Featured Article: Alterations of lecithin cholesterol acyltransferase activity and apolipoprotein A-I functionality in human sickle blood

Abstract

In sickle cell disease (SCD) cholesterol metabolism appears dysfunctional as evidenced by abnormal plasma cholesterol content in a subpopulation of SCD patients. Specific activity of the high density lipoprotein (HDL)-bound lecithin cholesterol acyltransferase (LCAT) enzyme, which catalyzes esterification of cholesterol, and generates lysoPC (LPC) was significantly lower in sickle plasma compared to normal. Inhibitory amounts of LPC were present in sickle plasma, and the red blood cell (RBC) lysophosphatidylcholine acyltransferase (LPCAT), essential for the removal of LPC, displayed a broad range of activity. The functionality of sickle HDL appeared to be altered as evidenced by a decreased HDL-Apolipoprotein A-I exchange in sickle plasma as compared to control. Increased levels of oxidized proteins including ApoA-I were detected in sickle plasma. In vitro incubation of sickle plasma with washed erythrocytes affected the ApoA-I-exchange supporting the view that the RBC blood compartment can affect cholesterol metabolism in plasma. HDL functionality appeared to decrease during acute vaso-occlusive episodes in sickle patients and was associated with an increase of secretory PLA 2 , a marker for increased inflammation. Simvastatin treatment to improve the anti-inflammatory function of HDL did not ameliorate HDL-ApoA-I exchange in sickle patients. Thus, the cumulative effect of an inflammatory and highly oxidative environment in sickle blood contributes to a decrease in cholesterol esterification and HDL function, related to hypocholesterolemia in SCD.

Featured Article: Depletion of HDL3high density lipoprotein and altered functionality of HDL2in blood from sickle cell patients

“…This is further supported by the increase in the HDL 2 /HDL 3 ratio and the lowering of PUC values during VOE (Figure 1). 17 Together, these observations suggest that measurement of the PUC parameter could represent a new diagnostic tool to rapidly detect plasma lipoprotein imbalance in SCD and perhaps in the early phase of a VOE.…”

“…Defects of the cholesterol esterification process in SCD blood are reflected in the difference of both the concentration and activity of several plasma proteins related to this process. Both levels of LCAT 16,17 and ApoA-I, [18][19][20] which stimulates LCAT activity, are lower in SCD plasma. This decreased abundance is also observed for the PC transfer protein (PCTP), 21 which can provide PC to the LCAT reaction.…”

“…We previously showed that ApoA-I exchange rates were lower in SCD plasma as compared to normal and this exchange rate further decreased during VOE. 17 Thus, the difference in the relative amount of HDL 2 /HDL 3 particles provides additional evidence of alterations that affect ApoA-I lipoproteins, in SCD plasma, which are further exacerbated during inflammatory events.…”

“…35 However, these changes were slow as they took more than 12 h to become apparent. We reported that ApoA-I exchange rates in SCD plasma (defined as the Plasma Unquenching Capacity (PUC) parameter) was affected during incubation for 1-2 h with washed RBC at 37 C. 17 The HDL 2 /HDL 3 distribution was analyzed after incubation of SCD or normal plasma with washed RBC for a relatively short period of 1 h at 37 C. Figure 2 shows that incubation of normal plasma with saline or with normal RBC did not change the HDL 2 /HDL 3 ratio. In contrast, the HDL 2 /HDL 3 ratio increased in the two SCD plasmas incubated in the presence of RBC.…”

“…19,25 In addition to lower levels, the activities of LCAT, ApoAI, and of the RBC lysophospholipid re-acylating enzymes are altered. 17 The ability of HDL particles to exchange ApoA-I was impaired in SCD plasma and this worsened during Through its de-acylating action, sPLA 2 generates bioactive lysophospholipids, which are implicated in acute and chronic inflammation. 23,24 During the acute phase response, significant remodeling of anti-inflammatory HDL to smaller pro-inflammatory entities can occur, [26][27][28] and both ApoA-I and LCAT on HDL are replaced by other plasma proteins such as serum amyloid A (SAA) and sPLA 2 .…”