Very low-density lipoprotein and the human health

Abstract

Very low-density lipoprotein (VLDL), released in the liver, is the only lipoprotein that includes apolipoprotein B (marker for cardiovascular risk), triglycerides, and cholesterol. VLDL is essential in transporting lipids and cholesterol to organs and cells for utilization. VLDL also contributes significantly to the advancement of atherosclerotic heart disease. We comprehensively summarize VLDL’s physiological roles and data supporting its pathological effects. VLDL has been proven to promote atherosclerosis in the metabolic syndrome. VLDL isolated from metabolic syndrome patients is cytotoxic to atrial myocytes, causing atrial myopathy and contributing to atrial fibrillation. Several endocrine diseases may impact VLDL levels, which can be boosted by supplementing with progesterone, estrogen, cortisol, and growth hormones. VLDL stimulates high blood pressure by secreting aldosterone. VLDL induces neuroinflammation, which may lead to cognitive impairment. VLDL is linked to chronic renal illness, autoimmune disorders, and some skin diseases. VLDL production outside the liver caused by intestinal dysbiosis is considered harmful. New evidence reveals that VLDL metabolism has a role in the development and risk of cancer, as well as sleep disturbances. Aside from this, VLDL metabolism and carcinogenesis might be altered by the VLDL receptor. Overall, growing findings point to the role of VLDL in many illnesses.

Key Words: Very low-density lipoprotein metabolism; Physiological health; Pathological function; Lipids; Cholesterol; High blood pressure-based cardiovascular disease

Core Tip: The liver secretes very low-density lipoprotein (VLDL), implicated in diseases such as atherosclerosis, metabolic-associated fatty liver disease, cognitive impairment, metabolic syndrome, autoimmune disorders, breast cancer, and head and neck cancer. VLDL contributes to atrial myopathy in the preclinical stage of atrial fibrillation and exhibits cytotoxic effects in myocardial infarction, though the mechanism remains unclear. Endocrine disorders can alter VLDL levels, and VLDL has been shown to increase aldosterone production. Its pathogenic role extends to extrahepatic release, neurological disorders, sleep disturbances, and various malignancies. Understanding VLDL regulation and metabolism, rather than just its levels, may clarify its role in disease and guide targeted therapeutic strategies.

INTRODUCTION

Very low-density lipoprotein (VLDL) is synthesized and secreted by the liver and is the precursor of intermediate-density lipoprotein (IDL), which is further metabolized to low-density lipoprotein (LDL). Lipoproteins such as chylomicrons, VLDL, IDL, LDL, and high-density lipoprotein (HDL) can be separated from blood or plasma using density-gradient ultracentrifugation techniques[1,2]. VLDL is predominantly composed of triglycerides (TGs; 50%-70%), while cholesterol constitutes approximately 10%-25%, and free fatty acids account for less than 10%. The principal structural protein of VLDL is apolipoprotein (apo) B100, along with exchangeable apos including apo E, apo C-I, apo C-II, and apo C-III. These apos act as ligands that regulate lipolysis and mediate interactions with cell-surface receptors[3]. VLDL transports TGs, cholesterol, and associated proteins from the liver to peripheral tissues to support essential metabolic functions. Hepatic availability of TGs and cholesterol, together with apo B100 synthesis, strongly influences the lipid composition and rate of VLDL production[4].

In the circulation, VLDL is hydrolyzed by lipoprotein lipase (LPL) located on the capillary endothelium, resulting in the removal of TGs and the formation of VLDL remnants, also known as IDL. Some VLDL particles may remain partially unmodified. During this process, apo C-II and other surface components are transferred to HDL. Cholesteryl ester transfer protein facilitates the exchange of TGs and cholesteryl esters between VLDL/IDL and HDL. IDL is subsequently taken up by the liver via LDL receptors or further metabolized into LDL following the loss of TGs and apo E[3]. The assembly and metabolism of VLDL are strongly influenced by insulin resistance and chronic nutrient excess, conditions commonly associated with metabolic disorders[5]. Beyond lipid transport, VLDL has been implicated in nitric oxide signaling, which plays a key role in vascular tone regulation and blood pressure homeostasis[6]. Additionally, VLDL has been shown to stimulate phospholipase D activity in the adrenal gland, leading to increased cytosolic calcium levels and enhanced aldosterone secretion[7]. Therefore, VLDL plays a multifaceted role not only in lipid transport but also in metabolic regulation and vascular function.

Hormonal regulation and endocrine disorders play a central role in modulating VLDL secretion and TG metabolism. Insulin is the primary inhibitory hormone regulating hepatic VLDL-TG production by suppressing adipose tissue lipolysis and limiting free fatty acid flux to the liver; insulin resistance therefore leads to VLDL overproduction and hypertriglyceridemia. Counter-regulatory hormones such as glucagon, cortisol, and catecholamines promote lipolysis and hepatic TG synthesis, indirectly enhancing VLDL secretion. Thyroid hormones influence TG clearance by regulating LPL activity and hepatic lipid oxidation, with hypothyroidism commonly associated with elevated VLDL-TG levels. Sex hormones also modulate VLDL metabolism, as estrogens generally reduce hepatic VLDL secretion, whereas androgen excess may exacerbate hypertriglyceridemia. Consequently, endocrine disorders including diabetes mellitus, metabolic syndrome (MetS), Cushing’s syndrome, hypothyroidism, and polycystic ovary syndrome are frequently characterized by dysregulated VLDL-TG metabolism, linking hormonal imbalance to cardiometabolic disease risk.

This review explores the hypothesis that dysregulated VLDL metabolism serves as a central node connecting diverse metabolic stressors to multi-organ pathogenesis, highlighting novel experimental insights into underlying mechanisms and potential therapeutic targets.

CLASSIFICATION OF VLDL

Nuclear magnetic resonance spectroscopy measures VLDL particle diameter. VLDL can be classified based on particle size, obtaining different fractions of diameters. High reproducibility is vital for measuring serum lipoproteins sub-fractions. To evaluate the quality control of plasma of lipoprotein samples, reproducibility was complied with, and nuclear magnetic resonance results from 5 laboratories and 11 spectrometers were compared. Subclasses have been defined: 6 for LDL, 4 for HDL, and 6 for VLDL[8].

