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.

Low-density lipoprotein particles in atherosclerosis

“…Furthermore, the elevated plasma levels of sdLDL are generally accompanied with reduced levels of HDL-C and Apo A-I, and elevated levels of TG and ApoB. It has been well-documented that HDL and Apo A-I are atheroprotective, while TG- and ApoB-containing lipoproteins are atherogenic ( Diffenderfer and Schaefer, 2014 ; Zhang et al, 2022 ).…”

“…However, PCSK9i show attractive lipid-lowering and anti-atherosclerotic effects in practice ( Cannon et al, 2015 ; Chaudhary et al, 2017 ; Guo et al, 2020 ). As we reviewed recently, angiopoietin-like protein (ANGPTL), such as ANGPTL3, plays a key in regulation of both cholesterol and TG via inhibition of LPL ( Zhang et al, 2022 ). The antisense oligonucleotide of ANGPTL3 has been applied to familial hypercholesterolemia and is now in phase 3 clinical trial ( Graham et al, 2017 ).…”

Fenofibrate enhances lipid deposition via modulating PPARγ, SREBP-1c, and gut microbiota in ob/ob mice fed a high-fat diet

“…To investigate the underlying mechanisms, real-time quantitative polymerase chain reaction (RT-qPCR) and Western Blotting experiments were used for determining the expression of lipid metabolism-related genes and proteins, respectively. As accumulating evidence have demonstrated that gut microbiota may modulate obesity ( 10 , 23 ), the effect of fenofibrate on gut microbiota in ob/ob mice was also analyzed in the present study.…”

“…For instance, TG accumulation in the liver is defined as fatty liver diseases including NALFD and non-alcoholic steatohepatitis, which currently have no approved drugs for therapy ( 8 , 9 ). Furthermore, TG is a residual risk factor of CVD ( 10 ). Theoretically, drugs with TG-lowering activity have a potential application for treatment of TG accumulation.…”

“…Mechanistically, fenofibrate can enhance the expression of the enzymes involved in fatty acid (FA) β-oxidation including acyl-CoA oxidase (ACOX) and liver X receptor in C57BL/6J mice and humans ( 14 , 16 , 17 ). However, fenofibrate shows limited beneficial effects on therapy of CVD ( 10 ).…”