Introduction

Very low-density lipoproteins (VLDL), along with chylomicrons, low-density lipoproteins (LDL), intermediate-density lipoproteins (IDL), and high-density lipoproteins (HDL) are the five major types of lipoproteins. These lipoproteins are responsible for transporting hydrophobic lipids such as phospholipids, triglycerides, and cholesterol in the plasma and extracellular fluids. Lipids, proteins, carbohydrates, and nucleic acids are the main components of cellular life. Lipids are vital for synthesizing cell membranes, energy storage, intracellular messaging, and transporting other essential organic substances such as vitamins. Lipoproteins allow for the transport of hydrophobic lipids in the hydrophilic environment of the body’s systemic circulation.[1]

The synthesis and secretion of VLDL into circulation by the liver is a highly complex and regulated process that plays a fundamental role in the overall homeostasis of lipids in the body. Recent evidence has shown that the enhanced production and secretion of VLDL or alterations in its regulatory system directly contribute to the development of multi-organ diseases such as atherosclerosis.[2][3][4] There is an ongoing research effort to better understand the basic and complicated mechanisms behind the regulation and signaling of VLDL biogenesis to develop effective targeted therapies in the future.

Fundamentals

The composition of VLDL consists of approximately 90% lipids and 10% proteins. This proportion gives VLDL a very low density of 0.96 to 1.006 g/ml, hence its name. Of its total lipid component, triglycerides take up to 70% of VLDL’s mass, with cholesterol esters and fatty acids making up the rest.[5] Regarding its lower protein component, VLDL is associated with multiple apolipoproteins: Apo B-100, Apo C-I, Apo C-II, Apo C-III, and Apo E.[6] Apolipoproteins serve as cofactors for numerous enzymes throughout the body, ligands for surface receptors, and essential structural elements. The biological functions and metabolism of VLDL are strongly related to these apolipoproteins, as well as VLDL’s potential role in disease development.[6]

Molecular Level

The lipid transport pathway starts in the small intestine when the dietary lipids (mainly triglycerides) are packaged into chylomicrons utilizing Apo B-48 as its backbone structure. Chylomicrons are then secreted into the lymphatic system to later travel throughout the systemic circulation. As they travel throughout the body, chylomicrons obtain Apo C-II and Apo-E from circulating HDL. The recently acquired Apo C-II acts as an activating cofactor for lipoprotein lipase (LPL), which hydrolyzes the triglycerides found in the chylomicrons’ core and allows it to release free fatty acids to the peripheral tissues. As chylomicrons lose their triglycerides by the action of peripheral LPL, they transform into chylomicron remnants. These remnants use their Apo-E as high-affinity ligands to bind to hepatic receptors and internalize into the liver[1]. 

In the hepatocytes, triglycerides and cholesterol esters are transferred to Apo B-100 by the action of the microsomal triglyceride transfer protein (MTTP). This lipidated Apo B-100 is now called nascent VLDL and is secreted to the circulation.[7][8] Nascent VLDL, similar to chylomicrons, obtains Apo C-II and Apo E from circulating HDL and is now termed mature VLDL. Mature VLDL transports endogenous lipids originating from the liver to the peripheral adipose, cardiac, and muscle tissues (unlike chylomicrons which carry exogenous dietary lipids from the small intestine).[9]

The Apo C-II in mature VLDL activates LPL in the capillary endothelium of tissues to cleave their stored triglycerides into one monoglyceride and two free fatty acids, releasing them from the VLDL and allowing them to be delivered to the tissues to be used for storage or energy production.[9][10] Insulin also upregulates the activity of Apo C-II and increases the hydrolysis of triglycerides into free fatty acids for tissue absorption. Simultaneously, the cholesterol ester transfer protein (CETP) promotes the exchange of VLDL’s triglycerides and phospholipids for HDL’s cholesterol esters. After releasing enough triglycerides either into the tissues or to HDL, the core of the VLDL gets reduced, and the VLDL remnant is now called IDL. Approximately half of the circulating IDL is then taken by the liver by binding to the Apo B-100 and Apo-E. The remaining half of the IDL loses its Apo-E and transforms into LDL through the action of the hepatic lipase. 

