Knowing the role of VLDL (very low-density lipoprotein) and chylomicrons is a key factor in understanding how lipids (fats) and lipoproteins are involved in atherosclerotic cardiovascular disease (ASCVD).
In the current era of adiposity and metabolic disease, VLDL has gained a bigger role than before and may help explain many of the disorders associated with the obesity epidemic such as non-alcoholic fatty liver disease (NAFLD), type-2 diabetes, hypertension, and heart disease.
Lipoproteins are important biochemical substances whose main purpose is to carry lipids from one tissue to another. VLDL is produced by liver cells and is an important carrier of triglycerides (TGs) and to a lesser extent cholesterol. Once in the circulation, VLDL is broken down in capillary beds by an enzyme called lipoprotein lipase, releasing lipids, mainly TGs, for energy utilization by cells or storage in adipose tissue.
Lipids can not be transported in blood on their own because of their insolubility in water. The lipoproteins may be regarded as transportation vehicles for lipids, hence making them soluble in blood. TGs, cholesteryl esters, free cholesterol, and phospholipids are the major lipids carried by the lipoproteins
A lipoprotein particle usually consists of a single outer layer of phospholipid covering a central core of TGs and cholesteryl esters. The proteins on the surface of the lipoprotein particle are termed apolipoproteins. Apolipoproteins help stabilize the lipoprotein structure, and they play a key role in lipoprotein metabolism. Apolipoprotein A (apoA), apolipoprotein B (apoB), apolipoprotein C (apoC), an apolipoprotein E (ApoE) are the four major lipoproteins.
Lipoproteins are usually classified based on their density by ultracentrifugation into five classes; chylomicrons, VLDLs, intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Chylomicrons, IDL’s, and VLDLs are TG-rich lipoproteins, while LDLs and HDLs contain abundant cholesterol.
Another lipoprotein, Lipoprotein (a), not included in the traditional biochemical classification of lipoproteins, is of importance as well. However, measurements of Lipoprotein(a) are not widely available and seldom used in routine clinical practice, despite the fact that it is a strong risk marker for ASCVD.
Most of us learn about the lipoproteins because of their association with cholesterol. Measurements of blood cholesterol are frequently performed to assess cardiovascular risk. The amount of cholesterol carried by LDL, or LDL-cholesterol (LDL-C), is used worldwide to estimate the risk of ASCVD and lowering LDL-C has emerged as an important target to reduce risk.
However, recent research suggests that TG-rich lipoproteins, such as VLDL and IDL may also play a significant role in the development of ASCVD (1).
Triglyceride Absorption and Metabolism – The Role of Triglyceride-Rich Lipoproteins
Most of the fat we consume in our diet is TG. TGs consist of three molecules of fatty acids attached to a glycerol molecule.
When TGs enter the small intestine, they are emulsified and enzymatically digested to yield monoglyceride and fatty acids, both of which can enter cells found in the intestinal wall called enterocytes. From there, the lipids have to be transported into blood to be utilized by the body.
Once inside the enterocyte, fatty acid and monoglyceride are used to synthesize TGs again. The TGs are then combined with phospholipids, cholesterol, and apolipoproteins to form a chylomicron.
The production of chylomicrons by the enterocytes takes place in an intracellular organ called the endoplasmic reticulum.
Phospholipids and apolipoproteins are used to construct a one layered membrane and the TGs and cholesterols are packaged inside this membrane. The spherical ball of outer phospholipid and protein with cholesterol and TG inside (away from the watery environment of the cell) is the chylomicron (2).
The chylomicrons enter lymphatic vessels from where they are transported to the bloodstream through the lymphatic system
Thus, the chylomicrons are the vehicles that enable the transport of lipids such as cholesterol, phospholipids, and TGs from the cells of the small intestine to the blood circulation.
A blood sample drawn after a fatty meal often looks milky due to the presence of chylomicrons. However, chylomicrons disappear from the circulation soon after the TGs are delivered to the tissues. The process may take few hours.
The liver is responsible for the removal of chylomicron remnants from the circulation.
Very Low-Density Lipoprotein (VLDL)
The primary role of chylomicrons is to transport digested lipids to the tissues of the body following a meal. Hence, chylomicrons are not needed in the fasting state, and they usually disappear within a few hours following a fatty meal.
However, TGs will still have to be transported between tissues in the absence of chylomicrons. TGs from the liver and adipose tissue need to be mobilized for fatty acids to be available as fuel for the cells of the body. VLDL is the leading carrier of TG within the circulation.
VLDL is produced by the liver. It carries both cholesterol and TGs. The ratio of the mass of TG to that of cholesterol in VLDL is about 5:1. The main apolipoproteins in VLDL are ApoB-100, ApoC and ApoE.
