Two Sides of Triglycerides in Atherogenesis: An Essential Contributor

Abstract

Atherosclerosis is chronic arterial wall damage, which often results in cardiovascular disease development. Since atherosclerosis is almost asymptomatic, it is difficult to detect this condition, but it is even more difficult to deal with the consequences. The reasons for the development of atherosclerosis are still not completely clear, but the mechanisms involved in atherogenesis are known. Among them, lipid metabolism alterations, oxidative stress, as well as impaired mitochondrial function take pride of place. In our review, we want to dwell in more detail on such a component as lipid metabolism disorders. In particular, triglycerides, their levels, and influence on the development of the disease. Triglycerides provide the second-largest source of energy. In the context of atherosclerosis, the question arises, is an increase in the level of triglycerides in the blood a cause, a biomarker, or a consequence of the processes accompanying atherogenesis?

Atherogenesis

Usually, atherosclerosis is an excessive fibrous-fatty, proliferative, and inflammatory reaction to artery wall damage. This reaction involves several types of cells, such as monocyte-derived macrophages, smooth muscle cells, dendritic cells, lymphocytes, and platelets. A characteristic feature of atherosclerosis is the deposition of intracellular cholesterol within the arterial wall, as well as the formation of foam cells. ¹

Circulating lipoproteins, low-density lipoproteins (LDL), very low-density lipoprotein remnants (VLDL remnants), and lipoprotein (a) are sources of lipids that can be stored in the artery wall. When entering the subendothelial intima, lipoproteins induce the storage of lipids in cells as an initial and essential step in the atherosclerosis lesions formation. ² Nevertheless, LDL must first undergo modification, which makes it atherogenic (due to its capability to induce intracellular deposition of lipids). For this process, the interaction between lipoproteins and components of the connective tissue matrix of the intima is necessary. This results in a retention of lipoproteins in the intima of the arteries, which elevates the likelihood of further interaction with intima cells to undergo complex cellular reactions, for example, the binding and internalization of modified lipoproteins and abnormal intracellular processing, culminating in the foam cells formation. ³

At the same time, intima cells also demonstrate a proliferative burst, increased synthesis of proteins and components of the connective tissue matrix, a pro-inflammatory reaction with the synthesis and secretion of cytokines, and the presentation of bound lipoproteins as autoantigens. Therefore, all the main signs of early atherosclerosis (lipidosis, fibrosis, proliferation, and inflammation) occur at the cellular level at this stage of atherogenesis. With a relatively positive resolution of the cellular response to pathogenic lipoproteins, early lesions can both undergo spontaneous regression and turn into stable atherosclerotic plaques. ¹

This result should be considered a compensatory remodeling of the arteries. However, the negative outcome is featured by a chronic inflammatory reaction, the involvement of immunocompetent cells from the circulation, and a vicious circle of lipid storage in the artery wall. This negative result can result in the growth of atherosclerotic plaque, the development of new lesions, and instability of the plaque, which, in turn, will result in a clinical event.^4,5

Obviously, this scheme is quite simple and reductive. This does not consider such factors as the efficiency of reverse cholesterol transport, the role of high-density lipoproteins (HDL), the immunogenicity of modified LDL, the formation of atherogenic immune complexes containing LDL, thrombotic events, and other undoubtedly important for atherogenesis. ⁶ Nevertheless, this scheme allows us to highlight unresolved problems with our understanding and knowledge of the molecular and cellular mechanisms of atherogenesis and to identify those areas that require in-depth research.

Intensive reduction of lipid levels is the only existing strategy for atherosclerosis prevention and treatment. This concept is based on the role of circulating lipoproteins in the initiation of atherogenesis. According to this concept, circulating lipoproteins are a source of cholesterol and a major player of atherosclerosis development. All modern medical approaches are based on an elevation of the lipid profile of blood plasma (lowering LDL cholesterol and triglycerides and increasing HDL cholesterol) and are focused on removing the main lipid risk factors for atherosclerosis.^7,8 HDL cholesterol is considered a good cholesterol. These particles have antioxidant and anti-inflammatory properties and, moreover, they participate in endothelial cells homeostasis maintaining. Also, HDL promote reverse cholesterol transport and delivers cholesterol from the vasculature to the liver. HDL can be useful in prediction. Of atherosclerosis and cardiovascular events. Thus, level below 40 mg/dL for men and 50 mg/dL for women is considered at risk. Levels above 60 mg/dL were associated with lower risk. However, the levels above 100 mg/dL appeared to be linked with the higher risk of heart diseases.^9,10

