Hepatic lipase, high density lipoproteins, and hypertriglyceridemia

Abstract

Hepatic lipase (HL) is a lipolytic enzyme that contributes to the regulation of plasma triglyceride (TG) levels. Elevated TG levels may increase the risk of developing coronary heart disease, and studies suggest that mutations in the HL gene may be associated with elevated TG levels and increased risk of coronary heart disease. Hepatic lipase facilitates the clearance of TG from the very low density lipoprotein (VLDL) pool, and this function is governed by the composition and quality of high density lipoprotein (HDL) particles. In humans, HL is a liver resident enzyme regulated by factors that release it from the liver and activate it in the bloodstream. HDL regulates the release of HL from the liver and HDL structure controls HL transport and activation in the circulation. Alterations in HDL-apolipoprotein composition can perturb HL function by inhibiting the release and activation of the enzyme. HDL structure may therefore affect plasma TG levels and coronary heart disease risk.

Figure 1

HDL regulates the release and activation of hepatic lipase (HL). The liver is a storage depot for catalytically inactive HL that is anchored to cell-surface heparan sulfate proteoglycans (HSPG). HDL binds to HL and releases the enzyme into the circulation. Fasting, ApoE-rich HDL is ineffective at releasing HL from cell surface HSPG. During a postprandial response, HDL loses ApoE to VLDL and the ApoE-deficient HDL is more efficient at releasing HL from the cell surface. HDL compositional changes can then release HDL-bound HL and activate the catalytic activity of the circulating enzyme. HDL therefore plays an important role in the mobilization and activation of HL.

Figure 2

HDL and hepatic lipase (HL) secretion are coregulated. HDL secretion regulates HL release from the liver through three potential mechanisms: 1) newly secreted HDL binds and displaces cell surface HL, 2) HDL and HL associate intracellularly and are cosecreted, and/or 3) HDL and HL secretion are coregulated by plasma membrane reuptake and degradation pathways. ER, endoplasmic reticulum.