Physiological regulation of lipoprotein lipase

Highlights

• Plasma TG levels are primarily determined by tissue LPL activity.

• The activity of LPL is modulated at the post-translational level by apolipoproteins and angiopoietin-like proteins.

• LPL activity is differentially regulated by physiological stimuli in various tissues.

Abstract

The enzyme lipoprotein lipase (LPL), originally identified as the clearing factor lipase, hydrolyzes triglycerides present in the triglyceride-rich lipoproteins VLDL and chylomicrons. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities such as the heart, skeletal muscle, brown adipose tissue and white adipose tissue. Upon production by the underlying parenchymal cells, LPL is transported and attached to the capillary endothelium by the protein GPIHBP1. Because LPL is rate limiting for plasma triglyceride clearance and tissue uptake of fatty acids, the activity of LPL is carefully controlled to adjust fatty acid uptake to the requirements of the underlying tissue via multiple mechanisms at the transcriptional and post-translational level. Although various stimuli influence LPL gene transcription, it is now evident that most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. These proteins can be divided into two main groups: the liver-derived apolipoproteins APOC1, APOC2, APOC3, APOA5, and APOE, and the angiopoietin-like proteins ANGPTL3, ANGPTL4 and ANGPTL8, which have a broader expression profile. This review will summarize the available literature on the regulation of LPL activity in various tissues, with an emphasis on the response to diverse physiological stimuli.

Introduction

Many tissues rely on plasma triglycerides (TG) as an important source of fatty acids for subsequent oxidation and/or storage. Plasma TG are packaged into the TG-rich lipoproteins chylomicrons and very low-density lipoproteins (VLDL), which carry TG coming from the diet or synthesized in the liver, respectively. Utilization of plasma TG is dependent on lipoprotein lipase (LPL), which is attached to the capillary endothelium and catalyzes the hydrolytic cleavage of TG into fatty acids. LPL, originally referred to as clearing factor lipase [1], is produced by a limited number of cells that include (cardio)myocytes and adipocytes, and upon release by these cells is transported to the lumenal side of the capillary endothelium by the protein GPIHBP1 [2], [3]. The luminal or endothelial LPL is referred to as the functional LPL pool, as it represents the portion of tissue LPL that is actively involved in plasma TG hydrolysis. Additionally, LPL is produced by macrophages and mammary gland secretory cells, and by fetal hepatocytes. Maturation of nascent LPL occurs in the endoplasmic reticulum and is promoted by the lipase maturation factor 1 [4]. The LPL enzyme is catalytically active as a dimer composed of two glycosylated 55 kDa subunits connected in a head-to-tail fashion by non-covalent interactions [5], [6].

The human LPL gene consists of 9 exons and encodes a protein of 475 amino acids that can be divided into distinct structural and functional domains, including an N-terminal signal sequence, a catalytic domain, a ‘lid’ domain that covers the active site, and a C-terminal domain [7], [8]. The catalytic triad for the active site is formed by the amino acids Ser159, Asp183, and His266. Recent evidence indicates that the C-terminal portion of LPL, which mediates binding to heparin, is sufficient for binding to GPIHBP1 [9], [10]. Accordingly, formation of the full length LPL homodimers is not required for interactions with GPIHBP1. Finally, LPL is subject to proteolytic cleavage by proprotein convertases at residue 297, which represents a potential regulatory mechanism [11].

The essential role of LPL in plasma TG clearance is illustrated by the severe hypertriglyceridemia in patients carrying mutations within the LPL gene [12]. Similarly, mice with a generalized deletion of LPL have markedly higher plasma TG levels at birth and die within 24 h due to an inability to process the milk lipids. At the time of death, LPL knockout (KO) pups are severely hypertriglyceridemic [13], [14]. Tissue-specific deletions of LPL have further demonstrated the importance of LPL for local fatty acid uptake [15], [16], [17]. Deletion or disabling mutations in the GPIHBP1 gene also give rise to marked hypertriglyceridemia in mice and humans [3], [18]. Conversely, transgenic mice overexpressing human LPL throughout the body show a 75% reduction in plasma TG [19].

Because LPL is a critical determinant of plasma TG clearance and resultant tissue uptake of fatty acids, the activity of LPL needs to be carefully regulated in order to match the rate of uptake of plasma TG-derived fatty acids to the needs of the underlying tissue and the ability of the tissue to dispose of the fatty acids, all while being confronted with huge fluctuations in the production of TG-rich lipoproteins. It will therefore come as no surprise that the activity of LPL is extensively regulated through multiple mechanisms, which primarily operate at the transcriptional and post-translational level. Regulation of DNA transcription is responsible for the upregulation of LPL gene expression and activity during (cardio)myogenesis and adipogenesis [20], [21], [22]. However, most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. This review will summarize the current literature on regulation of LPL activity in various tissues, focusing on LPL regulation in response to physiological stimuli.