The development of other approaches to anti-atherosclerotic therapy by influencing other major pathogenetic mechanisms is incredibly difficult since there is no fundamental knowledge about possible molecular and cellular targets for therapy and prevention. ¹¹

Among the currently investigated targets, we can name an endothelial dysfunction and local violation of the endothelial barrier permeability, atherogenic modification of lipoproteins, retention of lipoproteins in the subendothelial intima of the arteries, alternative ways of lipoprotein absorption by intima cells, fibrous and proliferative reactions of intima cells to modified lipoproteins, specificity of the reaction of various cells inhabiting the intima layer (smooth muscle cells, pericyte-like cells, macrophages, lymphocytes, other cells, migrated from the circulation), the development of a local inflammatory reaction, ineffective resolution of local inflammation, local innate immune response, mitochondrial dysfunction, mechanisms of atherosclerotic plaque stabilization and remodeling, and so on. ¹²

The review focuses on the role of triglycerides in atherosclerosis, exploring whether they act as contributors to the disease or are influenced by the disease itself. The review aims to delve into lipid metabolism disorders, specifically examining triglycerides, their levels, and their impact on atherosclerosis development.

Triglycerides

One of the main functions of triglycerides is the excess energy storing. Triglyceride (TG) and cholesteryl esters (CE) are hydrophobic, which corresponds to the form in which they circulate in the blood. This structure consists of the core of spherical lipoproteins, monolayer phospholipids, free cholesterol cover, and stabilizing apolipoproteins. ¹³ The main structural apolipoprotein is Apolipoprotein (apo)B, presented in2isoforms, liver-originated apoB100 and truncated intestine-originated apoB48. The presence of apoB of one of these isoforms defines the type of triglyceride-rich lipoprotein (TRL). Thus, VLDL is formed in the liver and contains the liver-originated form apoB100. ¹⁴ These particles are metabolized to VLDL remnants, intermediate-density lipoproteins (IDL), and LDL. In turn, chylomicrons are assembled in the intestine and contain apoB48. Chylomicrons are also metabolized to remnant particles, but not to IDL and LDL.^13,14

Lipoprotein lipase (LPL) plays a pivotal role in the metabolism of triglyceride-rich lipoproteins (TRLs). It forms a complex with glycosylphosphatidylinositol high-density lipoprotein protein 1 (GPIHBP1), an entity synthesized by endothelial capillary cells. This intricate binding process secures LPL to the endothelial cell surface, initiating lipolysis. During the hydrolysis of TGs by LPL, chylomicron (CM) and VLDL particles are broken down, giving rise to remnants. Simultaneously, these remnants become enriched with cholesterol esters due to the actions of cholesteryl ester transfer protein (CETP). ¹⁵

In addition, microsomal triglyceride transfer protein (MTP) relocates from the cytosol to the endoplasmic reticulum, accompanying the nascent APOB as chylomicrons and VLDL are assembled within enterocytes and hepatocytes. Disrupting MTP function through inhibition results in decreased MTP expression, effectively halting its function. Consequently, this disruption leads to a reduction in the biosynthesis and subsequent plasma levels of both chylomicrons and VLDL. As a result, the plasma levels of LDL and TGs are also lowered. ¹⁶

Triglycerides (TG) and Triglyceride-rich lipoproteins (TRLs) are crucial components of lipid metabolism in the body. TGs serve as a primary form of energy storage, found in adipose tissue and circulating in the bloodstream as part of TRLs.

