Hypertriglyceridemia: Molecular and Genetic Landscapes

Abstract

Lipid disorders represent one of the most worrisome cardiovascular risk factors. The focus on the impact of lipids on cardiac and vascular health usually concerns low-density lipoprotein cholesterol, while the role of triglycerides (TGs) is given poor attention. The literature provides data on the impact of higher plasma concentrations in TGs on the cardiovascular system and, therefore, on the outcomes and comorbidities of patients. The risk for coronary heart diseases varies from 57 to 76% in patients with hypertriglyceridemia. Specifically, the higher the plasma concentrations in TGs, the higher the incidence and prevalence of death, myocardial infarction, and stroke. Nevertheless, the metabolism of TGs and the exact physiopathologic mechanisms which try to explain the relationship between TGs and cardiovascular outcomes are not completely understood. The aims of this narrative review were as follows: to provide a comprehensive evaluation of the metabolism of triglycerides and a possible suggestion for understanding the targets for counteracting hypertriglyceridemia; to describe the inner physiopathological background for the relationship between vascular and cardiac damages derived from higher plasma concentrations in TGs; and to outline the need for promoting further insights in therapies for reducing TGs plasma levels.

Keywords: cardiovascular diseases; genetics; molecular mechanisms; physiopathology; triglycerides.

Figure 1

Metabolism of the triglycerides: the endogenous and exogenous pathways are represented, depicting the main biochemical mechanisms involved in the degradation, synthesis, and passage through organs of triglycerides. Abbreviations: ApoA-I: apolipoprotein A-I; ApoA-IV: apolipoprotein A-IV; ApoA-V: apolipoprotein A-V; ApoB-48: apolipoprotein B-48; ApoB-100: apolipoprotein B-100; ApoC-II: apolipoprotein C-II; ApoE: apolipoprotein E; CE: cholesteryl ester; CETP: cholesteryl ester transfer protein; CM: chylomicron; CMpri: primordial chylomicron; CMpre: pre-chylomicron; COPII: coat protein complex-II; DGAT2: diacylglycerol acyltransferase 2; ER: endoplasmic reticulum; FATP-4: fatty acid-transport protein 4; FFAs: free fatty acids; FFAs-CoA: free fatty acids–Coenzyme A; HDL: high-density lipoprotein; IDL: intermediate-density lipoprotein; I-FABP-2: intestinal fatty acid-binding protein plasma membrane-2; LPL: lipoprotein lipase; MAG: monoacylglycerol; MTP: microsomal triglyceride transfer protein; P: phospholipid; PCTV: pre-chylomicron transport vesicle; PTV: protein transport vesicles; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TG: triglycerides; VLDL: very low-density lipoprotein; VTV: VLDL transport vesicles.

Figure 2

Hypertriglyceridemia (HTG): definition and classification. Hypertriglyceridemia is classified as primary or secondary to conditions whose removal can theoretically reduce the increase in triglycerides plasma levels. Inherited conditions represent the main source for primary HTG: the left side of the figure outlines the Fredrickson’s classification and the genetic background of chylomicronemias. The right side of the figure represents the secondary causes for HTG. Upward arrows indicates the increase in the characgeristics. Downward arrows indicate the decrease. Abbreviations: ApoA-V: apolipoprotein A-V; ApoC-II: apolipoprotein C-II; ApoE-II: apolipoprotein E-II; CM: chylomicron; GPI-HBP1: glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1; HIV: Human Immunodeficiency Virus; LFM1: Chaperone protein for maturation of LPL; LDL: low-density lipoprotein; LPL: lipoprotein lipase; RXR: retinoid X receptor; TG: triglycerides; VLDL: very low-density lipoprotein.

Figure 3

Lipoprotein lipase (LPL) complex: A reappraisal of the genetic background of LPL action. Abbreviations: ANGPTL-4,-8-3: Angiopoietin-Like Proteins -4,-8,-3; ApoA-I: apolipoprotein A-I; ApoA-IV: apolipoprotein A-IV; ApoA-V: apolipoprotein A-V; ApoB-48: apolipoprotein B-48; ApoC-II: apolipoprotein C-II; ApoE: apolipoprotein E; ApoE-II: apolipoprotein E-II; CM: chylomicron; GPI-HBP1: glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1; HIV: Human Immunodeficiency Virus; LFM1: Chaperone protein for maturation of LPL; LDL: low-density lipoprotein; LPL: lipoprotein lipase; RXR: retinoid X receptor; TG: triglycerides; VLDL: very low-density lipoprotein.