However, an agreement has not been reached on consensus standard diameter ranges for classifying VLDL subfractions. For example, Phillips and Perry[9], 2015 categories are defined as small VLDL (< 42 nm), medium VLDL (42-60 nm) and large VLDL (including chylomicrons, if present, > 60 nm). Wang et al[10], 2012 explain the 6 classes of VLDL as follows: Small (36.8 nm), very small (31.3 nm), medium (44.5 nm), most significant chylomicrons (mean diameter, 64.0 nm). Garvey et al[11] identify the following three groups: Small VLDL (< 35 nm), medium VLDL (35-60 nm), and large VLDL (> 60 nm). Avogaro et al[12], 1988 identified the LDL for the first time based on surface charge but not on the size of solid exchange chromatography and divided it into LDL (-) and LDL (+) in 1988. In addition, Yang et al[13], 2003 and Chen et al[14], 2003 have classified them into five categories from L1-L5. Similarly, an attempt was made by Chen et al[15], 2012 to classify the VLDL into five subcategories from V1-V5 using anion exchange chromatography (Table 1).

Table 1 Nuclear magnetic resonance-based very low-density lipoprotein classification.

Classes	Associated impact	Ref.
Small VLDL	Metabolically fit individuals with smaller (below medium) VLDL size	[9]
Largest VLDL (including chylomicrons) and five different VLDL subclasses	The level of all lipid components in the VLDL subclasses was enhanced as glucose tolerance was reduced	[10]
Large and intermediate VLDL	Progressive insulin resistance was associated with enhanced VLDL size and an enhancement in large VLDL particles	[11]

VLDL: Very low-density lipoprotein.

Although VLDL and the VLDL receptor (VLDLR) share nomenclature, they represent functionally and biologically distinct entities. VLDL particles act as lipid transport vehicles and signaling mediators, whereas VLDLR is a cell-surface endocytic and signaling receptor that governs tissue-specific lipid uptake and intracellular signaling pathways. Conflation of their roles has led to ambiguity in mechanistic interpretations, particularly in cardiometabolic and inflammatory diseases.

VLDL particles

Nature: Circulating TG-rich lipoproteins synthesized and secreted by hepatocytes.

Primary function: Transport of endogenous TGs, cholesterol esters, and fat-soluble molecules to peripheral tissues.

Key apos: Apo B100 (structural), apo E, apo C-II, apo C-III.

Pathophysiological effects: Promote atherogenesis, endothelial dysfunction, lipotoxicity, inflammation, insulin resistance, and ectopic lipid deposition.

Mode of action: Systemic - via lipolysis by LPL, remnant formation, oxidative modification, and receptor-independent cellular effects.

VLDLR

Nature: Transmembrane member of the LDL receptor family.

Primary function: Tissue-specific uptake of TG-rich lipoproteins and modulation of intracellular signaling.

Expression profile: High in adipose tissue, heart, skeletal muscle, macrophages, brain, and endothelial cells; absent in adult hepatocytes.

Pathophysiological effects: Regulates lipid accumulation, cellular energy balance, inflammation, angiogenesis, neurodevelopment, and vascular remodeling.

Mode of action: Local - via receptor-mediated endocytosis and signal transduction pathways.

PATHOLOGICAL ROLE OF VLDL

Metabolism-associated fatty liver disease and liver disease

Metabolic-associated fatty liver disease (MAFLD) exhibits a raised VLDL secretion rate attributed to increased intrahepatic TGs hydrolysis. They apparent the absence of immediate VLDL secretion reduction yet maintained a consistent apo B100 secretion rate, as informed by previous studies[16,17]. The power to suppress insulin results on VLDL is compromised in males with MAFLD in terms of particle oxidation, concentration, secretion, and the decrease in particle size due to oxidation[18]. In individuals with insulin resistance and higher body weight, there is an elevation in apo C-III levels within VLDL. This increase enhances hepatocyte VLDL uptake[19-21]. However, in MAFLD patients with a severe TG/VLDL ratio, plasma TG levels, liver fibrosis, and total circulating VLDL were significantly reduced[22]. VLDL showed significant gender differentiation as far as MAFLD is concerned. Men are more likely to develop MAFLD than women[23]. The risk of MAFLD is increased due to decreased estrogen levels in postmenopausal women[24-26]. Recent animal experimentation has reflected that insufficiency of estrogen-related receptor results in the decreased production of VLDL, which causes increased lipid concentration and MAFLD progression. Estrogen-related receptor ERR is a nuclear hormone involved in various metabolic activities[23].

Decreased adiponectin levels (usually seen in patients with MetS and MAFLD) lead to a rise in VLDL size mass (Lucero et al[22], 2017). Activated protein kinase and mammalian target of rapamycin were the two molecules that were concerned with the expression of VLDL and MAFLD[27-29]. It has been found that ceramides (lipid portion among VLDL) are also associated with the MAFLD severity[30,31]. VLDL is also responsible for transporting plasma dihydroceramide (i.e., also connected to MAFLD exposure during type 2 diabetes)[31,32].

Hepatitis C virus (HCV) attaches to the TG-rich lipoproteins and VLDL, synthesizing lipoviral particles. A classic example is lipoviral particles that contain HCV glycoprotein E2, which has the capability to guard HCV against the immune system as well as help in spreading the pathogenicity of lipoprotein receptors inside the liver[33-35]. It has been noticed that HCV viral load negatively impacts LPL activity, while it reflects a positive impact with VLDL (apo C-III portion)[36]. Furthermore, HCV interferes with the host’s lipid metabolism through various mechanisms like reducing fatty acid oxidation, increasing lipogenesis, and reducing the amount of TG in secreted VLDL, thereby affecting lipid homeostasis[37]. Direct-acting antivirals that directly affect HCV have been shown to correct TG abnormalities in cholesterol and lipoprotein metabolism in VLDL and LDL[38].