Throughout the process of TRL metabolism, TGs are packaged into lipoproteins such as chylomicrons and very low-density lipoproteins (VLDL) in the intestine and liver, respectively. These TRLs facilitate the transport of TGs to various tissues for energy utilization or storage. Once in circulation, TRLs undergo hydrolysis by lipoprotein lipase, releasing free fatty acids and glycerol for cellular uptake and energy production. Remnant particles are formed after this process, and they are cleared from the bloodstream by the liver. Disruptions in TG and TRL metabolism can lead to dyslipidemia, a risk factor for cardiovascular diseases. Understanding the intricacies of TG and TRL metabolism is essential for managing lipid disorders and mitigating associated health risks effectively. ¹⁷

Usually, hypertriglyceridaemia (HTG) is characterized by a serum TG level exceeding 150 mg/dL. This condition holds pathological significance and is notably associated with a heightened risk of pancreatitis, particularly when TG levels surpass 1000 mg/dL. Furthermore, HTG is correlated with insulin resistance and the accumulation of lipids within internal organs such as the liver, pancreas, and epicardium. ¹⁸

In HTG, small, dense LDL and smaller and denser HDL particles with a perturbed lipidome and proteome and altered vasculoprotective functions are formed predominantly. VLDL particles are assembled in the liver, while chylomicrons are assembled in the small intestine. Considering atherogenic properties, large TRL is not atherogenic, but cholesterol-rich remnants which are formed by the lipoprotein lipase-mediated lipolysis, exhibit atherogenic properties. ¹⁹

Numerous prospective longitudinal cohort studies have identified HTG as an independent risk factor for both coronary artery disease (CAD) and acute cardiovascular (CV) events. Notably, even a moderate elevation in triglyceride levels can be correlated with an escalated risk of CVD. Framingham Offspring studies have revealed a consistent rise in risk as triglyceride levels progress from 100 to 200 mg/dL. The role of HTG in driving atherosclerotic disease has gained validation through genome-wide association studies and Mendelian inheritance studies as well. ²⁰

Recent research has spotlighted the link between lipoprotein remnants and the risk of CAD. This correlation has been substantiated across various studies, including the Copenhagen Heart Study, the Jackson Heart Study, the Framingham Study, and the cohorts of the PREDIMED. ²¹

During secondary prevention in patients who are already on statin therapy, an increase in cardiovascular risk aligns with heightened TRL levels. This relationship has been underscored by multiple investigations, such as the MIRACL study and the dalcetrapib OUTCOMES trial. The Bezafibrate Prevention Project further illustrates that all-cause mortality rises in an almost exponential manner as serum triglyceride levels increase in patients with established CAD over a 22-year follow-up period. ²²

Atherogenic effects of triglyceride-rich lipoproteins and their mechanisms

A recent investigation revealed that lipoproteins in the blood circulation most often are transported through the arterial wall via transcytosis. In addition, the transcytotic transport system is limited to lipoproteins with a diameter of less than about 70 nm, which excludes CM and larger VLDL particles. ²³ Concurrently, their remnants possess the ability to infiltrate the subendothelial space. Diverging from LDL, TRL remnants boast greater cholesterol content per particle due to their larger size. Distinctively, these particles don’t necessitate modification or oxidation to become atherogenic; they can be directly absorbed by macrophages. As previously highlighted, TRL remnants tend to exert a more potent atherogenic influence when contrasted with LDL. ²⁴

In human and Watanabe heritable hyperlipidemic rabbits, lipoproteins containing apob48 and apoB100 stimulating the development of atherosclerosis were found in the aortic intima lesion. The presence of triglyceride-containing residual lipoproteins in human atherosclerotic plaque has also been demonstrated, which proves that TRLs are involved in the development and progression of atherosclerotic lesions. Moreover, it has been confirmed that increased levels of circulating triglycerides in a fasting-free state, a marker of residual particles rich in triglycerides (TG), are linked with an elevated risk of premature CVD. ²⁵

To date, the mechanism of TRLs atherogenicity has increased attention but remains insufficiently studied. Recent investigations have compellingly demonstrated that TRLs exhibit a tendency to linger on the arterial wall, inflicting harm on the endothelium. They can infiltrate the arterial intima through endothelial breaches, such as at atherosclerotic plaque sites, subsequently intensifying the attraction and adhesion of monocytes, ultimately triggering the formation of foam cells [a hallmark of atherosclerosis]. At the same time, TRLs are involved in the development and progression of atherosclerosis, contributing to inflammation and regulating various cytokines. ²⁶ We provided a scheme of atherogenic TRLs effects (see Figure1).

