An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues

Abstract

In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissues (heart and skeletal muscle) for energy production, a process referred to as TG partitioning. Lipoprotein lipase (LPL), a rate-limiting enzyme in this fundamental physiological process, hydrolyzes circulating TG to generate free fatty acids that are taken up by peripheral tissues. The postprandial activity of LPL declines in oxidative tissues but rises in WAT, directing TG to WAT; the reverse is true during fasting. However, the molecular mechanism in regulating tissue-specific LPL activity during the fed-fast cycle has not been completely understood. Research on angiopoietin-like (ANGPTL) proteins (A3, A4, and A8) has resulted in an ANGPTL3-4-8 model to explain the TG partitioning between WAT and oxidative tissues. Food intake induces A8 expression in the liver and WAT. Liver A8 activates A3 by forming the A3-8 complex, which is then secreted into the circulation. The A3-8 complex acts in an endocrine manner to inhibit LPL in oxidative tissues. WAT A8 forms the A4-8 complex, which acts locally to block A4's LPL-inhibiting activity. Therefore, the postprandial activity of LPL is low in oxidative tissues but high in WAT, directing circulating TG to WAT. Conversely, during fasting, reduced A8 expression in the liver and WAT disables A3 from inhibiting oxidative-tissue LPL and restores WAT A4's LPL-inhibiting activity, respectively. Thus, the fasting LPL activity is high in oxidative tissues but low in WAT, directing TG to the former. According to the model, we hypothesize that A8 antagonism has the potential to simultaneously reduce TG and increase HDL-cholesterol plasma levels. Future research on A3, A4, and A8 can hopefully provide more insights into human health, disease, and therapeutics.

Keywords: ANGPTL3; ANGPTL4; ANGPTL8; Endothelial lipase; HDL-cholesterol; Lipoprotein lipase; Triglyceride.

Fig. 1.. A8 activates A3 but inactivates A4 to regulate LPL activity.

A) A3 by itself only has low LPL-inhibiting activity. A8 activates A3 by forming A3–8 complexes, which have much increased LPL-inhibiting activity (more than 100-fold more active, compared to A3 alone). A4 by itself strongly inhibits LPL. A8 inactivates A4 by forming A4–8 complexes, which have much decreased LPL-inhibiting activity (more than 100-fold less active, compared to A4 alone). B) Food intake strongly induces A8, which, in turn, forms A3–8 and A4–8 complexes to balance LPL activity in different nutritional states.

Fig. 2.. An ANGPTL3–4-8 model for triglyceride partitioning between adipose and oxidative tissues.

A) Food intake induces A8 expression in the liver and white adipose tissue (WAT). Liver A8 activates A3, forming the A3–8 complex (protein ratio, 3:1), which is then secreted into the circulation. As a potent LPL inhibitor, the A3–8 complex in turn inhibits LPL in oxidative tissues. WAT A8 mainly acts locally to inactivate A4 by forming the A4–8 complex (protein ratio, 1:1), which disables A4 from LPL inhibition. That is, the A3–8 complex, secreted by the liver, acts in an endocrine manner to inhibit oxidative-tissue LPL, while the A4–8 complex acts in an autocrine/paracrine manner to activate WAT LPL by disabling A4’s activity. Meanwhile, the A4–8 complex blocks the LPL-inhibiting activity of the circulating A3–8 complex, thus enabling it to specifically target LPL in oxidative tissues. Consequently, LPL activity is low in oxidative tissues but is high in WAT, directing TG to WAT for storage. B) During fasting, A4 is induced in WAT, and A8 expression is diminished, enabling A4 to inhibit WAT LPL. Reduced circulating A3–8 complex levels, due to reduced liver A8 expression, disable A3 from LPL inhibition, resulting in high LPL activity in oxidative tissues. Therefore, fasting LPL activity is low in WAT but high in oxidative tissues, enabling TG uptake into the latter for oxidation.

Fig. 3.. Phenotypes of tissue-specific A8 KO mice explained by the ANGPTL3–4-8 model.

A) Liver-specific A8 KO (LKO) mice show hypotriglyceridemia in the fed state. In LKO mice, A8 is specifically deleted in the liver, and therefore the liver fails to secrete A8 in the fed state, resulting in the absence of circulating A3–8 complexes and consequently the inability to inhibit LPL in oxidative tissues. Because adipose A8 is still induced, forming A4–8 complexes that block A4 from LPL inhibition. Therefore, LPL activity is high in both oxidative and adipose tissues, resulting in high post-heparin LPL activity and hypotriglyceridemia. B) Adipose-specific A8 KO (AKO) mice show hypertriglyceridemia in the fed state. Following food intake, liver A8 forms A3–8 complexes, which, after being secreted into circulation, inhibit LPL in oxidative tissues. Because A8 is specifically deleted in adipose tissues, A8 absence activates A4, hence reducing adipose LPL activity. Therefore, LPL activities are low in both oxidative and adipose tissues, resulting in low post-heparin LPL activity and TG accumulation (hypertriglyceridemia).