Insulin resistance and MetS

Insulin-hampered VLDL production, along with insulin resistance, leads to increased and decreased production of VLDL, often associated with hypertriglyceridemia[39-42]. Hepatic VLDL production is decreased by glucagon[43]. Due to insulin resistance, adipose tissue reflects low lipid concentration (i.e., responsible for the accumulation of ectopic lipids and hyperlipidemia)[44,45]. It has been observed that insulin has the capability to reduce VLDL production[46] among individuals suffering from type 2 diabetes. However, postprandial VLDL concentrations are enhanced, but postprandial VLDL clearance is like nondiabetic subjects[47]. A study examining VLDL kinetics during hyperinsulinemia using pre-labeled VLDL1 and VLDL2 particles showed that the size (TG/apo B ratio) and apo B100 level were reduced in a healthy individual. The rate of fatty acid oxidation is reduced in diabetic patients[48]. Emerging evidence indicates that VLDL is cytotoxic, proinflammatory, and atherogenic in MetS and is linked with many infections[49-54]. Enhanced levels of apo C-III, apo E-III, and apo E-IV among VLDL in MetS are responsible for decreased LPL concentration[55,56]. VLDL in MetS can encourage apoptosis via reactive oxygen species, especially in endothelial cells and subendothelial macrophages[55]. Moreover, proinflammatory impacts have been shown to be stimulated by VLDL lipolysis products[57]. VLDL size is thought to be related to the regulation of peroxisome proliferator activated receptor-α during plasma fatty acid clearance after VLDL hydrolysis[58]. The size of VLDL particles has been affected through the LPL activity and relates to MetS, insulin resistance, and VLDL particle size[59].

Other endocrinological disorders

This section elaborates on various hormones and endocrine-related disorders concerned with VLDL/TG metabolic pathways (Table 2).

Table 2 Summary of endocrinology effect on very low-density lipoprotein.

Disorder/syndrome	Impact due to VLDL	Ref.
Cushing syndrome	Enhanced production	[61]
Exogenous cortisol	Decrease in degradation and enhanced adipose lipolysis	[62]
Aldosterone	Stimulation of aldosterone secretion	[65-67]
Growth hormone deficiency	Enhanced secretion and decline in clearance	[61]
Growth hormone treatment	Increased adipose lipolysis and increased clearance	[61]
Hypothyroidism	Decreased degradation with enhanced secretion	[73,74]
Androgen	Androgen-deprivation treatment: Enhanced concentration; transgender males with testosterone treatment: Enhanced concentration	[80-82]
Polycystic ovary syndrome	Enhanced concentration	[84]
Estrogen/progesterone therapy	Enhanced concentration	[85,86]
Prolactinoma	Uncertain	[94-96]

VLDL: Very low-density lipoprotein.

Cushing syndrome: This syndrome occurs when the enhanced concentration of LDL and VLDL manifests as dyslipidemia along with increased levels of plasma cholesteryl ester and TG[60]. Enhanced release of VLDL in comparison to the usual amount with no change in VLDL clearance is responsible for the high VLDL concentration[61]. Figure 1 illustrates how excess cortisol drives dysregulated VLDL-TG metabolism. Elevated cortisol stimulates adipose tissue lipolysis, increasing the circulation of free fatty acids. These free fatty acids are taken up by the liver, where they fuel hepatic TG synthesis and VLDL overproduction, leading to hypertriglyceridemia. This process is further exacerbated by insulin resistance, which impairs normal suppression of VLDL secretion. Circulating VLDL is subsequently converted into LDL-cholesterol, contributing to atherogenic dyslipidemia. Overall, the pathway links cortisol excess to insulin resistance, VLDL overproduction, and adverse lipid profiles.

Figure 1 Cushing’s syndrome and very low-density lipoprotein dyslipidemia. FFAS: Free fatty acids; VLDL: Very low-density lipoprotein; LDL-C: Low-density lipoprotein cholesterol.

Exogenous cortisol: Stimulation of exogenous cortisol during glucocorticoid therapy decreases the apo B degradation and enhances adipose tissue lipolysis, ensuring increased VLDL[62]. Risk of cardiovascular sickness along with Cushing’s syndrome and dyslipidemia on corticosteroid therapy are associated with increased VLDL/TG levels[63,64]. Figure 2 depicts the metabolic effects of glucocorticoid excess on glucose and lipid homeostasis. Glucocorticoids activate glycogen synthase kinase-3, which inhibits glycogen synthesis and promotes hepatic gluconeogenesis, increasing glucose output. Concurrently, glucocorticoids induce insulin resistance by impairing glucose transporters type 4 translocation in skeletal muscle, reducing peripheral glucose uptake and leading to hyperglycemia. In parallel, glucocorticoid-stimulated proteolysis increases circulating amino acids that further fuel gluconeogenesis. Excess glucose is diverted toward TG synthesis and visceral fat accumulation, linking glucocorticoid signaling to insulin resistance, hyperglycemia, and central adiposity.

Figure 2 Effect of glucocorticoid hormones in muscle and adipose tissue. GSK-3: Glycogen synthase kinase 3; GLUT-4: Glucose transporter 4.

Aldosterone: Aldosterone, secreted from the adrenal gland, is also related to VLDL. Stimulation in VLDL endorses the secretion of aldosterone, which occurs through the phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP3)/protein kinase C (PKC) signaling pathway[65-67]. Through this mechanism, we can partly clarify how statins, a commonly used lipid-lowering drug, are associated with low aldosterone levels in high blood pressure and diabetes[68]. Figure 3 illustrates a signaling link between VLDL and aldosterone secretion in adrenal gland cells. VLDL interacts with adrenal cell surface receptors, activating the PLC pathway, which generates IP3 and activates PKC, leading to intracellular signaling that promotes aldosterone production. Statins interfere with this pathway by reducing circulating VLDL levels and attenuating PLC-IP3-PKC signaling, thereby decreasing aldosterone secretion. Overall, the diagram highlights a mechanistic connection between lipid metabolism and adrenal hormone regulation, suggesting that VLDL reduction can modulate aldosterone-dependent endocrine effects.

Figure 3 Very low-density lipoprotein induced signals mediating aldosterone. VLDL: Very low-density lipoprotein; PLC: Phospholipase C; IP3: Inositol 1,4,5-trisphosphate; PKC: Protein kinase C.