Figure 1.

Role of TRLs and remnants in atherogenesis. Chylomicron remnants, VLDL, and IDL particles enter the artery wall through transcytosis. These particles can adhere to proteoglycans of extracellular matrix via located on the surface (apo) CIII and apoE. Degradation of these particles releases bioactive lipids, contributing to endothelial dysfunction and inflammation. Monocytes and monocyte-derived macrophages are recruited from the circulation, internalize the arterial wall. Uptake of cholesterol-enriched lipoproteins by macrophages result in their transformation into foam cells.

TRLs and endothelial dysfunction

Endothelial dysfunction is a precursor to the formation of atherosclerotic lesions, marking one of the initial stages in the pathophysiology of atherosclerosis. A pivotal aspect of this cascade is the potential impact of TRL remnants on endothelial dysfunction, thereby exacerbating atherogenesis. Research has highlighted the connection between flow-mediated and acetylcholine-induced vasodilation and the endothelium’s release of NO, a sensitive indicator of endothelium-dependent vasodilation. ²⁷

Clinical investigations have substantiated the association between rapid postprandial serum triglyceride elevation, particularly after a high-fat meal, and endothelial dysfunction. This connection has been evaluated through assessments of flow-mediated vasodilation impairment. Additionally, evidence has emerged showcasing the disruptive effect of residual lipoproteins on endothelium-dependent vasomotor function within human coronary arteries. ²⁸

In 2016, Lucero et al. embarked on an analysis exploring the impact of isolated circulating TRLs on endothelial function in 40 patients with metabolic syndrome. Utilizing in vitro analysis, they established a compelling positive correlation between triglyceride content within TRLs and the extent of inhibition exerted by TRLs on acetylcholine-mediated vasorelaxation, as depicted through dose-response curves. ²⁹ During the same year, another study encompassing 4887 participants registered for FMD in Japan unfolded. The study aimed to unveil the interplay between serum triglyceride levels and endothelial function, gauged by assessing brachial artery flow-mediated vasodilation (FMD). ³⁰

Subsequently, it was ascertained that serum triglyceride levels surpassing 98.4 mg/dL exhibited an independent link with the lower quartile of FMD (less than 3.9%), even after accounting for variables like age, gender, and cardiovascular disease risk factors, including HDL-C. This underscores the hypothesis that triglycerides independently predict endothelial dysfunction. ³¹

Investigations on animal models have led to the same outcomes. In the Matsumoto et al. trial, a new dyslipidemic model was used, hereditary postprandial hypertriglyceridemic (PHT) rabbits, which showed very high serum TG levels after feeding standard rabbit chowder with a slight increase in serum cholesterol. Healthy Japanese white rabbits (JW rabbits) were used as a control group, and the study was dedicated to the relationship between increased TG levels after meals and endothelial dysfunction in the development of atherosclerosis. ³² It was shown that JW rabbits (12 months, 35 months) had no atherosclerotic lesion, however rabbits with hypertriglyceridemia (12-month-old PHT rabbits) had a very noticeable thickening of the intima in the aorta. The study demonstrated that the function of the endothelium in PHT rabbits was reduced because of acetylcholine-induced vascular relaxation, which is most likely due to an elevation in NO generation. The results of these studies have shown that hypertriglyceridemia can lead to endothelial dysfunction and can also be involved in the initiation and progression of atherosclerosis. ³³

Furthermore, investigations have revealed that remnants of TRLs hold the capacity to trigger the production of ROS. This, in turn, can escalate the permeability of the vascular endothelium, ultimately paving the way for heightened damage and cellular demise, particularly among endothelial cells. Comparable to lipoprotein particles, these remnants can disturb endothelial function by exerting both direct and indirect impacts on nitric oxide synthase. The delicate equilibrium between reactive oxygen species and NO can precipitate endothelial dysfunction, subsequently culminating in CV complications, with hypertriglyceridemia specifically implicated. ³⁴

Moreover, TRLs have been found to inhibit the athero-protective and anti-inflammatory effects inherent to HDL, resulting in a significant correlation with the disruption of endothelium-dependent coronary vasodilation. ³⁵

