Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis

Abstract

Cardiovascular disease (CVD) is still the leading cause of death globally, and atherosclerosis is the main pathological basis of CVDs. Low-density lipoprotein cholesterol (LDL-C) is a strong causal factor of atherosclerosis. However, the first-line lipid-lowering drugs, statins, only reduce approximately 30% of the CVD risk. Of note, atherosclerotic CVD (ASCVD) cannot be eliminated in a great number of patients even their LDL-C levels meet the recommended clinical goals. Previously, whether the elevated plasma level of triglyceride is causally associated with ASCVD has been controversial. Recent genetic and epidemiological studies have demonstrated that triglyceride and triglyceride-rich lipoprotein (TGRL) are the main causal risk factors of the residual ASCVD. TGRLs and their metabolites can promote atherosclerosis via modulating inflammation, oxidative stress, and formation of foam cells. In this article, we will make a short review of TG and TGRL metabolism, display evidence of association between TG and ASCVD, summarize the atherogenic factors of TGRLs and their metabolites, and discuss the current findings and advances in TG-lowering therapies. This review provides information useful for the researchers in the field of CVD as well as for pharmacologists and clinicians.

Keywords: cardiovascular disease; hypertriglyceridemia; lipid-lowering; residual risk; triglyceride-rich lipoprotein.

FIGURE 1

TG and TGRL metabolism. Dietary fat is metabolized by intestinal cells into FAs, which are reassembled with cholesterol, phospholipids, and apoB48 to form CMs. These CMs are released into blood via lymph. In the liver, exogenous and de novo synthesized FAs are assembled with cholesterol, phospholipids, and apoB100 to form VLDL with the assistant of MTP. In the circulation, LPL located at the surface of the capillary lumen hydrolyzes the TG in the core of TGRL (CM and VLDL) and promotes the production of TGRL remnants and free FAs. TGRL remnants are cleared by liver through receptors including HSPG, LDLR, LRP1, and other potentially unidentified receptors. Apo, apolipoprotein; CM, chylomicron; CMR, chylomicron residual; ER, endoplasmic reticulum; FA, fatty acid; FFA, free fatty acid; HSPG, heparan sulfate proteoglycan; IDL, intermediate density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; LRP1, LDLR-related protein 1; MTP, microsomal triglyceride transfer protein; PL, phospholipids; TG, triglycerides; VLDL, very low-density lipoproteins.

FIGURE 2

The mechanisms of TGRL on promoting atherosclerosis. In circulation, apoAII and apoAV enhance the activity of LPL, while apoAIII and ANGPTL3-4-8 suppress LPL-induced TGRL lipolysis. However, several studies demonstrate that apoAIII has no effect on the activity of LPL. The released FFA and the lipolysis process promote the production of ROS and secretion of inflammatory factors, leading to endothelial dysfunction and formation of foam cells. CETP-mediated lipid exchange between TGRL and HDL/LDL increases the production of small dense LDL and small dense HDL, further promoting deterioration of atherosclerosis. Furthermore, lipolytic products activate platelet and induce clot formation. ANGPTL, angiopoietin-like protein; Apo, apolipoprotein; CE, cholesteryl ester; CETP, cholesteryl ester transport protein; FFA, free fatty acid; HDL, high density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; Ox-FFA, oxidized FFA; ROS, reactive oxygen species; TG, triglycerides; TGRL, triglyceride-rich lipoprotein.

FIGURE 3

TGRL and TGRL metabolites-mediated inflammatory signaling pathways. In circulation, LPL converts TGRL to TGRL remnants, such as CMR and IDL, and promotes the production of FFA. These TGRL metabolites enhance inflammation by activating multiple receptors that located on the cell membrane. Furthermore, FFA can penetrate cell membrane and exert their functions intracellularly. AP-1, activating protein-1; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal-regulated kinase 1/2; FAK, focal adhesion kinase; FFA, free fatty acid; GFR, growth factor receptor; GPCR, G protein-coupled receptor; IKB, nuclear factor-kappa B inhibitor; IKKB, Inhibitor of kappa B kinase; IL-1β, interleukin-1β; IR, insulin receptor; IRS1, insulin receptor substrate 1; JNK, c-Jun NH2-terminal kinase; LRP, LDL receptor-related protein; MAPK, mitogen-activated protein kinase; MEK1/2, mitogen-activated protein kinase kinases 1/2; NF-kB, nuclear factor-kappa B; NLRP, nucleotide binding domain like receptor family pyrrole domain containing protein; NO, Nitric oxide; P38, P38 mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKC, protein kinase C; PTEN, phosphatase and tensin homolog; RhoA, Ras homolog family member A; TRL-4, Toll-like receptor 4.