The fatty acids used by the liver to produce VLDL are derived mainly from two sources. Firstly, during conditions such as obesity, diabetes, and insulin resistance, there is increased fatty acid flux from adipose tissue to the liver. Secondly, there is an increased de novo synthesis of fatty acids in the liver mainly from carbohydrates.
Hence, high blood levels of VLDL are associated with metabolic syndrome and insulin resistance (3). Furthermore, high consumption of added sugar and refined carbohydrates will promote VLDL production by the liver, a phenomenon, known as carbohydrate-induced hypertriglyceridemia. Feeding a high carbohydrate diet increases the production rate and reduces the clearance rate of VLDL particles.
Carbohydrate-induced hypertriglyceridemia may seem paradoxical because the increase in dietary carbohydrate usually comes at the expense of dietary fat. Thus, when the content of the carbohydrate in the diet increases, fat in the diet decreases, but the TG content in the blood still rises (4).
Dietary fat, on the other hand, is not is not a significant source of liver TG (5), and high-fat diets usually don’t raise fasting TGs.
After the release of triglycerides from VLDL, its composition changes and it becomes IDL. IDL is also defined as a TG-rich lipoprotein. Later, when the amount of cholesterol increases, IDL becomes LDL.
High concentration of TG-rich lipoproteins is associated with low levels of HDL-cholesterol (HDL-C). This is partly a result of an exchange of lipids between TG-rich lipoproteins and HDL, leading to TG-enriched HDL particles low in cholesterol. There is an association between low levels of HDL-C and increased risk of ASCVD (6).
TG-Rich Lipoproteins, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease
TG-rich remnant lipoproteins can penetrate the arterial wall and are easily retained. The entrapment of lipoproteins within the vascular wall may be a key factor in promoting atherosclerosis (7).
It has been suggested that the risk associated with TG-rich lipoproteins is mainly due to their cholesterol content, often called remnant cholesterol (8). Because of their larger size, TG-rich lipoproteins carry 5 to 20 times as much cholesterol per particle as LDL.
One study found that a nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for coronary heart disease (9).
Patients at increased risk of ASCVD often have a lipoprotein profile characterized by elevated plasma TG-rich lipoproteins, a predominance of small LDL particles, and low HDL-C. This lipid pattern is typical for patients with insulin resistance and metabolic syndrome.
Apolipoprotein C-III (Apo C-III) is found on the surface of TG lipoproteins. There is an association between high levels of apo-C-III and high TG levels and increased risk of ASCVD. Apo-C-III may contribute to the development of atherosclerosis by several mechanisms. The gene most strongly associated with plasma triglyceride levels is the gene encoding for apo-C-III, called APOC3 (10).
There is overwhelming evidence for VLDL and especially for VLDL remnants being an important contributor to ASCVD (11). It has been suggested that reducing plasma remnant lipoproteins rather than LDL should be the target for patients with metabolic syndrome.
How To Reduce VLDL
Measurements VLDL or VLDL-cholesterol (VLDL-C) are seldom performed in clinical practice. However, it is possible to estimate VLDL-C from the TG levels. As the ratio between TG and cholesterol in VLDL is usually 5:1, it can be assumed that VLDL-C is 1:5 of the TG value.
As VLDL is the main carrier of TG’s in the circulation, high VLDL is associated with high TG’s. So. the best way to reduce VLDL is to lower TG’s.
Following a fatty meal, blood levels of TG’s will rise. However, raised blood TG’s following a meal (postprandial hypertriglyceridemia) are caused by chylomicrons, whereas elevated fasting TG’s are due to VLDL produced from TG’s in the liver. The latter may often be a result of excessive carbohydrate intake.
Lifestyle modification is the first-line therapy for people with elevated TG’s and VLDL.
Many individuals with high TG’s have insulin resistance (3), often associated with visceral obesity, low levels of HDL-C, high blood pressure and type 2 diabetes. For these patients, weight loss, regular physical exercise, and avoidance of added sugars, high glycemic index foods, and high fructose foods are important measures (12). Other risk factors such as smoking and high blood pressure also have to be addressed (13).
The situation may be different in more severe hypertriglyceridemia (above 500 to 1000mg/dL (5.6 to 11.3 mmol/L)), where the clearance of chylomicrons becomes very slow. Under these circumstances, it may be crucial to reduce dietary fat intake to lower triglycerides.
It is necessary for patients with severe hypertriglyceridemia to avoid alcohol abuse as it can cause substantial increases in triglyceride levels and lead to acute inflammation of the pancreas (pancreatitis).