The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype

Abstract

Increased or decreased hepatic lipase (HL) activity has been associated with coronary artery disease (CAD). This is consistent with the findings that gene variants that influence HL activity were associated with increased CAD risk in some population studies but not in others. In this review, we will explain the conditions that influence the effects of HL on CAD. Increased HL is associated with smaller and denser LDL (sdLDL) and HDL (HDL(3)) particles, while decreased HL is associated with larger and more buoyant LDL and HDL particles. The effect of HL activity on CAD risk is dependent on the underlying lipoprotein phenotype or disorder. Central obesity with hypertriglyceridemia (HTG) is associated with high HL activity that leads to the formation of sdLDL that is pro-atherogenic. In the absence of HTG, where large buoyant cholesteryl ester-enriched LDL is prominent, elevation of HL does not raise the risk for CAD. In HTG patients, drug therapy that decreases HL activity selectively decreases sdLDL particles, an anti-atherogenic effect. Drug therapy that raises HDL(2) cholesterol has not decreased the risk for CAD. In trials where inhibition of cholesterol ester transfer protein (CETP) or HL occurs, the increase in HDL(2) most likely is due to inhibition of catabolism of HDL(2) and impairment of reverse cholesterol transport (RCT). In patients with isolated hypercholesterolemia, but with normal triglyceride levels and big-buoyant LDL particles, an increase in HL activity is beneficial; possibly because it increases RCT. Drugs that lower HL activity might decrease the risk for CAD only in hypertriglyceridemic patients with sdLDL by selectively clearing sdLDL particles from plasma, which would override the potentially pro-atherogenic effect on RCT. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

Figure 1

Hepatic lipase activity is highly correlated with hepatic lipase mass. The specific activity of hepatic lipase protein (neq FFA per min per ng protein) appears to be constant. From [7], with permission.

Figure 2

Pathway of formation and catabolism of HDL particles. ABC AI provides unesterified cholesterol and phospholipid to AI-phospholipid containing prebeta HDL. In humans PLTP may contribute up to 50% of the unesterified cholesterol and phospholipid for generation of HDL particles. These lipids are transferred from the redundant surface of triglyceride-rich lipoproteins following the action of LPL to decrease the core of these particles. LCAT esterifies cholesterol to cholesteryl ester to develop HDL₃ and then HDL₂ particles. Catabolism of HDL₂ involves HL, CETP, SRB1 and an interaction with apoB containing particles. Modified from [11].

Figure 3

CETP facilitates the exchange of triglyceride from triglyceride-rich particles with cholesteryl ester in LDL and HDL. The transfer of triglyceride to LDL and HDL makes them substrate for HL. Elevated plasma triglyceride levels and elevated HL activity enhance this pathway. Modified from [31].

Figure 4

Density gradient ultracentrifugation pattern of cholesterol distribution for FCHL, hFH and Lp(a). Note differences in LDL peak density.

Figure 5

The change in coronary stenosis during combination drug and placebo therapy in FATS is related to the change in LDL peak buoyancy: an increase in LDL buoyancy is associated with less coronary stenosis. Patients with FCHL and elevated Lp(a) treated with combination therapy had and increase in buoyancy, while those with hFH did not. Includes subjects treated with placebo. Modified from [14].

Figure 6

Stepwise multiple regression analysis indicates change in LDL buoyancy (or HL activity) was the best predictor of decreased coronary stenosis in FATS. Change in LDL cholesterol was next. The changes in HDL were not related to changes in stenosis. HL activity and LDL buoyancy were highly collinear as were LDL cholesterol and apoB. Modified from [41].

Figure 7

Change in LDL peak buoyancy with drug and placebo in FATS was inversely related to change in HL activity. Patients with FCHL and elevated Lp(a) changed LDL peak buoyancy. Patients with hFH did not change LDL buoyancy even though HL lipase activity changed. Modified from [14]. Includes subjects treated with placebo. Modified from [14].

Figure 8

Effect of drug therapy on hepatic lipase activity is constant across common familial from of dyslipidemia. However, the responses to changes in HL activity are dependent on the background lipid phenotype. In hypertriglyceridemic patients who have sdLDL and decreased HDL₂ particles, a decrease in HL activity is associated with an increase in the size and buoyancy of LDL, with selective clearance of sdLDL. This would be expected to be antiatherogenic. The concomitant increase in HDL₂ might be proatherogenic. In patients with normal triglyceride levels and bbLDL, a decrease in HL activity would have no effect on LDL particles, while the increase in HLD₂, probably due to decreased reverse cholesterol transport, might be proatherogenic, leading overall to a proatherogenic state.