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Omega-3 fatty acid regulation of lipoprotein lipase and FAT/CD36 and its impact on white adipose tissue lipid uptake

Lipids in Health and Disease volume 23, Article number: 386 (2024) Cite this article

Abstract

Lipid uptake by white adipose tissue (WAT) is critically important for storage of excess energy and to protect peripheral tissues from ectopic lipid deposition. When WAT becomes dysfunctional (i.e., with obesity), it is characterized by impaired lipid uptake and increased lipolysis which, together, promote whole-body dyslipidemia. Omega-3 polyunsaturated fatty acids (N-3 PUFA) are widely studied for their triacylglycerol (TAG)-lowering properties and cardiometabolic health benefits. One potential mechanism underlying these benefits is the modification of WAT lipid uptake; however, there are gaps in our understanding regarding the specific mechanisms by which N-3 PUFA function. Evidence to date suggests that N-3 PUFA promote TAG clearance by increasing lipoprotein lipase (LPL) activity and the abundance of fatty acid transporters. Specifically, N-3 PUFA have been shown to increase LPL activity through increased gene transcription and modifications of endogenously produced LPL regulators such as apolipoprotein C-II/III and angiopoietin-like proteins. This review presents and discusses the available in vitro and in vivo research to provide a comprehensive overview of N-3 PUFA regulation of WAT lipid uptake in healthy and obese contexts. Additionally, we highlight areas where more research is necessary to better understand the contribution of increased WAT lipid uptake in relation to the TAG-lowering properties associated with N-3 PUFA.

Introduction

White adipose tissue (WAT) plays a central role in the regulation of whole-body energy homeostasis by serving as the primary site for the storage of excess energy in the form of triacylglycerol (TAG). A chronic positive energy balance leading to the development of obesity therefore places a demand on WAT depots to remodel to accommodate increased TAG storage [1]. A key feature of dysfunctional WAT is impaired lipid uptake and an increased rate of lipolysis which, together, promote a whole-body dyslipidemia that is characterized by increased circulating TAG and non-esterified fatty acids (NEFA) [1]. This results in ectopic lipid deposition in peripheral tissues such as the liver, pancreas and skeletal muscle that can promote insulin resistance, an accumulation of reactive lipid species and inflammation, among other tissue-specific disruptions [1]. Therefore, there is considerable interest to identify lifestyle and pharmaceutical therapies to prevent and/or treat dyslipidemia. For example, thiazolidinediones (TZDs) are a class of insulin-sensitizing drugs used to treat type-2 diabetes. A common side effect associated with TZD use is increased WAT mass due to enhanced uptake and storage of excess lipids in conjunction with improvements in insulin sensitivity [2]. Similarly, dietary interventions such as the increased consumption of omega-3 polyunsaturated fatty acids (N-3 PUFA) are also associated with improvements in metabolic health due to their well-recognized TAG-lowering and anti-inflammatory properties [3,4,5].

Two of the most widely studied N-3 PUFA are the marine sourced eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA have potent TAG-lowering properties and many, but not all, clinical studies have concluded that higher intake of these fatty acids reduces risk of cardiovascular disease and related co-morbidities [6]. Despite these benefits, a recent survey of data collected from around the world revealed that EPA and DHA status (i.e., blood levels) is generally low in most populations [7]. Numerous studies exploring mechanisms of action related to EPA and DHA have uncovered their ability to reduce and resolve inflammatory signaling, lower hepatic de novo lipogenesis, and increase β-oxidation [4]. However, the roles of EPA and DHA in the regulation of lipid uptake in WAT is less well understood.

Briefly, the uptake and storage of lipids in WAT is coordinated by enzymes and transporters located at the plasma membrane, numerous intracellular transport proteins, and various transcription factors. TAG-rich lipoproteins (TRL) deliver dietary TAG (chylomicrons) or hepatic TAG (VLDL) to WAT. Fatty acids are then hydrolyzed from the glycerol backbone of TAG by the extracellular lipoprotein lipase (LPL) present on the vascular endothelial surface. These free fatty acids can then activate plasma membrane receptors or enter the adipocyte via specific transporters such as FAT/CD36 (fatty acid translocase/cluster of differentiation 36; hereon referred to as CD36). In obesity, these processes are dysregulated in WAT. For example, LPL activity is increased with obesity when expressed per cell, but is inversely correlated with insulin resistance and metabolic syndrome [8,9,10,11]. The mechanism underlying this relationship is not well defined; however, a recent study identified that protease activated receptor 2 (PAR2), which is increased in insulin-resistant obese WAT, was inversely associated with LPL expression through an increase in macrophage migrating inhibitory factor (MIF) signaling [12]. Similarly, CD36 expression is reported to be increased in models of obesity and its activity is altered with insulin resistance [13]. It is therefore important to understand the mechanisms regulating TAG uptake and storage in both healthy and dysfunctional WAT.