Hypertriglyceridemia’s role in atherosclerosis is substantiated by research. Managing plasma triglycerides emerges as a key strategy to mitigate residual CVD risk, aligning with guideline-recommended LDL cholesterol targets. Anticipated clinical trials will provide further insights. ³⁶

TRLs and foam cells

Activated macrophages, repositories for altered lipoproteins that evolve into lipid-laden foam cells, populate atherosclerotic lesions in substantial quantities. Under the strain of oxidative stress, triglycerides confined within macrophages are revealed to intensify mitochondrial generation of reactive oxygen species, consequently fueling the formation of foam cells.^{37 -39}

Furthermore, in patients with hypertriglyceridemia, LDL particles exhibit a heightened ApoE content. This alteration sets the stage for a transformation in the conformation of VLDL particles, facilitating their affinity for binding to macrophage scavenger receptors. The remnants of CM and IDL possess minute dimensions, allowing them to infiltrate the subendothelial space with ease. Here, they are readily assimilated by scavenger receptors residing on macrophages, effectively culminating in the formation of foam cells.^40,41

Additionally, the remnants of CM have demonstrated their capacity to incite the progression of atherosclerosis. By permeating into the subendothelial space, these remnants orchestrate the activation of leukocytes, thus fostering the emergence of foam cells. Moreover, they orchestrate the activation of monocytes, bolstering the influx of both monocytes and neutrophils post-meal. ⁴²

TRLs and inflammation

Some data sources consistently point out inflammation is a key risk factor for atherosclerosis initiation and progression. The accumulation of TRLs after eating resulted in the preservation of remnant particles in the arterial wall and provoked an inflammatory reaction, as well as oxidative stress. It was also found that cells are involved in inflammation in direct and indirect ways. ⁴³

It is believed that a high concentration of lipolytic products of LPL-mediated TRLs hydrolysis, such as oxidized free FA, along with TRLs themselves, activates a several pro-inflammatory and pro-apoptotic signaling pathways that are extremely important for atherosclerosis pathogenesis. Studies have shown that oxidized free FA induce inflammatory interleukins, causing endothelial inflammation. Remnants of TRLs increase endothelial ICAM-1 and VCAM-1 expression, promoting leukocyte migration to inflammation sites and enhancing the inflammatory response.^44,45

Bleda et al. found that elevated TG and VLDL-C levels trigger plaque rupture and arterial inflammation through mechanisms like the NLRP1 pathway. Activation of NLRP1 by TG and VLDL-C seems crucial for endothelial inflammation. ⁴⁶

In addition, TLRs can affect the level of HDL and its particle size. When higher TG levels are established, a greater exchange between TG lipoproteins containing apoB and CE HDL via CETP leads to the formation of HDL particles rich in TG and poor in CE, which can be catabolized faster than large and CE-rich HDL, and this process leads to a decrease in HDL-C levels. ⁴⁷ Another recent study also demonstrated that high postprandial triglyceridemia induced a shift in HDL size toward large particles and cholesterol depletion with enrichment of TG by HDL3 subclasses. ⁴⁸

Modification of HDL structure is closely tied to their antioxidant capability, a property susceptible to alteration through HDL remodeling. The prevailing perspective indicates that distinct subpopulations of HDL particles, formed by unique protein clusters, undertake specific biological roles. Notably, PON1, an atheroprotective protein, exhibits enhanced antioxidant, anti-inflammatory, and lipid transfer functions. It remains uncertain whether HDL particles abundant in TG and HDL particles lacking in CE possess differing PON1 content or experience changes in PON1 activity, contributing to atherosclerosis development. ⁴⁹