The alteration or deficiency of the enzymes involved in this complex metabolic process may lead to lipid disorders known as hyperlipoproteinemia. Depending on the pathophysiology and clinical presentation, these diseases are divided into five subtypes. Type I hyperlipoproteinemia (familial hyperchylomicronemia) is caused by a deficiency in LPL or Apo C-II, resulting in a significant increase in triglyceride concentration. These patients present with eruptive xanthomas, steatosis, recurrent episodes of acute pancreatitis, and no increased risk of atherosclerosis.[11] Type II hyperlipoproteinemia (familial hypercholesterolemia) is caused by defective or deficient LDL receptors or Apo B-100. This causes an important elevation in LDL (usually >600 mg/dl in homozygotes or >250 mg/dl in heterozygotes) and VLDL cholesterol. These patients present with tuberous xanthomas, xanthelasmas, and premature atherosclerosis, which may lead to acute coronary syndromes in young patients (<20 years of age).[12] Type III hyperlipoproteinemia (familial dysbetalipoproteinemia) is caused by an alteration in Apo-E, which results in an increase in VLDL and chylomicrons leading to premature atherosclerosis.[13] Type IV hyperlipoproteinemia (familial hypertriglyceridemia) is caused by hepatic overproduction of VLDL, leading to a massive increase in triglyceride concentrations (usually >1000 mg/dl), causing premature atherosclerosis and recurrent episodes of acute pancreatitis (similar to type I).[14][15] Finally, type V (mixed hyperlipidemia) is caused by a sporadic defect in Apo A5 and presents with xanthomas, abdominal pain, and clinical features of hyperglycemia.[16][17]

Function

LDL plays a key role in the formation of atherosclerotic plaques that leads to atherosclerotic cardiovascular disease. Directly measuring LDL and VLDL by ultracentrifugation is extremely expensive and time-consuming. For this reason, multiple time and money-saving equations have been developed throughout the years to estimate the LDL and VLDL cholesterol levels. Most famously known, the Friedewald equation subtracts HDL and VLDL from the total cholesterol level to estimate LDL concentration. In turn, VLDL levels are estimated by a fixed ratio of triglycerides/5.[18] 

Initially intended for research purposes only, this equation has been widely utilized over the last decades to clinically estimate LDL cholesterol levels.[19] This equation, however, is not without its limitations and inaccuracies. This measurement becomes unreliable at high triglyceride (>400 mg/dl) and low LDL concentrations. With the increased prevalence of obesity, metabolic syndrome, and diabetes, higher triglyceride levels are increasingly common, and special consideration needs to be taken when indirectly estimating both LDL and VLDL.[20]

Pathophysiology

Diet, sex, and race are factors that significantly influence VLDL production and secretion. VLDL synthesis is mainly related to lipid intake, with secretion increasing in the postprandial state. High-fat diets have been associated with higher VLDL secretion, usually presenting as increased blood triglyceride levels.[21][22] Studies have inconsistently reported the timing of postprandial VLDL peaks, ranging from 30 minutes up to 5 or 6 hours. Nonetheless, multiple studies have found that insulin resistance, metabolic syndrome, and obesity are strongly associated with longer plateaus and higher peaks of VLDL levels.[23][24] Women have also been shown to have lower VLDL concentrations than men, although the cause of this sex difference is not completely understood.[25] VLDL has been associated with the development of multiple pathological conditions involving the cardiovascular, endocrine, renal, hepatic, and nervous systems, as well as cancer and several autoimmune and dermatological diseases.