The various mechanisms underlying lipid uptake and storage in WAT are also influenced by N-3 PUFA. Specifically, N-3 PUFA have been reported to activate the plasma membrane receptor GPR120 and are transported into the adipocyte by CD36. Once inside the cell, EPA and DHA can act as ligands for peroxisome proliferator-activated receptor gamma (PPARγ), an important transcription factor in adipocytes. Through GPR120 and PPARγ activation, N-3 PUFA regulate numerous cellular pathways that ultimately impact WAT lipid metabolism. Many recent reviews have described how N-3 PUFA broadly influence adipocyte function [14,15,16,17,18]; however, an important, but less well described, consideration is how N-3 PUFA influence TAG hydrolysis and subsequent fatty acid uptake. Therefore, the goal of this review is to outline the current state of knowledge and existing gaps regarding N-3 PUFA regulation of WAT lipid uptake (Fig. 1).

Fig. 1
figure 1

Omega-3 Polyunsaturated Fatty Acid Regulation of White Adipose Tissue Lipid Uptake. TRL in circulation are hydrolyzed by endothelial-bound LPL to release fatty acid (including N-3 PUFA), which are then taken up by adipocytes by fatty acid transporters and re-esterified for storage or oxidized for energy. N-3 PUFA also function as ligands for GPR120, which is reported to increase PPARγ expression. N-3 PUFA are also purported to reduce circulating APO C-III levels, a component of TRL that inhibits LPL. Additionally, N-3 PUFA have been shown to reduce circulating APO C-II levels when they are elevated in metabolically unhealthy states. N-3 PUFA serve as ligands for PPARγ to promote its transcriptional activity and increase CD36 and LPL expression. N-3 PUFA may also modify levels of ANGPTL4/8 in circulation; however, this is not well studied. Solid lines correspond to effects well supported in the literature, while dotted lines indicate emerging areas of regulation, where arrows indicate an activation and blunt arrows indicate an inhibition. ANGPTL4: Angiopoietin-like Protein 4; ANGPTL8: Angiopoietin-like Protein 8; APO C-II: Apolipoprotein C2; APO C-III: Apolipoprotein C3; FA: fatty acid; FABP: Fatty Acid Binding Protein; FAT/CD36: Fatty Acid Translocase/Cluster of Differentiation 36; GPR120: G-protein Coupled Receptor 120; LPL: Lipoprotein Lipase; N-3 PUFA: Omega-3 Polyunsaturated Fatty Acid; PPARγ: Peroxisome Proliferator Activated Receptor Gamma; TAG: Triacylglycerol; TRL: Triacylglycerol-rich Lipoprotein. Created in BioRender. Mutch, D. (2024) https://BioRender.com/m31z704

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N-3 PUFA and postprandial TAG clearance

Postprandial clearance (i.e., uptake) of TAG comprises an important function of WAT. Numerous studies have demonstrated that N-3 PUFA can promote TAG clearance, thereby providing a partial explanation for their TAG-lowering properties. The two most commonly used methods to study TAG clearance by N-3 PUFA are: 1) determining TAG area under the curve (AUC) in response to a standardized test meal, and 2) the use of labelled lipid emulsions to study the kinetics of lipid clearance. Studies using the TAG AUC method generally report a lower AUC in both healthy and metabolically unhealthy individuals consuming a diet high in N-3 PUFA; thus indicating that N-3 PUFA increase postprandial TAG clearance [19,20,21,22]. However, a limitation with this approach is that one can not unequivocally state that TAG clearance occurred specifically in WAT due to other important factors that could be contributing to this outcome. For example, N-3 PUFA have been reported to decrease lipoprotein secretion from the gut and liver, as well as reduce apolipoprotein B-48 mRNA expression [19, 20]. This means that decreases in the TAG AUC may not stem from an increased rate of clearance by WAT exclusively, as the postprandial TAG response can not be attributed to a single tissue. Similarly, it is important to consider the impact of fasting TAG levels on postprandial lipemia, as N-3 PUFA are known to lower fasting TAG levels [23]. Indeed, Weintraub et al. [24] showed that postprandial TAG AUC was positively correlated with fasting TAG levels in humans. One possible interpretation of this is that lower fasting TAG stemming from reduced hepatic VLDL production may favour higher chylomicron clearance simply due to a lower competition for interactions with LPL [25]. While these AUC studies do not provide information regarding the specific contribution of WAT to TAG clearance, they do broadly support the notion that a diet high in N-3 PUFA may enhance postprandial clearance of lipids.

