Transgenic Model of Carboxyl-Ester Lipase-MODY (Maturity-Onset Diabetes of the Young)

“…Since protein misfolding may play a role in the pathogenic process [3] and species-specific differences in the unfolded protein response have been observed, at least in lower eukaryotes [36], similar species-specific differences between mouse and man may explain the negative findings. In addition, human CEL , in contrast to the murine Cel , is present in plasma [37], [38] probably by expression in human endothelial cells [39] and may cause systemic effects potentially affecting the pancreatic phenotype.…”

State of the art paper Low-density lipoprotein, its susceptibility to oxidation and the role of lipoprotein-associated phospholipase A2 and carboxyl ester lipase lipases in atherosclerotic plaque formation

“…Increases in Lp-B are also associated with increases in the free cholesterol-to-cholesterol ester ratio (FC/CE), which is not documented in the case of HDL [52]. This effect might be related to CEL's affinity to apoB, but not to apoA1 [53]. A change in the FC/CE ratio of Lp-B slows the degradation of Lp-B, which is likely to explain their elevated levels in plasma [53].…”

“…This effect might be related to CEL's affinity to apoB, but not to apoA1 [53]. A change in the FC/CE ratio of Lp-B slows the degradation of Lp-B, which is likely to explain their elevated levels in plasma [53]. The phenomenon of delayed plasma clearance of VLDL and LDL can be caused by the conformational change of apoB-100 in these molecules (through the accumulation of greater amounts of FC), following which the affinity of hepatic lipase to these Lps is decreased [53].…”

“…A change in the FC/CE ratio of Lp-B slows the degradation of Lp-B, which is likely to explain their elevated levels in plasma [53]. The phenomenon of delayed plasma clearance of VLDL and LDL can be caused by the conformational change of apoB-100 in these molecules (through the accumulation of greater amounts of FC), following which the affinity of hepatic lipase to these Lps is decreased [53]. It is also suggested that CEL in the normolipidemic population accelerates the conversion of LDL into sd-LDL and that its plasma concentrations correlate positively with levels of LDL [2].…”

“…The results from experimental studies showed that CEL decreases concentrations of lyso-PC in sd-LDL and consequently decreases its uptake by macrophages [53]. Moreover, CEL increases the uptake of CE, which is transported by HDL into liver cells; this increased uptake is partially independent of the SR B-1 scavenger receptor, thus accelerating the reverse transport of cholesterol and decreasing its tissue accumulation [54].…”