Understanding Hypertriglyceridemia: Integrating Genetic Insights

Abstract

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1 triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.

Keywords: Hypertriglyceridemia; familial chylomicronemia syndrome; multifactorial chylomicronemia syndrome.

Figure 1

Lipoprotein lipase complex bound to endothelial cells. The lipolytic process of TRLs by LPL involves a complex interplay of multiple proteins. LPL is chaperoned by LMF1 during the biosynthesis pathway facilitating LPL maturation. After secretion, LPL binds to HSPG and is stabilized. LPL forms a complex with GPIHBP1, which is shuttled to the endothelial cell surface within the capillary lumen. The catalytic activity of LPL is promoted by ApoA-V and Apo C-II, while ApoC-III serves as an inhibitory factor. ApoC-II is crucial for the enzymatic activity and ApoA-V contributes to the stabilization of the LPL–TRL complex by interacting with HSPG and GPIHBP1. Genetic variants within the genomic locus responsible for regulating these key proteins in the lipolytic process can significantly compromise catalytic activity. LPL catalytic impairment impedes the efficient clearance of TRLs, ultimately leading to HTG. ApoA-V—apolipoprotein A-V; ApoC-II—apolipoprotein C-II; ApoC-III—apolipoprotein C-III; APOA5—Apo A-V gene; APOC2—ApoC-II gene; APOC3—ApoC-III gene; LPL—lipoprotein lipase; LMF1—Lipase maturation factor 1; GPIHBP1—glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1; ER—endoplasmic reticulum; HSPG—heparan sulfate proteoglycans; TG—triglycerides; TRLs—triglyceride-rich lipoproteins; HTG—hypertriglyceridemia. Figure icons were created with BioRender.com, accessed on 9 January 2024.