Alternatively, other studies have employed labelled lipid emulsions to study the impact of N-3 PUFA on TAG clearance. Rats fed a diet containing fish oil for 2 weeks showed an increased clearance of a labelled chylomicron compared to rats fed an olive oil control [26]. Specifically, the remaining proportion of the [14C] and [3H] labelled chylomicrons in blood was lower with fish oil at all time points post-injection [26]. These findings were later independently corroborated by a study reporting higher [14C] labelled lipid accumulation in epididymal WAT (eWAT) of N-3 PUFA fed mice following an intragastric load of [14C] triolein; thus suggesting a greater capacity for lipid uptake in eWAT [27]. However, not all studies are in agreement. Ikeda et al. [28] showed no difference in the clearance of labelled chylomicrons in rats fed either a diet high in safflower oil (high in N-6) or fish oil (high in N-3) for 3 weeks. In contrast, a series of studies by Park et al. [29, 30] also investigated TAG clearance in humans consuming either fish oil or safflower oil. Specifically, healthy male and female adults receiving 4 g of EPA or DHA ethyl esters per day for 4 weeks showed a reduced half-life of a [3H] labelled lipid emulsion in blood compared to individuals receiving an equivalent dose of safflower oil ethyl esters in the fed state [30]; thus suggesting that N-3 PUFA increase TAG clearance. A strength of this study was that the authors matched for chylomicronemia between individuals by correcting for fat in the test meal to the reduction in fasting TAG induced by fish oil prior to the administration of the labelled lipid emulsion. In contrast, Ikeda et al. [28] did not indicate the nutritional state of rats when labelled chylomicrons were administered. This is notable, as Park et al. [30] reported no difference in chylomicron clearance in fasted individuals. Lastly, Qi et al. [31] showed an increase in the clearance of a [3H] labelled lipid emulsion in the fed state in mice consuming a fish oil diet (18% w/w fish oil) relative to an isocaloric soy oil diet for 4 months. Collectively, these studies suggest that N-3 PUFA increase the clearance rate of TAG from blood in the fed state rather than the fasted state. More research is necessary to fully understand the specific contribution of WAT to N-3 PUFA mediated improvements in TAG clearance in relation to nutritional state. Future studies should consider including measurements of LPL activity and/or fatty acid transporter activity in lean and obese WAT samples to clarify the underlying molecular mechanisms related to increased TAG clearance.

N-3 PUFA regulation of LPL activity

As mentioned previously, LPL activity is critical for lipid uptake into WAT by hydrolyzing TAG in TRL to release fatty acids. Previous research has demonstrated that LPL is regulated at the transcriptional level, through post-translational modification, and directly at the level of enzyme activity. The following subsections provide insight regarding the mechanisms by which N-3 PUFA regulate LPL in WAT.

N-3 PUFA regulation of LPL gene expression

LPL gene expression is induced by PPARγ and insulin signalling in the postprandial state. PPARγ activates LPL gene expression through a PPAR response element (PPRE) located ~ 150 bp upstream from the transcription start site [32]. When 3T3-L1 adipocytes were treated with rosiglitazone (a PPARγ agonist), Lpl expression was increased [33]. Of relevance to the current review, N-3 PUFA serve as ligands for PPARγ, leading to its activation [14]. Furthermore, some evidence exists to suggest that N-3 PUFA may also increase PPARγ transcriptional activity by reducing the obesity-associated inhibitory phosphorylation of PPARγ at Ser273 or by increasing PPARγ gene expression [34, 35]. Therefore, it is plausible that the N-3 PUFA mediated increase in LPL gene expression occurs in a PPARγ dependant manner. Similarly, insulin is known to induce LPL gene expression and activity in the postprandial state [36, 37]. This is relevant when investigating the potential benefits of N-3 PUFA, as a recent meta-analysis showed that N-3 PUFA have insulin-sensitizing effects [38]. Consequently, N-3 PUFA-mediated increases in LPL expression may be partially attributed to their ability to improve insulin sensitivity.

In vitro studies

There is considerable in vitro evidence supporting that N-3 PUFA can increase Lpl gene expression in 3T3-L1 adipocytes and human primary adipocytes. A common feature across these different studies was that they all used similar concentrations of N-3 PUFA (EPA, DHA, or DPAn-3); however, there were important differences in treatment duration. In a study where differentiated 3T3-L1 adipocytes were treated with 50 μM EPA or 10 μM DPAn-3 for 48 h, an increase in Lpl gene expression was observed with DPAn-3 but not EPA [39]. Independent studies using 3T3-L1 adipocytes treated with 50 or 100 μM EPA throughout differentiation reported an increase in Lpl gene expression relative to controls [40, 41]. Collectively, these studies suggest that N-3 PUFA are capable of increasing Lpl gene expression in cultured adipocytes; however, it remains unclear if all N-3 PUFA have this effect. Given that EPA can be converted into DPAn-3 and DHA in adipocytes [42], it is not possible to definitely conclude which N-3 PUFA is the primary activator of Lpl gene expression.