Growth hormone deficiency and treatment: Growth hormone insufficiency is associated with increased VLDL synthesis, reduced VLDL clearance, and increased TG concentration. VLDL clearance is promoted through growth hormone replacement treatment but concurrently enhances the VLDL release from adipose tissue by promoting lipolysis[69]. As a result, even if growth hormones encourage fatty acid oxidation, there is no decrease in VLDL production. However, it can also enhance plasma VLDL and TG concentration[70]. This incidence may clarify why patients with hypopituitarism may develop cardiovascular and cerebrovascular diseases[71]. Another form of acromegaly is associated with excess growth hormone causing LPL activity, increased plasma non-esterified fatty acids, and excess liver VLDL[72].

Hypothyroidism: It has been found that lipoprotein metabolism, LPL function, and cholesterol activity are affected by thyroid hormones. LPL activity decreases, and hepatic VLDL secretion increases during hypothyroidism[73,74]. Hypothyroidism develops when the level of thyroid stimulating hormone > 10 mIU/L and is responsible for heart and blood-related infections and dyslipidemia, like an increase in total LDL, cholesterol, TG, and low HDL. However, the meta-analysis did not reflect considerable differentiation among VLDL, apo A-I, or apo B levels[75]. Thyromimetic drugs (thyroid regulators) can increase energy disbursement and lipid-lowering by improving the lipid profile[76].

Androgen: As far as sex hormones are concerned, VLDL metabolism is not affected by testosterone[77,78]. On the other hand, a deficiency of androgen results in the rise of VLDL levels[79]. It has been found that patients undergoing testosterone treatment along with androgen deprivation showed partial impact over VLDL levels. However, an increase in VLDL/TG was observed after testosterone treatment in transgenic men, possibly due to the estrogen combination[80-82].

Polycystic ovary syndrome: Enhanced VLDL concentration is typical in patients with polycystic ovary syndrome and may resolve after successful treatment of polycystic ovary syndrome (polycystic ovary syndrome). It reflects no impact on remaining lipid profiles[83,84].

Estrogen/progesterone therapy: VLDL metabolism is affected through hormone replacement therapy, and it is still disputed. Several findings have shown that due to estrogen supplementation, the VLDL and body fat mass have increased[85], and similar results were obtained with progesterone remedy[86]. For adult females of childbearing age, an increased risk of heart-related issues has been observed with increased estrogen in addition to oral contraceptives alone[87]. Increased VLDL concentration in hormone replacement therapy has also been noted and is found to be related to high cardiac hazard (Figure 4)[88].

Figure 4 Effect of estrogen and progesterone therapy on very low-density lipoprotein metabolism. VLDL: Very low-density lipoprotein; LPL: Lipoprotein lipase.

VLDL concentration is elevated in pregnant women due to decreased LPL and high lipase activity[89,90]. Hormone-sensitive lipase in adipose tissue also promotes VLDL production during pregnancy[91]. Mother and placenta get energy from fatty acids and cholesterol through VLDL[92]. VLDL levels also increase in pregnant women with gestational diabetes and preeclampsia due to increased insulin resistance[91,93].

Prolactinoma: Elevated LDL may cause Prolactinomas, though the impact of prolactin on VLDL/TG is still unclear[94-97]. The usual prolactinoma treatment is dopamine agonist therapy, which improves insulin sensitivity, lowers LDL cholesterol and improves body mass index[75]. Various animal studies have shown that the circadian rhythm affects lipid metabolism, suggesting the underlying mechanism is changes in the gut microbiota[98-100].

Experimental studies collectively indicate that hormonal regulation of VLDL-TG metabolism converges on a limited set of shared mechanistic nodes rather than hormone-specific pathways. A central mechanism is the control of adipose tissue lipolysis and hepatic free fatty acid flux, whereby glucocorticoids, catecholamines, and insulin resistance enhance free fatty acid release, providing substrate for hepatic TG synthesis and VLDL overproduction. At the hepatic level, hormones modulate intracellular signaling pathways (e.g., PLC-IP3-PKC, glycogen synthase kinase-3, and insulin-protein kinase B signaling) that regulate lipogenesis, apo B stability, and VLDL assembly. Concurrently, impaired insulin signaling and glucose transporters type 4 translocation in peripheral tissues reduces glucose uptake, indirectly diverting excess carbon toward TG synthesis and visceral fat accumulation. Hormonal effects also converge on lipoprotein clearance mechanisms, particularly through regulation of LPL activity and VLDL-to-LDL conversion, shaping circulating lipid profiles. Collectively, experimental evidence supports a model in which endocrine disturbances drive dyslipidemia by synchronously increasing lipid substrate availability, enhancing hepatic VLDL secretion, and impairing peripheral lipid utilization, thereby linking hormonal imbalance to cardiometabolic risk.

Cardiovascular disorders

The effects of VLDL on cardiovascular infection are reflected through the connection between atherosclerosis and coronary events[101], as it is directly linked with carotid intima-media thickness and arterial stiffness[102]. Current research reflected that plasma VLDL concentration is positively associated with the severity of symptoms in peripheral arterial occlusive infection[103,104]. The addition of TG-rich lipoproteins results in the rupturing of atherosclerotic plaque. A massive study from China reflects a connection between increased VLDL concentrations and heart disease[105]. VLDL concentration is also associated with enhanced mortality among patients with coronary heart disease[106]. Increasing VLDL levels enhance blood viscosity, increasing microvascular events in type 2 diabetes[107]. Other potential mechanisms include proatherogenic effects and hypercoagulable states that promote thromboembolism[108,109].

The apo compounds influence the atherogenic effects of VLDL. It has become evident through the clinical analysis that cardiovascular risk relates to the increased apo B and decreased apo C-III in VLDL[110]. The main component of atherosclerosis development is apo B. In addition, apo C-III loss-of-function mutations are associated with a reduced risk of cardiovascular disease[111]. However, the effect of apo C-III on VLDL is problematic because it inhibits the interaction of VLDL with its receptor. Moreover, apo B, apo C, and apo E can act as ligands for receptors on macrophages to promote cell swelling and inflammatory processes, thereby triggering atherosclerosis[112-114].