Nevertheless,1study demonstrated that the activity of PON1 did not decrease, but on the contrary, significantly increased at the postprandial stage.^{50 -52} Clearly, there is a pressing need for further research to assess the implications of these structural modifications (including other constituents or proteins like apo AI, myeloperoxidase, and acetylhydrolase of the platelet-activating factor) on additional anti-atherogenic functions of HDL, particularly in the context of stable postprandial lipemia. Understanding how the mechanism of TG enrichment in HDL subclasses 3 contributes to atherosclerosis development is equally paramount. HDL has been observed to transport apoB-bound S1P, a lipid mediator with anti-inflammatory attributes that supports the generation of inflammatory Th1 cells by impeding Treg cell differentiation. Consequently, elevated TG levels may reshape HDL concentration and size toward reduced large TG-rich HDL, which may hinder engagement in the anti-inflammatory process mediated by T-regulatory cells. Conversely, this transformation could potentially foster inflammation through pro-inflammatory T cells. ⁵³

Mild-moderate hypertriglyceridemia (TG levels: 200-800 mg/dL) is linked to low HDL cholesterol, sd-LDL particles, and TG-rich atherogenic remnants. sd-LDL arises from hepatic lipase modification of VLDL1, associated with cardiovascular risk in hypertriglyceridemia. ⁵⁴ The atherogenicity of sd-LDL is attributed to multiple factors. Their small size enables easy arterial wall penetration, prolonged subendothelial presence due to proteoglycan affinity, promoting lipid accumulation and atherosclerosis. ⁵⁵ sd-LDL’s lower antioxidant content, like vitamin E, renders them oxidation-prone. Other mechanisms include potential activation of plasminogen-activator-inhibitor 1 and accelerated thromboxane A2 synthesis. Furthermore, TRLs or remnants can trigger early monocyte and neutrophil activation, fostering inflammation. ⁵⁶

Atherosclerosis is influenced by several key cytokines, with apoptosis contributing to vascular damage. Remnants of triglyceride-rich lipoproteins (TRLs) trigger endothelial cell apoptosis by increasing pro-apoptotic cytokines, notably TNF-α and IL-1β. TNF-α significantly impacts endothelial dysfunction, fueling inflammation and affecting nitric oxide production. Elevated TNF-α levels correlate positively with VLDL-C, even in PTH rabbits. Recent research links heightened TNF-α to increased JAM-1 expression, fostering atherosclerosis. ⁵⁷

Adipocytes release adipocytokines like anti-atherogenic adiponectin and lipolytic leptin. Reduced adiponectin levels and mRNA in PTH rabbits suggest a link to atherogenesis. ⁵⁸

TRLs and remnants promote a procoagulant state, enhancing platelet aggregation and clot formation, elevating fibrinogen levels, factors VII and XII, and plasminogen activator inhibitor-1 expression. ⁵⁹

Triglycerides and residual risk

In modern cardiology, the focus is on identifying ASCVD risk even in individuals with low LDL-C levels. Unstable, inflamed plaques prone to rupture necessitate recognition of additional risk factors for vascular inflammation and plaque instability, irrespective of the estimated CVD risk.

The PESA study explored hypertriglyceridemia’s impact (TGs > 150 mg/dL) on non-coronary atherosclerosis and vascular inflammation. Participants, mainly young (average age ~45), with low-to-moderate 10-year risk, showed early atherosclerosis onset. Those with TGs < 100 mg/dL had subclinical atherosclerosis, and around 40% had more inflammation. TGs > 150 mg/dLsignificantly raised atherosclerosis risk and vascular territory involvement, irrespective of LDL cholesterol levels. Arterial inflammation and plaque count correlated with TG levels. High TGs doubled arterial inflammation risk, and elevated TSH levels correlated with systemic disease. ⁶⁰

This study underscores TG’s independent role in atherosclerosis and vascular inflammation, serving as significant risk indicators. ⁶¹ Despite the REDUCE-IT trial showing cardiovascular event reduction in HTG patients, its impact wasn’t solely due to TG reduction. The ongoing PROMINENT study may offer more insights into lowering TG levels for ASCVD risk. ⁶²

Targeting triglycerides for therapy of atherosclerosis

However, currently used drugs, such as mipomersen (an antisense oligonucleotide [ASO] inhibitor of apoB translation) and lomitapide (an inhibitor of microsomal triglyceride transport protein activity) can, apart from the beneficial effects, stimulate the non-alcoholic fatty liver disease. This makes this strategy imperfect and requires further research.^{63 -65}