In vivo studies

The effect of N-3 PUFA on LPL gene expression in vivo are equivocal. Khan et al. [43] provided normal, healthy males expressing an atherogenic lipoprotein phenotype with 6 g of fish oil per day for 6 weeks, and reported an increase in LPL gene expression in subcutaneous white adipose tissue (scWAT) compared to an olive oil control, along with reduced plasma TAG and increased LPL activity. Mice fed a high-fat diet had lower Lpl gene expression compared to mice fed a standard diet; however, Lpl expression was rescued in mice fed a high-fat diet supplemented with EPA/DHA and a TZD, but neither group alone [44]. This suggests a potential synergistic effect between N-3 PUFA and TZDs. In contrast, healthy adult males consuming foods enriched with a fish oil concentrate (providing ~ 1.8 g EPA/DHA per day) showed no change in scWAT LPL gene expression [45]. However, this study did not report reductions in blood TAG levels in individuals consuming fish oil, suggesting that the supplementation dose may have been too low or the intervention period too short to elicit a change [45]. Despite this, the authors did report a significant inverse correlation between fasting TAG and TAG AUC with LPL gene expression [45]. Lastly, rats fed high-fat diets containing DHA or a mix of EPA/DHA showed a significant reduction in Lpl gene expression in retroperitoneal white adipose tissue (rpWAT) relative to a lard-olive oil control group [46]. This was observed alongside decreases in rpWAT fat content and weight. Interestingly, this effect was not seen in inguinal WAT (iWAT); suggesting that N-3 PUFA may have depot-specific effects on lipid partitioning into different WAT depots.

Overall, these studies suggest that N-3 PUFA may regulate LPL gene expression in WAT; however, inconsistent findings may stem from differences in the dose, as well as the type and duration of N-3 PUFA supplementation. Furthermore, the results also suggest potential depot-specific responses to N-3 PUFA that ultimately influence TAG clearance, i.e., preferential uptake into subcutaneous depots versus visceral depots. This would align with past research showing that N-3 PUFA promote a reduction in visceral adiposity [47,48,49,50,51]. More research in the area is needed to fully elucidate the response of LPL gene expression to N-3 PUFA in different WAT depots.

Indirect regulation of LPL activity by N-3 PUFA

LPL activity is regulated by both apolipoproteins (APO) and members of the angiopoietin-like protein (ANGPTL) family. Emerging evidence suggests that N-3 PUFA may also regulate LPL activity by modulating specific apolipoproteins and ANGPTL family members. Apolipoproteins are structural components of TRLs synthesized in the intestine (chylomicrons) and liver (VLDL). APO C-I and APO C-III are inhibitors of LPL activity [52]. These proteins act by displacing LPL from lipoprotein particles, thereby reducing LPL activity. Moreover, APO C-I and APO C-III have also been shown to promote LPL inhibition by rendering it more susceptible to inactivation by ANGPTL4 [53]. In contrast, APO C-II is a cofactor for LPL, thus facilitating its binding to lipoproteins and influencing its enzymatic activity [52], while Apo A-V potentiates LPL activity by increasing the activity of APO C-II and suppressing inhibition by ANGPTL3/8 [52, 54].

Apolipoproteins

A recent meta-analysis of 11 clinical trials in healthy and metabolically unhealthy individuals showed that N-3 PUFA intake reduce circulating APO C-III levels [55]. Since APO C-III is known to reduce LPL activity, this suggests that N-3 PUFA may promote LPL activity by lowering circulating APO C-III levels. However, it remains unclear if modest reductions in APO C-III are functionally relevant for LPL activity; therefore, future studies should aim to specifically address the relationship between changes in APO C-III levels with N-3 PUFA feeding and potential changes in LPL activity.

To our knowledge, little research to date has examined the role of N-3 PUFA on the levels of LPL activators such as APO C-II. However, the limited evidence available does not support the idea that N-3 PUFA increase APO C-II in vivo, but rather that they reduce it [56,57,58]. Although this may initially seem paradoxical, it was suggested by Schmidt et al. that N-3 PUFA reduce APO C-II levels specifically in individuals with dyslipidemia. Indeed, overweight individuals with dyslipidemia were found to have elevated APO C-II mRNA expression, which coincided with lower LPL-mediated TRL hydrolysis [59]. The authors suggested that n-3 PUFA may re-establish an APO C-II/LPL balance to favour LPL-mediated TAG clearance by reducing APO C-II levels. While the role of N-3 PUFA on apolipoproteins requires further clarification, this presents an intriguing avenue for future exploration.

ANGPTL family

ANGPTLs are proteins produced and secreted from various tissues. ANGPTL3, ANGPTL4, and ANGPTL8 play a direct role in regulating TAG clearance by modifying LPL activity [54, 60]. Briefly, ANGPTL3 and ANGPTL4 inhibit LPL activity, and their activity is regulated by forming complexes with adipose and liver derived ANGPTL8 (referred to as ANGPTL3/8 and ANGPTL4/8 complexes, respectively) [54, 60]. These proteins work in concert to attenuate adipose tissue LPL activity in the fasted state whilst promoting it in the fed state, with the opposite being true for other tissues such as skeletal muscle [54, 60]. Consequently, this limits lipid uptake into WAT in the fasted state (thus favouring mobilization of stored TAG) and promotes lipid uptake into WAT in the fed state (thus favouring storage). While the precise mechanisms regarding ANGPTL4 inhibition of LPL are not fully elucidated, available evidence suggests that ANGPTL4 may reduce LPL activity by promoting the unfolding of its catalytic domain [61]. Additionally, there is evidence to suggest ANGPTL4 may also potentiate cleavage and inactivation of LPL via proprotein convertase 3 (PCSK3) [62, 63]. Furthermore, the ANGPTL4 gene contains a PPRE, which suggests that PPARγ may provide an additional mechanism for the regulation of LPL activity [64].