Neurological disorders

The expression of VLDLR is very high in the peripheral nervous system, cerebral cortex, cerebellum, and cerebral cortex. Clinical studies have shown that VLDLR is implicated in Alzheimer’s disease[115-117]. Moreover, the senile plaques of the brain have been the prime site for VLDLR detection[118]. Recent studies have shown that VLDLR can interact with various ligands and molecules associated with Alzheimer’s disease, such as reelin and clusterin. While reelin depletion is considered an early event in Alzheimer’s disease[119,120], clusterin promotes the removal of amyloid-β[121,122]. At present, VLDLR, but not VLDL, is thought to influence the commencement and development of Alzheimer’s disease.

There is some confirmation that VLDL plays a role in mental illness. The data show the association between insulin resistance, increased VLDL concentration[123], and enhanced medium and large VLDL concentrations in patients with schizophrenia[124,125]. In addition, the risk of suicide and cognitive impairment is also connected with the increased TG/VLDL ratio[126,127]. A decrease in VLDL and apo B levels was observed with the increase of fatty acids during autism spectrum disorders[128]. Insufficient sleep can affect VLDL metabolism. Poor daytime activity due to poor sleep, use of sleeping pills, and poor sleep have been associated with increased VLDL levels in clinical studies[129]. This study can link cardiovascular risk and poor sleep[130].

Kidney diseases

The patients having chronic kidney disease with dyslipidemia were generally affected with hypertriglyceridemia[131], mainly due to impaired VLDL clearance[132]. During chronic kidney disease, the hydrolysis of VLDL gets impaired, and HDL levels decrease. Increased concentration of VLDL results in oxidative stress in chronic kidney disease[133]. In addition, plasma apo C-III in the chronic kidney disease group was higher than in the average population, resulting in increased insulin resistance and hyperglycemia[134]. Decreased concentration of VLDL is responsible for nephrotic syndrome. An animal study showed that the mechanism was the inhibition of VLDLR[135], inhibiting LPL activity due to increased levels of angiopoietin-like protein 4[136,137]. Moreover, VLDL can be absorbed by mesangial cells and exert cytotoxicity, leading to the development of nephrotic syndrome.

Inflammation, autoimmune disorders and miscellanies

In general, MetS is regarded as a chronic disease condition, and VLDL affects the microinflammation of endothelial cells, activation of monocytes in extrahepatic tissue, and cytokines expression[138,139].

During MetS and insulin resistance, ceramide expression in blood plasma is enhanced[140,141], and excessive consumption of VLDL lipolysis products increases the activity of macrophages[142-144]. Upregulation of intracellular ceramides occurs in macrophages and shows a proinflammatory response after incubation with VLDL[57]. On the other hand, the VLDL concentration can be enhanced by specific cytokines like interleukin (IL)-1, IL-2, and IL-6[145]. It has been noticed that when these ILs encounter lipopolysaccharides, the VLDL concentrations are enhanced within 2 hours and remain constant for 24 hours[146].

In several autoimmune diseases, the VLDL concentration is increased. Similar results were also obtained with the patients suffering from systemic lupus erythematosus[147,148]. Moreover, females suffering from systemic lupus erythematosus were more prone to cardiovascular disorders related to dyslipidemia and irregular VLDL expression[149]. By regulating the action of apo C-III, there is a reduction in VLDL clearance and VLDL concentration enhanced among patients suffering from antiphospholipid syndrome[150]. It has been noticed that VLDL concentration among MetS patients is positively linked with rheumatoid arthritis[151]. Steroids are found to be the most potent therapeutic agent for individuals having autoimmune diseases, and they also enhance the plasma VLDL concentration[152]. Because VLDL can cause inflammation, monitoring lipids, including VLDL concentrations, is essential during disease management among autoimmune infections. VLDL was also found to affect skin infections. Due to the oxidative stress in melanocytes, the issue related to hyper-pigmentation occurs and is called vitiligo, usually at increased TG concentration[153]. MetS is found to be a poor interpreter of psoriasis. Moreover, it has been noticed that enhanced VLDL concentration was found among psoriasis individuals along with MetS in comparison to psoriasis individuals without MetS[154].

Association of VLDL in cancers

The development and progression of several malignancies are frequently accompanied by dyslipidemia[155]. Similar to normal cells, lipid-regulated cellular and intracellular signaling in tumor cells can modulate membrane fluidity and lipid raft organization, thereby influencing lipid-derived signaling mediators. These lipid-driven alterations play critical roles in cancer biology, including tumor cell invasion, metastasis, and immune evasion[156,157]. Recent studies have identified CD36, a well-characterized fatty acid translocase, as a key regulator of cancer metastatic potential, with emerging evidence linking CD36 activity to hepatic VLDL secretion[158]. Notably, upregulation of CD36 has been correlated with increased metastatic aggressiveness, particularly in epithelial carcinomas, and is concomitant with enhanced VLDL release[159].

Table 3 summarizes how strong the experimental evidence is for VLDL/VLDLR involvement across different cancers: Hepatocellular carcinoma (HCC): Direct functional experiments show that knocking down VLDLR in hepatoma cells reduces proliferation, clearly demonstrating that VLDLR actively supports tumor cell growth rather than being a passive marker. Clear-cell renal cell carcinoma: SiRNA studies reveal that VLDLR is required for abnormal lipid uptake in RCC cells, linking VLDLR to the lipid-rich phenotype characteristic of this cancer subtype. Breast cancer: Both receptor-level manipulation (VLDLR knockdown/overexpression) and VLDL exposure in animal models show enhanced invasion and metastasis, indicating that VLDLR-mediated lipid uptake and circulating VLDL directly promote tumor aggressiveness. Gastrointestinal cancers: Changes in VLDLR subtype expression are observed in tumor cell lines and tissues, suggesting a role in tumor differentiation; however, functional knockdown or in vivo validation is still limited. Colorectal cancer: Most evidence is correlative, with altered VLDLR expression associated with tumor features, but direct mechanistic and causal studies are still emerging.

Table 3 Cancer types where experimental evidence directly implicates very low-density lipoprotein/very low-density lipoprotein receptor in experimental models.

