Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet

Abstract

Hepatic lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL 2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity. The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia. Hepatic lipase (HL) is a key enzyme involved in lipoprotein metabolism. Its catalytic activity contributes to the remodelling of chylomicron remnants, IDLs, LDLs, and HDLs, and participates in the reverse cholesterol transport (1). These effects possibly influence the process of atherosclerosis. Recent reviews on HL have focused on its evolution (2), structure, function, and regulation (3), and its potential role in atherosclerosis (4). The focus of this review will be on the interaction between genetic variants, obesity, sex hormones, and diet in influencing HL activity and on clinical implications of variation in this activity. HL AND DYSLIPIDEMIA Lipolytic role of HL in remodeling of human remnant and LDLIn vitro and in vivo studies have clearly demonstrated that HL plays a key role in lipoprotein metabolism (5, 6). Multiple lines of evidence suggest that human HL modulates the lipid composition of IDL remnants and large, buoyant LDLs, resulting in denser lipoprotein particles both in patients with cardiovascular disease (CVD) and in normal subjects (7,8). LDL size and buoyancy are inversely proportional to HL activity, which seems to be correlated also with both the fractional catabolic rate and the input rate of LDL apolipoprotein B (apoB) in men with varying plasma triglyceride (TG) concentrations (9). Patients with high HL have smaller, denser LDL particles, relatively depleted in phospholipids (PLs) and free cholesterol, as compared with subjects with low HL activity (7) ( Fig. 1A ). Individuals with CVD, characterized by the predominance of small, dense LDL as determined by gradient gel electrophoresis (also defined as pattern B LDL subclass distribution), have significantly higher HL activity than patients with CVD but large, buoyant LDL particles (pattern A) (10). Interestingly, HL activity is not associated with LDL cholesterol levels.More direct evidence that HL plays a key role in human lipoprotein metabolism is obtained from studies of individuals with HL deficiency. Few patients with true HL deficiency have been identified (1,11). Patients with complete HL deficiency present with elevated plasma concentrations of cholesterol and TG, and with a lipoprotein profile characterized by the presence of large ␤ -VLDL and large, buoyant 13). ...

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

“…Thus, any changes in plasma lipoproteins or atherosclerosis observed in the study transgenic mice are a result of increased liver HL transgene expression. The levels of HL overexpression (3-5-fold) achieved in our transgenic mice were within the physiological range reported previously for various metabolic states such as sex, dietary status, diabetes, and hormonal stimulation (6,10). This contrasts with previous studies in which HL-WT and catalytically inactive HL were overexpressed by either 10-fold (25) or 20-fold (26) in E-KO mice expressing endogenous HL.…”

“…Thus, the increased atherosclerosis in E-KO ϫ HL-WT versus E-KO ϫ HL-KO mice can be ascribed to the lipolytic function of liver-expressed HL-WT. Hepatic expression of HL-WT was associated with decreased plasma HDL levels and the formation of smaller, lipid-poor LDL, both associated in humans with increased atherogenic risk (3)(4)(5)(6)(7).…”

“…HL functions both as an acylglycerol hydrolase and a phospholipase, hydrolyzing triglycerides (TG) and phospholipids (PL) in chylomicron remnants and intermediate density lipoproteins (IDL). In humans, HL plays a major role in determining low density lipoprotein (LDL) subclass distribution, which may in turn modulate atherogenic risk (3)(4)(5)(6)(7). HL is also an important determinant of high density lipoprotein (HDL) concentration and subclass distribution, converting the phospholipid-rich HDL 2 to HDL 3 (3, 4, 8 -14).…”

Foxa2 Activity Increases Plasma High Density Lipoprotein Levels by Regulating Apolipoprotein M

“…Leptin-deficient ob/ob mice also exhibit defective hepatic HDL particle uptake, possibly because of a post-transcriptional decrease in hepatic SR-B1 levels, which results in decreased recycling, degradation, and selective lipid uptake (14 -16). Furthermore, in human obesity and insulin-resistant states, increased activity of hepatic lipase, an enzyme involved in the hydrolysis of triglycerides and phospholipids in HDL, produces smaller HDL particles and facilitates HDL clearance (17), whereas in obese mice hepatic lipase is significantly reduced (18).…”

Atherogenic Indices and HDL Particle Size as Laboratory Parameters to Evaluate Cardiovascular Risk in the Presence of Dyslipidemia

“…The remodeling of lipoprotein particle is due to the action of enzymes and transfer proteins that participates in the metabolism of HDL, such as hepatic lipase (HL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL) and lecithin cholesterol acyltransferase (LCAT) [2]- [4]. Dyslipidemia may be negatively implicated in the enzymes and transfer proteins action mechanisms leading to changes in physical-chemical, structural and functional characteristics that, consequently, cause instability in the whole lipoprotein metabolism [5].…”