To the best of our knowledge, no studies have directly investigated the relationship between ANGPTL family members, LPL activity, and N-3 PUFA in WAT. However, studies in 3T3-L1 adipocytes [65], the heart [66], skeletal muscle [67], and blood [68, 69] provide intriguing support for this line of investigation. For example, differentiated 3T3-L1 adipocytes treated with 10 µM DHA showed reduced Angptl3 gene expression but no effect on Angptl4 [65]; however, it remains to be seen whether the higher doses of N-3 PUFA typically used in other studies (i.e., 50–100 µM) have different effects. Georgiadi et al. [66] showed that ALA (plant-sourced N-3 PUFA) increased Angptl4 gene expression and reduced lipid peroxidation in mouse cardiac muscle, suggesting that ANGPTL4 may protect the heart from lipid peroxidation through reductions in lipid uptake. However, an important caveat is that ALA is continuously converted into other N-3 PUFA; therefore, it is not clear if ALA directly increased Angtl4 expression or if it was another N-3 PUFA. Brands et al. [68] demonstrated that infusion of a fish oil-containing lipid emulsion during a 3 h hyperinsulinemic clamp in healthy, normal weight males attenuated the insulin-induced inhibition of ANGPTL4. In a different study, a 7 day PUFA rich diet decreased fasting and postprandial levels of ANGPTL3 and ANGPTL8 in females, but had no influence on ANGPTL4 [69]. Lastly, a study in THP-1 macrophages showed that treatment with a synthetic PPAR agonist increased Angptl4 expression and reduced LPL enzymatic activity [70]. Despite this, it is important to note that ANGPTL4 expression is induced in the fasted state, and not the fed state when lipid uptake into WAT is highest [54, 60]. Interestingly, it has been demonstrated that the ANGPTL4/8 complex protects LPL from inhibition by other circulating factors such as ANGPTL3 to preserve WAT LPL function in the fed state [71]. Therefore, it is plausible that changes in ANGPTL expression induced by N-3 PUFA may modify WAT lipid uptake differently according to the nutritional state. Future studies in this area should include these proteins as potential mediators of the beneficial effects of N-3 PUFA, especially given the possible link between N-3 PUFA, PPARγ, and ANGPTL4.

LPL activity assays

There are several methods presented in the literature regarding the measurement of LPL activity. As such, we first provide a brief overview of these methods to help contextualize the current state of knowledge regarding N-3 PUFA regulation of LPL activity. LPL activity can be measured directly in a tissue through the collection of a biopsy or can be assessed in blood. While the use of a tissue biopsy allows researchers to determine tissue-specific LPL activity, the use of blood samples provides insight into whole-body LPL activity. However, a caveat when using blood samples is that other lipases, such as hepatic lipase (HL) and endothelial lipase (EL), are also present and capable of TAG hydrolysis to varying degrees [72, 73]; therefore, we use the more general term “lipase activity” hereon due to the inability to attribute activity to a specific family member. Critical to the analysis of lipase activity in blood is the need to use heparin, which causes lipases to be efficiently displaced from the proteins anchoring it to the vessel wall, thus facilitating its measurement [52]. In contrast, a limitation of using pre-heparin lipase activity is that only a small amount of TAG lipase activity will be captured that may not meet assay sensitivity. Despite its widespread use, the biological relevance of measuring post-heparin lipase activity has been questioned [25, 29]. Park et al. [29] outlined the differences between the various methods used to measure lipase activity, and proposed margination (sequestration) volume as an alternate method (see [29] for methodological details). Significant positive correlations were reported in male and female adults between margination volume and pre-heparin activity in the fed state only, along with a significant inverse correlation between margination volume and chylomicron half lives [29]. Intriguingly, no correlations were found between post-heparin lipase activity and margination volume, pre-heparin lipase activity, chylomicron half lives, or fasting TAG [29]. As such, caution is warranted when attempting to reconcile findings regarding N-3 PUFA regulation of LPL activity collected using different methodologies.

N-3 PUFA regulation of adipose-specific LPL activity

Several studies have examined adipose-specific LPL activity in response to N-3 PUFA. LPL activity in eWAT was increased in rats fed a high-fat diet supplemented with fish oil [74]. This result is supported by several independent studies showing that rpWAT-specific LPL activity was increased in rats fed a diet high in fish oil [28, 75, 76]. Interestingly, Ikeda et al. [28] also measured post-heparin lipase activity and reported no difference despite the increase in adipose-specific LPL activity. This demonstrates how the biological interpretation of study findings can change depending on the methodology used to measure LPL activity. Additionally, Peyron-Caso et al. [76] also measured LPL activity in eWAT, scWAT, and skeletal muscle of rats fed fish oil, and observed increased LPL activity in all WAT depots with no change in skeletal muscle LPL activity. Finally, Gaíva et al. [27] did not find a change in adipose-specific LPL activity in rats fed a diet containing N-3 PUFA; however, there was an increased uptake of fatty acids in eWAT following an intragastric load of [14C] labelled triolein, a function attributed to LPL.

