We have investigated the role that hepatic lipase (HL) plays in the development of atherosclerosis by either overexpressing or inducing HL deficiency (KO) in different mouse models. Infusion of 2x108 pfu of recombinant adenovirus expressing human HL (rHLAdV, n=10) in apoE-KO mice with baseline values of (mg/dl) TC = 740+/-48, TG = 217+/-39, PL = 410+/-24, CE = 536+/38, HDL-C = 19+/12, apoB = 65+/3 and apoA-I = 46+/-4 led to HL activity = 32+/-4 mmol/min/ml and to marked reductions (all p<0.009) in TC (37%), TG (70%), PL (36%), CE (40%), HDL-C (35%), nonHDL-C (37%), apoA-I (62%) and apoB (43%). FPLC analysis demonstrated decreased VLDL, IDL/LDL and HDL-C. No changes were observed in rLucif-AdV injected mice (2x109; n=11). Mean aortic lesion area 21 days after rHL-AdV infusion was increased by 22% (rLuc-AdV = 22+/2x103 mm2, rHL-AdV = 27+/-2x103 mm2). Conversely, on a pro-atherogenic diet HL-KO mice (n=15) with increased PL (34%), HDL-C (48%) and apoA-II (55%) compared ton controls (n=11) (all p<0.05); and HL-KO x LCAT-Tg mice (n=13) with increased TC (29%), PL (34%), CE (31%) and apoB (36%) compared to LCAT-Tg (n=11) had significantly decreased aortic atherosclerosis in mm2x103 (HL-KO; 1+/-0.4 vs. controls 29+/-6; and HL-KO x LCAT-Tg 5+/-1 vs. LCAT-Tg 39+/-3). Analysis of the differential expression of hepatic genes in control and HL-KO mice by using oligonucleotide arrays revealed significant increases in the transcript level of know lipid genes as well as novel HL-regulation hepatic genes with diverse biological functions. In summary: Despite decreases in nonHDL-C, HL expression enhances atherosclerosis in apoE-KO mice. In contrast, HL deficient increases nonHDL-C but decreases diet-induced atherosclerosis in C57BL and LCAT-Tg mice. These combined data indicate a pro-atherogenic role for HL independent of plasma lipid changes. Analysis of gene expression by oligonucleotide arrays provides new insights into potential mechanisms leading to HL-induced alterations in atherogenic risk.
