Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expresser line with serum triglycerides of -280 mg/dl, and a high expressor line with serum triglycerides of -1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expresser mice, respectively. Under electron microscopy, VLDL particles from low and high expresser mice were found to have a larger mean diameter, 55.2±16.6 and 58.2±17.8 nm, respectively, compared with 51.0±13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expresser mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expresser mice and no differences were observed. Also, VLDLs obtained from control and high expresser mice were found to be equally good substrates for purified LPL

The mechanism of apolipoprotein (apo) CIII-induced hypertriglyceridemia remains uncertain. We crossed apoCIII transgenic and apoE gene knockout (apoE 0 ) mice, and observed severe hypertriglyceridemia with plasma triglyceride levels of 4,521 Ϯ 6,394 mg/dl vs. 423 Ϯ 106 mg/dl in apoE 0 mice, P Ͻ 0.00001 for log(triglycerides [TG]). Cholesterols were 1,181 Ϯ 487 mg/dl vs. 658 Ϯ 151 mg/dl, P Ͻ 0.0001. Lipoprotein fractionation showed a marked increase in triglyceride-enriched chylomicrons ϩ VLDL. This increase was limited to the lowest density (chylomicrons and S f 100-400) subfractions. Intermediate density lipoproteins (IDL) ϩ LDL increased moderately, and HDL decreased. There was no significant increase in triglyceride production in apoCIII transgenic/apoE 0 mice. The clearance of VLDL triglycerides, however, was significantly decreased. Lipoprotein lipase in postheparin plasma was elevated, but activation studies suggested LPL inhibition by both apoCIII transgenic and apoCIII transgenic/apoE 0 plasma. ApoCIII overexpression also produced a marked decrease in VLDL glycosaminoglycan binding which was independent of apoE. The predominant mechanism of apoCIII-induced hypertriglyceridemia appears to be decreased lipolysis at the cell surface. The altered lipoprotein profile that was produced also allowed us to address the question of the direct atherogenicity of chylomicrons and large VLDL. Quantitative arteriosclerosis studies showed identical results in both apoCIII transgenic/apoE 0 and apoE 0 mice, supporting the view that very large triglyceride-enriched particles are not directly atherogenic. ( J. Clin. Invest. 1997. 99:2672-2681.)

We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (

Cholesteryl ester storage disease (CESD) is characterized by the deficient activity of lysosomal cholesteryl ester (CE) hydrolase, accumulation of LDL-derived CE in lysosomes, and hyperlipidemia. We studied the kinetics of VLDL and LDL apolipoprotein B (apoB), using 125I-VLDL and "1I-LDL, in a 9-yr-old female with CESD and elevated total cholesterol (TC) (271.0±4.4 mg/dl), triglyceride (TG) (150.0±7.8 mg/dl), and LDL cholesterol (184.7±3.4 mg/dl). These studies demonstrated a markedly elevated production rate (PR) of apoB, primarily in LDL, with normal fractional catabolism of apoB in VLDL and LDL. Urine mevalonate levels were elevated, indicative of increased synthesis of endogenous cholesterol. Treatment with lovastatin, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, resulted in significant reductions in TC (196.8±7.9 mg/dl), TG (100.8±20.6 mg/dl), and LDL cholesterol (102.0±10.9 mg/dl). Therapy reduced VLDL apoB PR (5.2 vs. 12.2 mg/kg per d pretreatment) and LDL apoB PR (12.7 vs. 24.2 mg/kg per d pretreatment). Urine mevalonate levels also decreased during therapy. These results indicate that, in CESD, the inability to release free cholesterol from lysosomal CE resulted in elevated synthesis of endogenous cholesterol and increased production of apoB-containing lipoproteins. Lovastatin reduced both the rate of cholesterol synthesis and the secretion of apoB-containing lipoproteins.

Mechanisms that might be responsible for the low levels of high density lipoprotein (HDL) associated with hypertriglyceridemia were studied in an animal model. Specific monoclonal antibodies were infused into female cynomolgus monkeys to inhibit lipoprotein lipase (LPL), the rate-limiting enzyme for triglyceride catabolism. LPL inhibition produced marked and sustained hypertriglyceridemia, with plasma triglyceride levels of 633-1240 mg/dl. HDL protein and cholesterol and plasma apolipoprotein (apo) Al levels decreased; HDL triglyceride (TG) levels increased. The fractional catabolic rate of homologous monkey HDL apolipoproteins injected into LPL-inhibited animals (n = 7) was more than double that of normal animals (0.094±0.010 vs. 0.037±0.001 pools of HDL protein removed per hour, average±SEM). The fractional catabolic rate of low density lipoprotein apolipoprotein did not differ between the two groups of animals. Using HDL apolipoproteins labeled with tyramine-cellobiose, the tissues responsible for this increased HDL apolipoprotein catabolism were explored. A greater proportion of HDL apolipoprotein degradation occurred in the kidneys of hypertriglyceridemic than normal animals; the proportions in liver were the same in normal and LPL-inhibited monkeys.Hypertriglyceridemia due to LPL deficiency is associated with low levels of circulating HDL cholesterol and apo Al. This is due, in part, to increased fractional catabolism of apo Al. Our studies suggest that variations in the rate of LPL-mediated lipolysis of TG-rich lipoproteins may lead to differences in HDL apolipoprotein fractional catabolic rate. (J. Clin. Invest. 1990. 86:463-473.)