Collectively, most results suggest that N-3 PUFA increase WAT-specific LPL activity; however, it is important to recognize that these findings are specific to WAT and can not be generalized to other tissues. Moreover, most research to date has studied LPL activity in visceral WAT depots (eWAT, rpWAT) and not scWAT. This is notable given that LPL expression and activity varies between different WAT depots [76]. Further, the collection of an adipose tissue biopsy, while technically feasible, remains a far more invasive method than blood sampling. This may provide a partial explanation why human studies in which adipose-specific LPL activity was examined are scarce. Nevertheless, the studies available suggest that N-3 PUFA can increase LPL activity in WAT. This is of importance given that WAT is the primary site for lipid storage in the body, which could reduce lipid deposition in peripheral tissues.

N-3 PUFA regulation of pre-heparin plasma lipase activity

Studies examining the effects of N-3 PUFA on pre-heparin plasma lipase activity also observed increased activity. A crossover study in 20 healthy adult male and female participants, and 6 hypertriglyceridemic male and female participants, showed higher pre-heparin lipase activity and lower fasting blood TAG following the consumption of N-3 PUFA (5 g of fish oil per 70 kg of body weight per day for 4 weeks) compared to an olive oil control in both groups of subjects [77]. These results were subsequently supported in a series of human intervention studies from the same research group in which pre-heparin lipase activity was increased in response to fish oil feeding in healthy individuals [29, 30]. Klingel et al. [78] investigated pre-heparin lipase activity in healthy male and female adults supplemented with 3 g of EPA or DHA per day for 12 weeks and reported that DHA supplementation in particular increased fasted pre-heparin lipase activity [78]. Concomitantly, individuals in the DHA supplementation group also had a significant reduction in fasting blood TAG [78]. However, a limitation of this study was the lack of measurements in the fed state, as this would have provided an opportunity to clarify if the effects of N-3 PUFA on pre-heparin lipase activity varied according to the nutritional state. Nevertheless, results to date suggest that N-3 PUFA increase pre-heparin plasma lipase activity.

N-3 PUFA regulation of post-heparin plasma lipase activity

Studies investigating post-heparin lipase activity and N-3 PUFA are equivocal, with some studies suggesting an increase, while others suggest no change. As previously mentioned, heparin displaces and activates endothelial-bound lipases prior to their collection and analysis. Consequently, an important caveat is that it’s unclear if post-heparin results accurately represent in-situ activity, since the administration of heparin frees and activates all lipases [25]. Despite this, post-heparin collection provides useful insight into whole-body lipase activity. Studies in humans suggest little-to-no effect of N-3 PUFA on post-heparin lipase activity. For example, Weintraub et al. [24] reported no difference in post-heparin lipase activity in normolipidemic males consuming a diet containing 3.5 g N-3 PUFA/1000 kcal for 25 days, despite reductions in fasting TAG levels. In agreement with this, an independent study also showed no difference in post-heparin lipase activity in normolipidemic male and female adults consuming an experimental diet for 4 weeks in which N-3 PUFA contributed ~ 20% of the calories from total fat [79].

A recent study showed that mice fed a high-fat diet comprised solely of fish oil for 4 months had higher pre- and post-heparin lipase activity in the fed state compared to mice consuming a high-fat diet containing soybean oil (N-6) [31]. Only the high-fat soybean oil group showed increased plasma TAG [31]. This suggests that N-3 PUFA, compared to N-6 PUFA, may prevent increases in plasma TAG in the context of high-fat diet feeding, along with a preservation of pre- and post-heparin lipase activity in the fed state only [31]. However, human studies exist showing an increase in post-heparin lipase activity with N-3 PUFA. For example, Kasim-Karakas et al. [80] observed an increase in post-heparin lipase activity in hypertriglyceridemic male and female adults consuming 3.3 g/d of N-3 PUFA for 1 month. A potential difference between this study and the previous studies reporting no effect of N-3 PUFA on post-heparin lipase activity was the methodological approach used to infuse heparin. Specifically, Kasim-Karakas et al. [80] slowly infused heparin over 2 h, while the other studies infused heparin as a single bolus amount. Further, this result suggests that n-3 PUFA may modify lipase activity in individuals with dyslipidemia but not normolipidemic individuals. Lastly, a crossover study in 51 male adults with an atherogenic lipoprotein phenotype also observed an increase in post-heparin lipase activity with 3 g of N-3 PUFA per day; however, this effect was only shown at 5 min but not 15 min post-heparin infusion [43]. Interestingly, LPL gene expression in scWAT was increased in these participants, highlighting a disconnect between changes in gene expression and changes in lipase activity. It is possible that the lack of effect observed at 15 min post-heparin may be due to the release of other lipases that were not impacted by N-3 PUFA, thereby confounding the result [43].

In summary, differences in the method of heparin injection, study populations, dosages and treatment times most likely contribute to the discordant findings reported in the literature regarding N-3 PUFA regulation of lipase activity. Collectively, the lack of consensus regarding the effects of N-3 PUFA on post-heparin lipase activity means that additional investigations are required.