Another strategy is to decrease the TG availability for VLDL assembly. The decrease in VLDL–TG and apoB secretion by 25–30% can be achieved via the use of high-dose omega-3 FA (3–4 g/day, usually the combination of docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]). However, the results of EPA use are controversial.^66,67

Reducing cholesteryl ester enrichment of remnants is also an approach. An essential step in remnant lipoprotein formation is a CE transfer from HDL to TRL, so the inhibition of CETP is potentially beneficial. A significant decrease in the cholesterol/TG ratio in VLDL was observed in studies with evacetrapib or anacetrapib. ⁶⁸ However, CETP inhibitors appeared to be ineffective in cardiovascular disease prevention. Today, studies on obicetrapib are on the way, and it demonstrates the therapeutic potential. ⁶⁹

One more way to reduce plasma TG in a range of patients is the stimulation of lipolysis. The standard choice is the use of fibrates that stimulate lipolysis through the increase in the activity of LpL and reduce the apoCIII synthesis, which, in turn, increases the efficiency of VLDL clearance. The effectiveness of stimulating lipolysis to decrease the concentration of remnants depends on the efficiency of hepatic uptake pathways. ApoCIII and ANGPTL3 are known to inhibit LpL, and targeting these 2elements can be beneficial, according to several studies.^{70 -73}

One more strategy to mention is the increasing of remnants clearance. Statin therapy can up-regulate the LDL receptor, which should trigger remnant catabolism and reduce remnant particles level. Moreover, statins stimulate chylomicron remnant clearance and lower lipemia following a fat-rich meal. ⁷⁴ PCSK9 inhibitors were also reported to enhance the activity of LDL receptors and the clearance rate of IDL in healthy subjects, but their effectiveness is less than with the use of statins. ⁷

PPARs, integral nuclear receptors, play a pivotal role in modulating genes related to lipid metabolism, inflammation, and vascular functions. By harnessing the diverse effects of PPAR activation, such as reducing inflammation, improving lipid profiles, and enhancing insulin sensitivity, researchers are uncovering novel strategies to combat atherosclerosis.

Clinical investigations into PPAR agonists, including fibrates and thiazolidinediones, have showcased their ability to mitigate atherosclerosis by regulating lipid metabolism and dampening vascular inflammation. Moreover, the development of dual or pan-PPAR agonists, capable of targeting multiple PPAR isoforms concurrently, offers a glimpse into potential synergistic effects for enhanced therapeutic outcomes.

As ongoing research endeavors delve deeper into understanding the nuanced roles of distinct PPAR isoforms in atherosclerosis, the prospect of tailored and innovative treatments continues to brighten. Through the convergence of cutting-edge science and clinical trials, the landscape of atherosclerosis therapy stands poised for advancements that could revolutionize cardiovascular care. ⁷⁵

Pemafibrate, a selective PPARα modulator, shows promise in treating atherosclerosis in patients with hypertriglyceridemia and low HDL-C. ⁷⁶ In the PROMINENT study, pemafibrate reduced triglycerides, VLDL-cholesterol, remnant cholesterol, and apo C-III levels but showed no significant difference in cardiovascular events compared to placebo. Despite some adverse effects, pemafibrate’s advantages over traditional fibrates like fenofibrate include stronger PPARα activation and reduced incidence of adverse events. Research suggests pemafibrate’s potential in managing atherogenic dyslipidemia and warrants further exploration for preventing cardiovascular events and managing atherosclerosis.^77,78

Conclusion

Lipid metabolism disorders are one of the most important components of the development of atherosclerosis. In this review, we observed the role of triglycerides in atherogenesis. HTG is pathogenic and is linked with a high risk of pancreatitis, insulin resistance, and steatosis. Concerning atherosclerosis, studies have confirmed the relationship between elevated levels of triglycerides and the risk of developing atherosclerosis, as well as other cardiovascular diseases.

Another important component is TRLs, and considering the available data, we can conclude that in one way or another, these molecules play a role in all key processes of atherogenesis. We tend to believe that the role of triglycerides and TRLs in the development of cardiovascular diseases, and especially atherosclerosis, is far from being fully understood. In addition, there is potential to use blood triglyceride levels as a prognostic factor. However, to date, the evaluation criteria have not been developed or prescribed either.