“ApoC3 appears to be a critical regulator of processes associated with peripheral management of dietary lipids and their conversion into energy”
Lipoproteins are an ingenious solution for transporting water-insoluble entities, namely, triglycerides and cholesterol, in the aqueous environment of blood. They comprise a lipid coated with a single-layer shell of phospholipids, with their hydrophobic heads facing towards the lipid and their hydrophilic tails to the outside.
Different lipoproteins are distinguished by the specific proteins attached to the outer phospholipid layer—apolipoproteins. Very low-density lipoproteins (VLDL), which transport newly synthesized lipids and cholesterol from the liver to other tissues around the body, have five different apolipoproteins (apoB100, apoC1, apoC2, apoC3 and apoE). While intermediate-density lipoproteins (IDL) are associated with two and low-density lipoproteins (LDL) are associated with only one.
High density lipoproteins (HDL), which remove cholesterol from the blood to transport to the liver to be broken down, is generally associated with apoA1. Since HDL removes lipids from the blood, high levels of HDL are generally considered to be an indicator of a reduced risk of developing heart disease or stroke.
ApoC3 is produced mainly by the liver and intestine and is thought to inhibit uptake of triglyceride-rich particles by the liver, which delays their breakdown1. ApoC3 plays an important role in regulating triglyceride metabolism and plasma levels have been shown to correlate directly with plasma triglyceride levels.
Approximately half of all plasma apoC3 ends up associated with HDL, which would suggest that it would temper the positive function of HDL2. It has recently been shown that apoC3-HDL only arises through de novo biosynthesis in the liver and requires the presence of lipid transporter ABca13.
Studies in mice demonstrated that ABca1 and apoC3-HDL play key roles in the prevention of apoC3-induced hypertriglyceridemia3. ApoC3-HDL levels are also increased in morbidly obese patients. This variety of HDL is thus shown to be involved in the maintenance of plasma triglyceride homeostasis.
The importance of apo3-HDL in regulating the rate at which triglycerides are hydrolyzed in the liver prompted research into its function in adipose tissue. The effects of apoC3 expression on HDL and on metabolic activity in adipose tissue were recently investigated in mice by infecting them with an adenovirus expressing human APOC34.
The apolipoprotein composition of HDL from the mice was then analyzed along with mitochondria from white and brown adipose tissue. Serum metabolomic analysis was performed using a Bruker Avance III HD 700 MHz nuclear magnetic resonance spectrometer equipped with a TCI cryogenically cooled probe.
The data obtained revealed that apoC3 does modify HDL structure and function. ApoC3-HDL contained more phospholipid and free cholesterol and had higher antioxidant activity than control HDL. Furthermore, it selectively promoted metabolic activity within brown (but not white) adipose tissue allowing more energy-providing adenosine triphosphate to be produced4.
This latest research quashes concerns that apoC3 could negate the cardioprotective effects of HDL. It highlights that it is the function of the lipoprotein rather than HDL levels per se that determine cardiovascular risk.
ApoC3 plays an important role in normal lipid metabolism. Although it may be beneficial to reduce apoC3 expression to restore physiological levels in certain types of hypertriglyceridemia, completely blocking it could be seriously detrimental.
References
Mendivil CO, et al. Metabolism of very-low-density lipoprotein and low-density lipoprotein containing apolipoprotein C-III and not other small apolipoproteins. Arteriosclerosis, Thrombosis, and Vascular Biology 2010;30 (2): 239–245.
Onat A, et al. Apolipoprotein C-III, a strong discriminant of coronary risk in men and a determinant of the metabolic syndrome in both genders. Atherosclerosis 2003;168: 81‑89.
Kypreos KE. ABCA1 Promotes the de Novo Biogenesis of Apolipoprotein CIII-Containing HDL Particles in Vivo and Modulates the Severity of Apolipoprotein CIII-Induced Hypertriglyceridemia. Biochemistry 2008;47:10491–10502.
Zvintzou E, et al. Pleiotropic Effects of Apolipoprotein C3 on HDL Functionality and Adipose Tissue Metabolic Activity. J Lipid Res. 2017;58(9):1869‑1883.