N-3 PUFA regulation of fatty acid transporters and receptors

Once fatty acids are hydrolyzed from the glycerol backbone of a TAG molecule, they are then primarily transported into an adipocyte through membrane-bound fatty acid transporters such as CD36, fatty acid transport proteins (FATP) and fatty acid binding proteins (FABP). Consequently, the abundance and activity of these various fatty acid transporters will impact lipid uptake into WAT. For example, WAT fatty acid uptake was strongly reduced in CD36 knockout mice [81]. Similarly, the individual overexpression of CD36, FATP1, and FATP4 in rat skeletal muscle all led to increased palmitate uptake, with CD36 having the largest impact [82]. N-3 PUFA regulation of fatty acid transporter gene expression therefore provides an additional level of regulation regarding WAT lipid uptake. Additionally, the GPR120 receptor resides on the plasma membrane of adipocytes and is activated by fatty acids, including N-3 PUFA [83]. GPR120 is primarily implicated in the attenuation of inflammatory signalling pathways [84]; however, studies also suggest a potential role for GPR120 in the regulation of lipid metabolism. For instance, a recent study reported that mice treated with a synthetic GPR120 agonist had lower hepatic Srebp-1c, Cd36, and Fabp1 gene expression compared to control animals [85]. N-3 PUFA activation of GPR120 was found to initiate a signalling cascade resulting in increased cytoplasmic cAMP levels [83]. Hilgendorf et al. [83] described the role that N-3 PUFA-mediated GPR120 signalling plays in adipogenesis and suggested that increased cAMP can influence downstream processes relevant for fatty acid uptake and storage. Moreover, Yang et al. [86] proposed that GPR120 could influence PPARγ expression. Specifically, the authors demonstrated that GPR120 activation by N-3 PUFA led to increased PPARγ gene expression that was attenuated when 3T3-L1 adipocytes were concomitantly treated with a GPR120 antagonist. Similarly, Paschoal and Oh [87] reported that GPR120 activation may lead to a reduction in the inhibitory phosphorylation of PPARγ at the Ser273 residue. Finally, GPR120 activation is also associated with increased insulin sensitivity in WAT; however, this is thought to be secondary to GPR120 regulation of inflammatory signaling pathways [86]. Nevertheless, increased insulin sensitivity is relevant given that insulin promotes lipid uptake and storage in WAT. Therefore, it is possible that N-3 PUFA activation of GPR120 can lead to increased lipid uptake through both PPARγ and insulin signaling pathways.

N-3 PUFA regulation of fatty acid transport proteins

Fatty acid transporters such as CD36, FABP4, and FATP1 are under transcriptional regulation by PPARγ [14]. Indeed, Cd36, Fabp4, and Fatp1 gene expression was shown to increase in 3T3-L1 adipocytes treated with PPARγ agonists [33, 88]. Since N-3 PUFA can activate PPARγ in WAT, this provides a plausible mechanism by which N-3 PUFA can increase the expression of these fatty acid transport proteins. Moreover, insulin has been shown to enhance CD36 cycling to the plasma membrane, leading to an increase in fatty acid transport [13]. As such, it is possible that N-3 PUFA regulate the expression of these transporters both through a transcriptional mechanism (PPARγ) and through the insulin signaling pathway.

In vitro studies

Several in vitro studies have examined the impact of N-3 PUFA on fatty acid transporter gene expression and protein content; however, the outcomes are inconsistent, with some studies showing an increase in gene expression, while others show a null or lowering effect. Prostek et al. [89] examined the effects of EPA (100uM) and DHA (50uM) on fatty acid transporter gene expression in differentiated 3T3-L1 adipocytes and reported that 50–100 μM EPA or DHA increased Fatp1 and Fatp4 gene expression [89]. Similarly, differentiated 3T3-L1 cells treated with 50 μM EPA showed increased Fabp4 and Cd36 gene expression [39, 40]. Interestingly, these effects were not seen when 3T3-L1 adipocytes were treated with N-3 PUFA throughout differentiation. For example, 3T3-L1 adipocytes treated with 200 μM of stearidonic acid (an EPA and DHA precursor) throughout differentiation showed lower lipid accumulation concomitant with reduced Fabp4 and Pparγ expression compared to a vehicle control [90]. This aligns with an independent study reporting that differentiating 3T3-L1 adipocytes treated with 100 μM EPA or 50 μM DHA had lower lipid accumulation and Cd36 gene expression [91]. Therefore, the response of 3T3-L1 cells to N-3 PUFA appears to differ between undifferentiated and differentiated adipocytes. Another study showed that Fabp4 gene expression and protein content was reduced in a dose-dependent manner in differentiated 3T3-L1 adipocytes treated with varying (0–100 μM) concentrations of EPA or DHA [92]. Important limitations with this study include the lack of a functional outcome (i.e., lipid accumulation) and the lack of measurements for other fatty acid transporters such as Fatp1 or Cd36. As such, it is unclear whether the decrease in Fabp4 was functionally significant for lipid uptake. Overall, these cell culture results suggest that differentiated adipocytes treated with EPA and DHA show increased expression of fatty acid transporters; however, this effect may be lost in cells that are actively differentiating.