Cancer type	Model evidence	Mechanistic insight
HCC	shRNA knockdown reduces proliferation in hepatoma cells	VLDLR supports tumor cell growth
ccRCC	siRNA knockdown reduces lipid uptake in RCC cells	VLDLR mediates pathological lipid uptake
Breast cancer	VLDLR manipulation alters cancer cell behavior; VLDL increases metastasis in vivo	VLDLR/VLDL enhance tumor aggressiveness
Gastrointestinal cancer	Altered VLDLR subtype expression in tumor cell lines/tissues	Suggests involvement in differentiation but not fully functional yet
Colorectal cancer	Altered expression correlates with tumor features	Functional causality still emerging

HCC: Hepatocellular carcinoma; ccRCC: Clear-cell renal cell carcinoma; VLDLR: Very low-density lipoprotein receptor; VLDL: Very low-density lipoprotein.

Breast cancer: The most critical research analysis in breast cancer has paid attention to the effects of VLDL, which has been shown to encourage cancer growth and development by facilitating cell migration, invasion, and angiogenesis. MDA-MB-231 cells, which cause breast cancer in a mouse model, are first loaded with LDL (L1 and L5) and VLDL sub-fractions and then enter the animals’ muscles. The outcomes reflected that incubation of lung tumor cells with VLDL, L5, or L1 support invasion, but VLDL incubation alone was addictive and resulted in more lung metastases. Based on these observations, we can conclude that VLDL encourages lung metastasis under in vivo conditions[160]. Ingestion of VLDL takes up lipids and provides stable energy to cancer cells[161]. Comparison of the impacts of various lipoproteins on human epidermal growth factor receptor 2 and excessive expression of breast tumor cells reflected that VLDL induces tumor cell development and morphological modification and encourages cell viability[162].

HCC: The prime risk factor for HCC is lipid deposition because of the MAFLD and/or genetic predisposition[163]. Like breast tumors, VLDL is associated to influenced the growth and development of HCC. Current animal experimentation has shown that mutations in the transmembrane 6 superfamily member 2 (TM6SF2) genes are responsible for fibrosis and support carcinogenesis in MAFLD. TM6SF2 is contained to the endoplasmic reticulum membrane and is necessary for the lipidation of apo B at the duration of VLDL synthesis. Damage to TM6SF2 leads to reduced VLDL secretion, leading to hepatic steatosis (MAFLD) and severe liver fibrosis[164,165]. In HCC cells, hypoxia-inducible factor-1 (HIF-1) is upregulated, which increases VLDLR expression and cellular uptake of VLDL. Such mechanisms enhance the chances of cancer development[166].

Table 4 summarizes that in breast cancer; experimental models show that circulating VLDL mainly serves as an external lipid fuel. Breast cancer cells take up VLDL-derived fatty acids through CD36 and VLDLR, which supports energy production, membrane synthesis, and redox balance. This lipid supply directly enhances cell migration, invasion, cancer stem-like properties, and metastatic spread, as demonstrated in cell culture studies and mouse metastasis models. Hypoxia plays only an indirect role, mainly by increasing metabolic stress and lipid dependence rather than directly regulating VLDLRs. In HCC, VLDL functions primarily as an external lipid source that supports tumor cell survival and proliferation. A key mechanistic difference is the direct involvement of hypoxia: Stabilization of HIF-1α under low-oxygen conditions transcriptionally upregulates VLDLR, leading to increased VLDL uptake. This enhanced lipid acquisition promotes cell growth and resistance to apoptosis, as shown in HCC cell culture and hypoxia-based experimental models. Overall, while both cancers exploit VLDL to meet metabolic demands, breast cancer uses VLDL mainly to drive aggressiveness and metastasis, whereas HCC uses hypoxia-induced VLDLR expression to sustain proliferation and survival.

Table 4 Mechanistic links demonstrated in vitro and in vivo for breast cancer and hepatocellular carcinoma.

Feature	Breast cancer	Hepatocellular carcinoma
Primary role of VLDL	External lipid fuel for growth and metastasis	External lipid source supporting survival
Key receptors	CD36, VLDLR	VLDLR
Hypoxia involvement	Indirect (metabolic stress adaptation)	Direct via HIF-1α to VLDLR
Demonstrated outcomes	Increased metastasis, invasion, stemness	Increased proliferation, survival
Experimental proof	Cell culture + mouse metastasis models	Cell culture + hypoxia models

VLDL: Very low-density lipoprotein; VLDLR: Very low-density lipoprotein receptor; HIF: Hypoxia-inducible factor.

Other cancers: The concentration of VLDL increased among cancer patients in comparison to non-cancer patients[167]. On the other hand, the most predictive factor for cancer patients is the HDL level[168]. Yet the exact function of VLDL during lung cancer is still not clear. Two studies conducted in India have shown an association between blood VLDL concentration and leukoplakia, a predecessor to oral cancer[169,170]. The key risk factors include smoking, drinking alcohol, and eating nuts may result in oral cancer. These factors lead to the production of free radicals and further cause harm to cell membranes. Reduced VLDL concentration is thought to result from increased oxidative stress and cell membrane repair. Blood VLDL concentrations have also been shown to be the benchmark of oral cancer and early lesions. While research on VLDL and other cancers is scarce, several studies have shown an association between high TG concentration and cancer risk for ovarian cancer, pancreatic cancer, small cell lung cancer, and breast cancer. However, the fundamental mechanisms are still not precise.

Table 5 summarizes that breast cancer and HCC represent the strongest cases for a causal role of VLDL/VLDLR in cancer biology. In breast cancer, both in vitro and in vivo functional studies demonstrate that VLDL uptake and its receptors directly drive tumor growth, invasion, stemness, and metastasis, establishing a mechanistic link. Similarly, in HCC, cell culture and hypoxia-based mechanistic studies show that HIF-1α-mediated upregulation of VLDLR enhances VLDL uptake, promoting tumor cell proliferation and survival, again supporting direct causality. In contrast, evidence in oral/head and neck squamous cell carcinoma is largely associative, relying mainly on correlations between tumor VLDLR expression or circulating lipid levels and disease features, without functional validation. Ovarian cancer shows a similar pattern, where clinical correlations and expression analyses suggest a possible role for VLDL/VLDLR, but direct experimental manipulation is limited, resulting in only weak to moderate causal support. Finally, in pancreatic cancer, the proposed involvement of VLDL/VLDLR is largely speculative, inferred from general lipid metabolic dependencies rather than direct experimental evidence.

