A unified model for regulating lipoprotein lipase activity

Abstract

The regulation of triglyceride (TG) tissue distribution, storage, and utilization, a fundamental process of energy homeostasis, critically depends on lipoprotein lipase (LPL). We review the intricate mechanisms by which LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, 4, 8), apolipoproteins (APOA5, APOC3, APOC2), and the cAMP-responsive element-binding protein H (CREBH). ANGPTL8 functions as a molecular switch, through complex formation, activating ANGPTL3 while deactivating ANGPTL4 in their LPL inhibition. The ANGPTL3-4-8 model integrates the roles of the aforementioned proteins in TG partitioning between white adipose tissue (WAT) and oxidative tissues (heart and skeletal muscles) during the feed/fast cycle. This model offers a unified perspective on LPL regulation, providing insights into TG metabolism, metabolic diseases, and therapeutics.

Keywords: ANGPTL3; ANGPTL4; ANGPTL8; APOA5; APOC2; APOC3; CREBH; lipoprotein lipase.

Figure 1.. The ANGPTL3-4-8 model.

(A) Fasting reduces ANGPTL8 (A8) expression in both liver and white adipose tissue (WAT) but induces WAT A4, which inhibits LPL locally. Fasting triggers the expression and secretion of APOA5 and CREBH-C, which dampen plasma A3/8, thus fully reviving oxidative-tissue LPL. Therefore, fasting LPL activity declines in WAT but increases in oxidative tissues, channeling triglycerides (TGs) to the latter. (B) Conversely, feeding increases liver A8, forming the A3/8 complex (3:1 ratio), which, after being secreted into the circulation, inhibits oxidative-tissue LPL in an endocrine manner. Feeding also increases WAT A8, which forms the A4/8 complex (1:1 ratio) and blocks the inhibitory effect of A4 on LPL. The A4/8 complex, after a series of steps (squared region; detailed in Figure 2), generates plasmin that protects LPL from being inhibited by circulating A3/8. Consequently, postprandial LPL activity surges in WAT but diminishes in oxidative tissues, thereby channeling TGs to the former.

Figure 2.. Mechanisms of how ANGPTL4/8 in white adipose tissue (WAT) generates plasmin that cleaves LPL inhibitors in the fed state.

Following food intake (1) WAT ANGPTL8 (A8) is dramatically increased. A8 blocks the LPL-inhibiting activity of A4, and A8 also inhibits A4 secretion. (2) The A4/8 complex binds tightly to LPL that is anchored by GPIHBP1. (3) This in turn translocates LPL/A4/8 to the capillary lumen. (4) A4/8 recruits tPA and plasminogen that is bound by its receptor PLG-R. (5) This leads to the generation of plasmin. (6) Plasmin then cuts A4/8, A3/8, A4, APOC3, thus protecting LPL and restoring its activity. Meanwhile, APOC2 functionality is preserved. This intricate choreography ensures active postprandial LPL in WAT.

Figure 3.. Explanation of the phenotypes of Angptl3 knockout (KO) mice by the ANGPTL3-4-8 model.

During fasting, in wild-type (WT) mice, ANGPTL3/ANGPTL8 (A3/8) and A4/8 are present at comparable concentrations. In A3 KO mice, A3/8 is removed, leading to more availability of A3-free A8, thus increasing the formation of A4/8 and releasing WAT LPL activity. Therefore, WAT LPL activity is increased in A3 KO mice. Further increasing A8 levels by overexpression (OE) leads to more A4/8 and higher WAT LPL activity, and thus reduces triglyceride (TG) levels compared to mice without exogenous A8.

Figure 4.. Therapeutic potential of treating APOA5 or CREBH deficiency patients with an antibody (Ab) against ANGPTL3/ANGPTL8 (A3/8).

During fasting, APOA5 or CREBH-C deficiency leads to the hyperactive A3/8 complex and hypertriglyceridemia. In these patients, the A3/8 antibody has the potential to correct this condition and normalize plasma triglyceride (TG) levels.