Modest diet-induced weight loss reduces macrophage cholesterol efflux to plasma of patients with metabolic syndrome

Abstract

BACKGROUND Obesity-linked metabolic syndrome (MetS) is associated with a dyslipidemic profile that includes hypertriglyceridemia and low plasma high-density lipoprotein cholesterol (HDL-C). HDL initiates reverse cholesterol transport (RCT) via macrophage cholesterol efflux (MCE). Some hypothesize that dyslipidemic patients have impaired RCT. MCE to patient plasma, a metric of HDL function, inversely correlates with atherosclerotic burden. Paradoxically, MCE to plasma of hypertriglyceridemic subjects is higher than that to normolipidemic (NL) plasma. OBJECTIVE Although weight-loss reduces dyslipidemia, its effect on MCE to the plasma of obese, MetS patients is unknown. Thus, we tested the hypothesis that reducing dyslipidemia with weight-loss reduces the MCE capacity of MetS plasma to that of NL plasma. METHODS Cholesterol efflux (MCE) from THP-1 macrophages to plasma from NL controls and to obese, MetS patients before and after weight-loss was measured. RESULTS MCE to plasma of obese, MetS patients was higher than that to control plasma (p=0.006). Weight-loss in MetS patients (mean = −9.77 kg) reduced dyslipidemia, insulin resistance and systolic blood pressure. HDL-C was unchanged and apolipoprotein A-I decreased with weight-loss. Weight-loss in MetS patients normalized MCE (p<0.001) to that of NL subjects. MCE correlated with apolipoprotein B levels (r2 = 0.13 – 0.38). Chromatography showed that macrophage cholesterol initially associates with HDL but accumulates in apolipoprotein B-containing lipoproteins at later times. CONCLUSIONS While the initial acceptor of macrophage cholesterol efflux is HDL, the elevated apo B lipoproteins are a cholesterol sink that increase MCE in MetS patients. Weight loss results in decreased apo B-lipoproteins and decreased MCE to plasma of MetS patients.

Relationship between Serum Cholesterol Efflux Capacity and Glucose Intolerance in Japanese-Americans

“…This observation is consistent with other recentfindingsindicatingthatdeterminantsofserum cholesteroleffluxincludeHDLandapo-AI,whichact directly as acceptors of cholesterol, and that efflux depends on the ability of HDL to pass cholesterol acquiredfromcellstocholesterolpoolswithinapo-Bcontaining lipoproteins, such asVLDL and LDL via CETP [41][42][43][44] .Onthe other hand,in thepresentstudy, HDL-Candapo-AIwereeachobservedtohaveasignificantpositiveassociationwiththeserumcholesterol efflux capacity based on the results of a multiple regressionanalysisadjustedforageandsex,butnota multiple regression analysis further adjusted for glucose intolerance. These results suggest a strong relationship between glucose intolerance and both HDL-Candapo-AIduetothemodificationofHDL byhyperglycemia 39) ,astatethatdiminishedthedirect relationships observed between serum cholesterol efflux and both HDL-C and apo-AI after adjusting glucoseintolerance.…”

ABCA1-Derived Nascent High-Density Lipoprotein–Apolipoprotein AI and Lipids Metabolically Segregate

“…In whole serum the number of HDL particles is ten times that of all other lipoprotein particles combined 43 so that based on collision theory the first encounter of desorbing nHDL-[ 3 H]FC is expected to be HDL, the same as that found for plasma acceptors of macrophage FC efflux. 44 nHDL- and HDL-[ 3 H]FC are esterified to [ 3 H]CE by LCAT. 21 However, the FC esterification rate is slow compared to the rate of transfer such that >90% of the [ 3 H] activity transferred to LDL in the initial 10 min is [ 3 H]FC, not [ 3 H]CE (Supplementary Figure II).…”

Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo

“…SOF-mediated conversion of HDL-CE to CERM-CE increases both the rate and capacity of uptake to values that are closer to those for LDL-CE. Whereas apo AI and HDL are the initial acceptors of free cholesterol from macrophages, the initiating RCT step, in plasma, cholesterol readily transfers to the apo B-containing lipoproteins, LDL and very low density lipoproteins, as well as red blood cells [22, 27, 28]. In addition to these steps, CETP activity transfers HDL-CE to the apo B-containing lipoproteins so that in human RCT, IDL and LDL likely play a more important quantitative role in delivery of excess cholesterol to the liver for disposal.…”