Table 5 Mechanistic hypothesis in other cancers.

Cancer type	Evidence type	Strength of causality
Breast cancer	In vitro + in vivo functional studies	Strong (mechanistic)
Hepatocellular carcinoma	In vitro + hypoxia-driven mechanistic studies	Strong (mechanistic)
Oral/HNSCC	Expression + serum lipid correlations	Weak (associative)
Ovarian cancer	Clinical correlations + expression data	Weak-moderate (associative)
Pancreatic cancer	Indirect metabolic inference	Speculative (hypothesis)

HNSCC: Head and neck squamous cell carcinoma.

Overall, the table highlights a clear evidence hierarchy, distinguishing cancers with demonstrated mechanistic involvement of VLDL/VLDLR from those where roles remain correlative or hypothetical and require rigorous functional validation.

MECHANISTIC INSIGHTS INTO THE BIOLOGICAL EFFECTS OF VLDL IN EXPERIMENTAL MODELS

Experimental studies using in vitro cell systems, animal models, and translational approaches have revealed that VLDL exerts its effects through multiple, interconnected molecular and cellular mechanisms that extend well beyond its classical role as a lipid transport particle. These effects are mediated through lipolytic products, receptor-dependent signaling, intracellular lipid accumulation, inflammatory activation, oxidative stress, and endocrine modulation.

Lipolysis-dependent cytotoxicity and lipotoxic stress

One of the most consistently demonstrated mechanisms of VLDL action in experimental models is lipolysis-driven cytotoxicity. VLDL particles are hydrolyzed by LPL at the endothelial surface, releasing free fatty acids, monoacylglycerols, and remnant particles. In vitro models of cardiomyocytes, endothelial cells, hepatocytes, and pancreatic β-cells, excess free fatty acids derived from VLDL lipolysis induce lipotoxic stress, characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis[57].

Animal studies of insulin resistance and MetS demonstrate that chronic exposure to VLDL-derived free fatty acids promotes intracellular lipid droplet accumulation, activation of stress kinases (e.g., c-Jun N-terminal kinase, p38 mitogen-activated protein kinase), and impaired cellular metabolism. These effects are particularly evident in cardiac tissue, where VLDL lipolysis products contribute to cardiomyocyte hypertrophy, reduced contractility, and atrial structural remodeling, thereby linking VLDL to atrial myopathy and arrhythmogenic substrates.

Receptor-mediated signaling pathways

Beyond lipid delivery, VLDL interacts directly with cell-surface receptors, triggering intracellular signaling cascades. Experimental models have identified several key receptors involved in VLDL-mediated effects, including: (1) VLDLR; (2) LDL receptor; (3) LDL receptor-related protein 1; and (4) Scavenger receptors.

Binding of VLDL or its remnants to these receptors activates signaling pathways independent of lipid uptake. For instance, VLDLR-mediated signaling has been shown to regulate cellular calcium flux, cytoskeletal remodeling, and metabolic gene expression. In endothelial and smooth muscle cells, receptor engagement by VLDL promotes pro-inflammatory gene transcription via nuclear factor kappaB activation and enhances vascular dysfunction[65].

Induction of oxidative stress and endothelial dysfunction

Multiple experimental studies demonstrate that VLDL increases reactive oxygen species (ROS) production in endothelial cells. VLDL exposure impairs nitric oxide bioavailability by uncoupling endothelial nitric oxide synthase, leading to reduced vasodilation and increased vascular tone. This oxidative stress-nitric oxide imbalance contributes to endothelial dysfunction, a key early event in atherosclerosis[92].

Animal models of hypertriglyceridemia further show that elevated VLDL promotes vascular inflammation, increased adhesion molecule expression (vascular cell adhesion molecule 1, intercellular adhesion molecule 1), and monocyte recruitment, thereby accelerating plaque development independently of LDL cholesterol levels.

Pro-inflammatory and immune-modulatory effects

VLDL has been shown in macrophage and immune cell models to exert direct immunomodulatory effects. VLDL and its remnants activate toll-like receptor-associated pathways and inflammasome components, leading to increased secretion of pro-inflammatory cytokines such as tumor necrosis factor-α, IL-6, and IL-1β. These responses are amplified under conditions of insulin resistance and chronic nutrient excess[57].

In autoimmune and inflammatory disease models, altered VLDL composition (e.g., enriched in saturated fatty acids or apo C-III) enhances macrophage foam cell formation and skews immune responses toward a pro-inflammatory phenotype. Apo C-III-rich VLDL, in particular, has been shown to inhibit lipoprotein clearance and directly activate inflammatory signaling pathways.

Endocrine and hormonal regulation

Experimental evidence indicates that VLDL plays a role in endocrine signaling, particularly within the adrenal gland. VLDL exposure stimulates phospholipase D activity, leading to increased intracellular calcium concentrations and enhanced aldosterone synthesis. This mechanism provides a link between dyslipidemia and hypertension, as excess aldosterone promotes sodium retention, vascular remodeling, and cardiac fibrosis[61]. Additionally, VLDL-induced hormonal alterations may exacerbate insulin resistance, creating a feed-forward loop that further increases hepatic VLDL production.

Neurological and extrahepatic effects

Emerging experimental models suggest that VLDL may influence neurological function indirectly through vascular and inflammatory mechanisms. In animal models, elevated VLDL is associated with blood-brain barrier dysfunction, neuroinflammation, and impaired cerebral perfusion, which may contribute to cognitive decline. Altered sleep patterns observed in metabolic disease models have also been linked to dysregulated VLDL metabolism, possibly through hypothalamic inflammation and hormonal imbalance[115].

