EFFECTS OF INTRAVENOUS-INFUSION OF LIPID-FREE APO A-I IN HUMANS

Apolipoprotein (apo) A-I is the principal protein component of the pla sma high density lipoproteins (HDLs). Tissue culture studies have sugg ested that lipid-free apo A-T may, by recruiting phospholipids (PLs) a nd unesterified cholesterol from cell membranes, initiate reverse chol esterol transport and provide a nidus for the formation, via lipid-poo r, pre-beta-migrating HDLs, of spheroidal alpha-migrating HDLs. Apo A- I has also been shown to inhibit hepatic lipase (HL) and lipoprotein l ipase (LPL) in vitro. To further study its functions and fate in vivo, we gave lipid-free apo A-I intravenously on a total of 32 occasions t o six men with low HDL cholesterol (30 to 38 mg/dL) by bolus injection (25 mg/kg) and/or by infusion over 5 hours (1.25, 2.5, 5.0, and 10.0 mg . kg(-1). h(-1)). The procedure was well tolerated: there were no c linical, biochemical, or hematologic changes, and there was no evidenc e of allergic, immunologic, or acute-phase responses. The 5-hour infus ions increased plasma total apo A-I concentration in a dose-related ma nner by 10 to 50 mg/dL after which it decreased, with a half-life of 1 5 to 54 hours. Coinfusion of Intralipid reduced the clearance rate. Th e apparent volume of distribution exceeded the known extracellular spa ce in humans, suggesting extensive first-pass clearance by one or more organs. No apo A-I appeared in the urine. Increases in apo A-I mass w ere confined to the pre-beta region on crossed immunoelectrophoresis o f plasma and to HDL-size particles on size exclusion chromatography. I ncreases were recorded in HDL Pt, but not in HDL unesterified or ester ified cholesterol. Increases also occurred in LDL Pt and in very low d ensity lipoprotein cholesterol, triglycerides, and Pt but not in plasm a total apo B concentration. These results can all be explained by com bined inhibition of HL and LPL activities. Owing to the effects that t his would have had on HDL metabolism, no conclusions can be drawn from these data about the role of lipid-free apo A-I in the removal of Pt and cholesterol from peripheral tissues in humans. The kinetic data su ggest that the fractional catabolic rate of lipid-free apo A-I exceeds that of spheroidal HDLs and is reduced in the presence of surplus PL.