Clinical Significance

The impact of VLDL on cardiovascular diseases is mainly correlated to its role in atherosclerosis and coronary disease.[26] The accumulation of triglyceride-predominant lipoproteins such as chylomicrons and VLDL strongly contributes to the rupture of atherosclerotic plaques. Additionally, VLDL has been associated with peripheral artery disease leading to occlusive limb events, vascular stiffness, and carotid artery thickness.[27] Besides the lipidic components of VLDL, its apolipoprotein composition also directly affects the development of cardiovascular disorders. Studies have shown that higher Apo-B and lower Apo C-III concentrations are associated with higher cardiovascular risk.[28][29] This leads to the hypothesis that Apo-B is one of the major drivers in the development of atherosclerosis.[30]

Beyond its direct relation with atherosclerosis, VLDL also plays an important role in metabolic syndrome and insulin resistance. In a normal physiologic state, insulin suppresses the production and secretion of VLDL. In subjects with insulin resistance, there is an enhanced synthesis, and reduced clearance of VLDL is often detected as increased plasma triglyceride levels.[31][32] In these subjects with insulin resistance, there is also a dysfunction in lipid storage in adipose tissue, making them prone to hyperlipidemia. Further, VLDL in metabolic syndrome can induce macrophage apoptosis by increasing reactive oxygen species production. These cytotoxic properties cause VLDL to be highly pro-inflammatory and atherogenic.[29]

VLDL cholesterol is also associated with hepatic disorders such as non-alcoholic fatty liver disease (NAFLD) and hepatitis. Liver fat content has been previously associated with other features of chronic insulin resistance, such as glucose intolerance, increased insulin levels, and intra-abdominal fat.[2] In subjects with NAFLD, there is increased hydrolysis of intrahepatic triglycerides leading to increased secretion of VLDL. Patients with NAFLD also have an altered synthesis, oxidation, and reduction of VLDL particles due to the impaired effects of insulin.[31] It has been theorized that the lessened effects of insulin lead to an increase in lipid deposition from adipose tissue to the liver. Elevations in blood glucose can further increase fat accumulation in the liver, resulting in enhanced production of VLDL and leading to the expected hyperlipidemia associated with diabetes.[2]

VLDL levels are also affected by various hormones, with its metabolism being closely related to several endocrinological mechanisms. In Cushing syndrome, the increased concentration of cortisol increases the plasma levels of both VLDL and LDL cholesterol by reducing the degradation of Apo B and increasing the rate of adipose tissue lipolysis.[33] This results in expected dyslipidemia and increased cardiovascular risk associated with Cushing syndrome. Aldosterone production is stimulated by VLDL and potentially leads to hypertension. This also explains how statins are associated with a decrease in aldosterone concentrations.[34] Growth hormone also has a direct effect on VLDL metabolism.[35] Growth hormone deficiency is associated with increased VLDL synthesis and decreased clearance. This mechanism explains the association between hypopituitarism and a higher cardiovascular and cerebrovascular risk. Moreover, thyroid hormones affect the activity of LPL and have a strong relation with cholesterol metabolism. The deficiency of thyroid hormones in hypothyroidism leads to reduced LPL function and increased hepatic VLDL production associated with hyperlipidemia and higher cardiovascular risk.[36] VLDL has also been implicated in developing neurocognitive dysfunction, chronic kidney disease, and cancer.[37][38][39]

In conclusion, VLDL cholesterol is synthesized in the liver to transport endogenous lipids such as triglycerides and cholesterol esters to the peripheral (mainly adipose, skeletal, and cardiac) tissues. It has been strongly associated with developing several multi-organ diseases such as atherosclerosis, coronary artery disease, non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome, neurocognitive impairment, autoimmune disease, dermatological disorders, and cancer. It is crucial to study and understand the mechanisms behind VLDL’s biosynthesis, regulation, signaling, and secretion to comprehend its contribution to human health and to potentially develop targeted therapies that may lead directly to better patient care.