FUTURE RESEARCH DIRECTIONS AND THERAPEUTIC TARGETING OF VLDL BASED ON MECHANISTIC INSIGHTS

Dissecting cell-specific VLDL signaling mechanisms

Although VLDL has traditionally been viewed as a lipid transport particle, emerging evidence suggests that VLDL exerts direct, cell-specific signaling effects independent of its role in TG delivery[65]. Future studies should: Elucidate VLDL-induced intracellular signaling cascades (e.g., mitogen-activated protein kinase, nuclear factor kappaB, phosphoinositide 3 kinase-protein kinase B) in hepatocytes, endothelial cells, cardiomyocytes, adipocytes, immune cells, and atrial myocytes. Distinguish signaling effects mediated by VLDL particles per se vs those mediated through VLDLR, LDLR, and LDL receptor-related protein 1. Define how lipid composition (TG-rich vs cholesterol-enriched VLDL) alters receptor engagement and downstream signaling. Therapeutic implication is that targeting VLDL-triggered signaling pathways may prevent inflammation, fibrosis, or electrical remodeling without necessarily lowering circulating lipid levels.

Structural heterogeneity of VLDL as a determinant of pathogenicity

VLDL particles are highly heterogeneous in size, density, apo content, and lipid composition. Key research priorities include: Characterization of pathogenic VLDL subfractions using lipidomic, proteomics, and cryo-electron microscopy. Understanding how apo C-III, apo E isoforms, and oxidized lipids influence VLDL clearance, receptor binding, and pro-inflammatory activity. Investigating disease-specific VLDL signatures in MAFLD, atrial fibrillation, neurodegeneration, cancer, and autoimmune disorders[23]. Therapeutic implication is that precision therapies targeting specific VLDL subclasses rather than total VLDL may yield better efficacy with fewer metabolic side effects.

VLDL-VLDLR axis as a therapeutic target

The VLDLR is increasingly recognized as a mediator of tissue lipid uptake and pathological remodeling, particularly in the heart, skeletal muscle, adipose tissue, and brain[166]. Future research should: Define context-dependent roles of VLDLR under physiological vs disease states. Explore how VLDLR overexpression or aberrant activation contributes to lipotoxicity, atrial myopathy, insulin resistance, and neuroinflammation. Investigate VLDLR crosstalk with reelin signaling, Wnt pathways, and inflammatory mediators. Therapeutic implication is that tissue-selective modulation of VLDLR (rather than systemic lipid lowering) could prevent local lipid overload and organ-specific pathology.

Linking hepatic VLDL overproduction to systemic disease

Excessive hepatic VLDL secretion is a hallmark of insulin resistance and MAFLD. However, the causal mechanisms linking hepatic VLDL output to extrahepatic disease remain poorly defined. Future directions include: Identifying how hepatic metabolic stress alters VLDL composition and bioactivity. Understanding endocrine-like actions of liver-derived VLDL on distant organs. Exploring transcriptional regulators (sterol regulatory element-binding protein-1c, carbohydrate-responsive element-binding protein, peroxisome proliferator-activated receptor-α) and post-translational mechanisms controlling VLDL assembly. Therapeutic implication is that modulating hepatic VLDL secretion or composition - rather than complete suppression - may reduce cardiometabolic risk while preserving physiological lipid transport.

Inflammation, immunometabolism, and VLDL

VLDL has been shown to interact with immune cells and promote low-grade chronic inflammation. Future research should: Clarify how VLDL influences macrophage polarization, T-cell activation, and inflammasome signaling. Examine the role of modified VLDL in autoimmune and inflammatory diseases. Investigate interactions between VLDL, gut microbiota, and endotoxemia. Therapeutic implication is that anti-inflammatory strategies targeting VLDL-immune cell interactions could complement lipid-lowering therapies.

Translational and therapeutic strategies targeting VLDL

Mechanistic insights support multiple therapeutic avenues: Apo C-III inhibitors (antisense oligonucleotides, siRNA) to enhance VLDL clearance. Angiopoietin-like 3/4 inhibition to improve LPL activity and reduce VLDL-TG. Small molecules or biologics targeting VLDL-receptor interactions or downstream signaling. Lifestyle and nutraceutical interventions that specifically alter VLDL composition and secretion. Future clinical trials should incorporate VLDL-specific biomarkers, tissue imaging, and functional endpoints rather than relying solely on plasma TG levels.

Systems biology and precision medicine approaches

Integrative approaches combining lipidomic, transcriptomics, metabolomics, and machine learning will be essential to: Identify individuals with VLDL-driven disease phenotypes. Predict therapeutic responsiveness to VLDL-targeted interventions. Develop personalized treatment strategies across metabolic, cardiovascular, and inflammatory disorders.

CONCLUSION

The liver is the primary site of VLDL synthesis and secretion, and dysregulated VLDL metabolism has been implicated in a wide spectrum of diseases, including atherosclerosis, MAFLD, cognitive impairment, MetS, autoimmune disorders, breast cancer, and head and neck cancers. Emerging evidence suggests that elevated VLDL levels may contribute to atrial myopathy during the preclinical stage of atrial fibrillation. Moreover, VLDL has been reported to exert cytotoxic effects on cardiomyocytes under MetS-associated conditions, although the precise molecular mechanisms underlying these effects remain unclear.

Endocrine disturbances significantly influence circulating VLDL concentrations, and experimental studies indicate that VLDL is associated with the stimulation of aldosterone synthesis, thereby linking lipoprotein metabolism with hormonal regulation. Despite increasing associations between VLDL and diverse pathological states - including extrahepatic VLDL secretion, neurological disorders, sleep disturbances, and various malignancies - the causal and pathogenic roles of VLDL remain incompletely defined.

Nonetheless, accumulating experimental and clinical evidence supports a predominantly deleterious role of elevated VLDL levels in multisystem disorders. Advancing our understanding of VLDL biology will require a shift in focus from simple associations with circulating levels toward a deeper investigation of VLDL regulation, assembly, secretion, and metabolism. Such mechanistic insights are expected to facilitate the identification and development of VLDL-targeted therapeutic strategies for metabolic, cardiovascular, and systemic diseases. Future research will ultimately lead to discovering and implementing potential VLDL-targeted solutions.

ACKNOWLEDGEMENTS

The authors are grateful to Dr. Shoor Vir Singh, Department of Biotechnology at GLA University (Mathura) for help and support during the present study.