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. 2024 Jan 12;23(1):14.
doi: 10.1186/s12944-023-01993-y.

Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets

Jingfei Chen  1 , Zhenfei Fang  2   3 , Qin Luo  2   3 , Xiao Wang  4 , Mohamad Warda  5   6 , Avash Das  7 , Federico Oldoni  8 , Fei Luo  9   10
Affiliations

Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets

Jingfei Chen et al. Lipids Health Dis. .

Abstract

Reducing circulating lipid levels is the centerpiece of strategies for preventing and treating atherosclerotic cardiovascular disease (ASCVD). Despite many available lipid-lowering medications, a substantial residual cardiovascular risk remains. Current clinical guidelines focus on plasma levels of low-density lipoprotein (LDL). Recent attention has been given to very low-density lipoprotein (VLDL), the precursor to LDL, and its role in the development of coronary atherosclerosis. Preclinical investigations have revealed that interventions targeting VLDL production or promoting VLDL metabolism, independent of the LDL receptor, can potentially decrease cholesterol levels and provide therapeutic benefits. Currently, methods, such as mipomersen, lomitapide, and ANGPTL3 inhibitors, are used to reduce plasma cholesterol and triglyceride levels by regulating the lipidation, secretion, and metabolism of VLDL. Targeting VLDL represents an avenue for new lipid-lowering strategies. Interventions aimed at reducing VLDL production or enhancing VLDL metabolism, independent of the LDL receptor, hold promise for lowering cholesterol levels and providing therapeutic benefits beyond LDL in the management of ASCVD.

Keywords: Atherosclerotic cardiovascular disease; LDL receptor-independent pathway; Low-density lipoprotein; Very low-density lipoprotein.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic figure of apolipoproteins and the lipid composition of VLDL. Very low-density lipoprotein (VLDL) contains apolipoprotein B100 (APOB) on its surface as a structural protein and a surface monolayer of phospholipids; free cholesterol; and apolipoproteins such as apolipoprotein C2 (APOC2), APOC3, apolipoprotein E (APOE), and APOA5. The central core of VLDL contains cholesterol esters and triglycerides
Fig. 2
Fig. 2
Biogenesis, lipidation and intracellular trafficking of VLDL. The assembly of VLDL in the liver begins with the cotranslational translation of apolipoprotein B (APOB) across the rough endoplasmic reticulum (RER) membrane. Microsomal triglyceride transfer protein (MTP) plays an essential role in the initial lipidation of APOB by extracting phospholipids and triglycerides (TGs) from the endoplasmic reticulum (ER). Without sufficient lipidation, nascent APOB is degraded. After the initial lipidation, VLDL is further lipidated with a large amount of lipids to form mature VLDL. To exit the endoplasmic reticulum, VLDL is packaged into transport vesicles called coat protein complex II (COPII), which is initiated by the activation of the small Ras-like GTPase SAR1.
Fig. 3
Fig. 3
Metabolism of VLDL in circulation. After entering the bloodstream, VLDL undergoes hydrolysis by lipoprotein lipase (LPL), endothelial lipase, and hepatic lipase, leading to the release of free fatty acids from the core triglycerides and surface phospholipids. The activity of LPL is inhibited by apolipoprotein C3 (APOC3) and angiopoietin-like protein (ANGPTL)3/4/8, while it is activated by APOA5 and APOC2. When a large amount of triglycerides in VLDL is hydrolyzed, VLDL can be further metabolized into VLDL remnants, nearly half of which are absorbed by the liver, while the remaining VLDL remnants are further metabolized into low-density lipoprotein (LDL). LDL can bind to LDL receptors (LDLRs) and be taken up by the liver. Excessive VLDL remnants and LDL can deposit in the blood vessel walls, forming atherosclerotic plaques
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