Time-Restricted Eating, ANGPTL4, and Reduction in Residual Cardiovascular Risk

Figures

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  Figure 1. Residual cardiovascular risk, importance, and main mechanisms proposed. (A) Residual risk is the remaining risk after optimization of (B) LDL-C levels. (C) Inflammation plays a key role. (D) High levels of Lp (a) prevalent in 10% of the population. (E) Subjacent insulin resistance and its expression as MetS or diabetes are important factors. (F) Increased TRL and its remnants are receiving much attention and are the focus of this article. Increased TRL may be due to either (G) increased production (fatty acids, fructose, alcohol) or decreased catabolism (H), or both. Catabolism, in turn, depends on LPL and its complex regulation. It has a key circadian component (J), where ANGPTL proteins play a critical role in cycling fast and fed status in different tissues, of which ANGPTL4 and 8 are the focus of this paper. (I) LPL regulation also depends on optimal insulin action and the role of activators and inhibitors, of which apoCIII has the most attention at present (K). ANGPTL: angiopoietin-like protein; Lp(a): lipoprotein (a); IR: insulin resistance; MetS: metabolic syndrome; TRL: triglyceride-rich lipoproteins; LPL: lipoprotein lipase. The Figure was partly generated using Servier…

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  Figure 2. Overview of fasting TRL intravascular catabolism and potential production of atherogenic remnants. (A) Liver produces VLDL, which is catabolized mainly by (B) muscle in the fasting state. VLDL carries (among others) apoB100, apoE (critical for reuptake of its remnants), apo CII, and apoCIII (activator and inhibitor or LPL, respectively). (C) Lipoprotein lipase (LPL) releases FA for tissue oxidation, thereby reducing VLDL size. The whole process is regulated by activators and exchanges of lipid and apolipoproteins with HDL. (D). The importance of cholesteryl-ester transfer protein (CETP) is underlined. Smaller size VLDLs are then acted upon by hepatic and endothelial lipases (E) in a delicate balance that produces LDL or small–dense LDL (G) and, depending on residence time (balanced or imbalanced actions of apoE, CII, and CIII), may produce atherogenic TRL remnants (F and J) that are either captured by the liver (H) through several specific receptors (I) or may linger to enter subintima in arteries and result in atherogenesis (K). CII: apoCII; CIII: apoCIII; E: apoE; CETP: cholesteryl-ester transfer protein; sd-LDL: small–dense LDL; LDL-R: LDL receptor; LRP-1: LDL-receptor like…

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  Figure 3. Time-restricted eating (TRE) is a dietary strategy associated with several potential benefits for weight management and cardiovascular health. TRE produces health benefits through five known pathways, along with an additional mechanism proposed in this article. (A) This method restricts daily calories to a set time frame. The most studied is the 16:8 protocol—16 h fasting, 8 h eating. (B) Circadian rhythms, governed by molecular clocks, help cells and organisms adjust to routine environmental changes like activity cycles and energy intake. Overall, TRE can help reset the circadian clock by affecting AgRP-regulated circadian genes and raising the liver AMP/ATP ratio. (C) Circadian clocks include the master pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The hypothalamus controls appetite through anti-appetite neurons (POMC, CART) and appetite-stimulating neurons (NPY, AgRP). In addition, TRE influences appetite by affecting hormones and peptides such as leptin, insulin, and ghrelin. (D) TRE promotes repairing autophagy by increasing AMPK and reducing mTORC activities. (E) By the same mechanism, it increases mitochondrial function and may reduce inflammation.…

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  Figure 4. Overview of LPL physiology and the effect of prolonged daily fasting as in TRE on VLDL fate in circulation. (A) LPL is synthesized (B) and matured in the ER, then (C) binds to heparan sulfate proteoglycans (HSPG) during transport, transported to (D) capillaries via proteins like GPIHBP1 which also help anchor it to endothelial cells. (E) In adipose tissue, fasting induces the production of ANGPTL4, which inhibits LPL. (F) The VLDL secreted by the liver is the acted upon, preferentially, by muscle LPL (G), which is very active (via other mechanisms). (H) It releases FA for (I) oxidation in muscle, together with (J) those released from adipocyte stores. ANGPTL4: angiopoietin-like protein 4; GPIHBP1: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1; FA: fatty acids; LPL: lipoprotein lipase. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

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  Figure 5. ANGPTL 4 impairs adipose uptake of FA and increases their release from the stores. (A) Fasting via its (B) hormonal and metabolic milieu, induces ANGPTL4 expression by adipocytes (C). (D) ANGPTL 4 schematic structure. By its action on LPL, (E) it promotes dissociation from GPIHBP1 (F); this dissociation (G) facilitates the action of PCSK3 (H) and proteolysis. These actions depend on an intact C-terminal (I). The fibrinogen-like domain (J) activates adipocyte HSL (K) promoting release of FA (L). ANGPTL4: angiopoietin-like protein 4; GPIHBP1: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1; HSL: hormone-sensitive lipase; LPL: lipoprotein lipase; PCSK3: proprotein convertase subtilisin/kexin type 3. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

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  Figure 6. Integration of regulators of the fast-fed cycle of tissue-specific LPL activity: fasting state. (A) The liver secretes an inhibitor of muscle LPL, ANGPTL3, keeping a stable concentration throughout the day. ANGPTL8 is needed for full activation of ANGPTL3, by forming a 3/1 ANGPTL3/8 complex that acts on muscle LPL. As seen before, ANGPTL8 secretion is depressed during the fasting state (B), reducing the concentration of ANGPTL3/8 complex and (C) liberating muscle LPL from inhibition. (D) ANGPTL8 is also a potent inhibitor of ANGPTL4. They share structural similarities in their N-terminal region; ANGPTL8 lacks the fibrinogen-like domain. Lower ANGPTL8 during fasting (E) allows new ANGPTL4 to work uninhibited, (F) shutting down adipose LPL. ANGPTL4: angiopoietin-like protein 4; ANGPTL3: angiopoietin-like protein 3; ANGPTL8: angiopoietin-like protein 8; LPL: lipoprotein lipase. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

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  Figure 7. Fasting, via absence of chylomicrons (CM), further optimizes VLDL catabolism and reduces residence time. (A) During the postprandial period, CM are produced (B) and are acted upon by LPL (C) in a very fast catabolism (D), leading to remnants taken up by the liver. The liver secretes VLDL continuously (E). CM are the preferred substrate, effectively competing for LPL (F). This results in (G) longer residence times and opportunity for further actions of HL and EL (H), favoring the production of remnants and smaller LDL (I), which are atherogenic (J). Ergo, TRE, by its reduction in the time frame where CM are in circulation, indirectly favors and optimizes VLDL catabolism. CM: chylomicrons; HL: hepatic lipase; EL: endothelial lipase; Sd-LDL: small and dense LDL. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.