To investigate the role of apoM in high density lipoprotein (HDL) metabolism and atherogenesis, we generated human apoM transgenic (apoM-Tg) and apoM-deficient (apoM ؊/؊ ) mice. Plasma apoM was predominantly associated with 10 -12-nm ␣-migrating HDL particles. Human apoM overexpression (11-fold) increased plasma cholesterol concentration by 13-22%, whereas apoM deficiency decreased it by 17-21%. The size and charge of apoA-I-containing HDL in plasma were not changed in apoM-Tg or apoM ؊/؊ mice. However, in plasma incubated at 37°C, lecithin:cholesterol acyltransferase-dependent conversion of ␣-to pre-␣-migrating HDL was delayed in apoM-Tg mice. Moreover, lecithin: cholesterol acyltransferase-independent generation of pre--migrating apoA-I-containing particles in plasma was increased in apoM-Tg mice (4.2 ؎ 1.1%, p ؍ 0.06) and decreased in apoM ؊/؊ mice (0.5 ؎ 0.3%, p ؍ 0.03) versus controls (1.8 ؎ 0.05%). In the setting of low density lipoprotein receptor deficiency, apoM-Tg mice with ϳ2-fold increased plasma apoM concentrations developed smaller atherosclerotic lesions than controls. The effect of apoM on atherosclerosis may be facilitated by enzymatic modulation of plasma HDL particles, increased cholesterol efflux from foam cells, and an antioxidative effect of apoM-containing HDL.Epidemiological studies have demonstrated a strong inverse association between plasma HDL 3 concentrations and risk of premature coronary heart disease (1). However, the molecular heterogeneity of HDL has posed difficulties in understanding HDL metabolism and its effects in atherogenesis. In 1999, Xu and Dahlbäck (2) discovered apoM, which is mainly associated with HDL, with smaller amounts in LDL and VLDL. ApoM appears to have a novel role in murine HDL metabolism by affecting pre--HDL formation (3). Pre--HDL is considered antiatherogenic, because it mediates ATP-binding cassette transporter A1 (ABCA1)-dependent efflux of cholesterol from foam cells as part of the reverse cholesterol transport. Pre--HDLs, the precursor of mature HDLs, are ϳ7-nm particles containing apoA-I and phospholipid and can be derived from two sources (4, 5). First, pre--HDL can arise from newly synthesized hepatic apoA-I, acquiring free cholesterol and phospholipids through the interaction of apoA-I with ABCA1 (6). The small phospholipid-containing apoA-I particles can act via ABCG1 and remove cholesterol from foam cells (7-9). The free cholesterol in HDL can be esterified by lecithin:cholesterol acyltransferase (LCAT) (10, 11), changing the electrophoretic mobility of HDL from pre- to ␣ (12-14). In mice, overexpression of LCAT converts ␣-HDL to pre-␣-HDL (15). Second, pre--HDL can arise from ␣-HDL through the action of phospholipid transfer protein (PLTP), which induces fusion of ␣-HDL particles and concomitant dissociation of small pre--HDL particles (16 -18). Also, hepatic lipase (HL) can generate pre--HDL from ␣-HDL through its triglyceride lipase activity, either in concert with cholesteryl ester transfer protein (19) or alone (as in mice, w...