In vivo studies

There is some evidence to support that N-3 PUFA can increase fatty acid transporter gene expression in WAT in vivo. For example, spontaneously hypertensive rats fed a diet containing fish oil had Cd36 expression levels comparable to healthy chow-fed animals, which were higher than that seen in rats fed a corn oil diet (N-6 PUFA) [93]. This study suggests that N-3 PUFA may function to rescue Cd36 expression to healthy levels. In a separate study by the same research group, rats fed an obesogenic diet containing fish oil showed higher Cd36 gene expression and protein content in WAT compared to rats fed a corn-canola oil diet [94]. This aligned with lower circulating TAG and NEFA levels [94]. Finally, mice fed a diet containing menhaden fish oil (27% wt/wt) for 15 days had a significant increase in Cd36 gene expression in eWAT, and a non-significant increase in iWAT [95]. Together, these results suggest that N-3 PUFA may be able to increase Cd36 expression, or restore it to healthy levels, to favour increased lipid uptake into WAT. One thing which remains unclear, however, is whether changes in Cd36 expression in WAT depots relates solely to changes in adipocytes or whether this also captures changes in WAT endothelial cells. To our knowledge, no studies exist in which changes in fatty acid transporters in these two WAT cell types in response to N-3 PUFA have been distinguished, and thus represents a gap in our current understanding regarding the precise mechanism by which N-3 PUFA may modify WAT lipid uptake.

Future areas of investigation

Research to date suggests that N-3 PUFA have multiple avenues through which they can regulate WAT lipid uptake; however, several important gaps in knowledge remain. First, it is unclear to what extent post-heparin blood lipase measurements accurately capture WAT LPL activity due to the contribution of hepatic and endothelial lipases. Indeed, this may underlie discrepant results between post-heparin blood and WAT lipase regulation, as seen by Ikeda et al. [28]. Moreover, LPL activity may also be differentially regulated in distinct WAT depots to coordinate lipid partitioning for storage. For example, LPL gene expression in scWAT, but not visceral WAT, was positively correlated with plasma LPL mass [11]. Additionally, N-3 PUFA regulation of LPL activity in other tissues beyond WAT remains an area for further exploration. For example, higher LPL activity in skeletal muscle promotes ectopic lipid deposition and insulin resistance [96]; however, N-3 PUFA were reported to have no effect on muscle LPL activity [76]. Nevertheless, a comprehensive investigation of LPL activity in various tissues, including post-heparin blood, are needed to better understand potential tissue-specific regulation by N-3 PUFA. This will also help to reconcile discrepancies between LPL activity and individual WAT depot weights, and may reveal that N-3 PUFA promote a metabolically favourable partitioning of lipid uptake into subcutaneous depots rather than visceral depots. Second, it will also be important to consider how N-3 PUFA impact fatty acid transporters and lipolytic enzymes in different WAT depots, as these processes also impact adiposity. Third, future studies should consider measuring WAT LPL activity, gene expression and TAG content together to better clarify the relationships between LPL transcription regulation and functional outcomes. Fourth, evidence to date suggests that the regulation of WAT lipid uptake by N-3 PUFA may vary according to metabolic status. Indeed, LPL activity and fatty acid transporters appear to be regulated differently in obese versus obese insulin resistant WAT; however, this has not been thoroughly investigated. Further, it appears that N-3 PUFA may rescue WAT lipid uptake in models of insulin resistance or dyslipidemia to the levels seen in healthy controls, suggesting that these important fatty acids may help optimize lipid partitioning. Additional studies in this area are warranted to better understand the benefits of N-3 PUFA in healthy and unhealthy states. Fifth, the regulation of apolipoproteins and ANGPTL family members highlight the complexity by which N-3 PUFA may influence WAT lipid uptake; however, this area of investigation remains in its infancy. Sixth, most research to date has focused on EPA and DHA, rather than other N-3 PUFA such as ALA, SDA or DPAn-3. Given the continuous conversion through the fatty acid desaturase and elongase pathway, it remains challenging to tease apart their independent effects on WAT lipid uptake. Moreover, EPA and DHA can be converted into oxygenated lipid mediators that may also impact these processes. Thus, considerable work determining the independent effects of different N-3 PUFA and related lipids will be insightful. Finally, sex differences exist regarding lipid storage in various WAT depots; however, the effects of biological sex on N-3 PUFA regulation of lipid partitioning remains poorly studied.

Conclusion

Mounting evidence suggests a beneficial effect of N-3 PUFA on WAT lipid uptake capacity in both animals and humans, which may have importance as a possible lifestyle intervention for individuals with obesity and dyslipidemia. Importantly, results in rodent models are generally in agreement with existing data in human studies. However, the role of N-3 PUFA on WAT lipid uptake in models of obesity remain poorly described. Two potential mechanisms of interest by which N-3 PUFA regulate LPL activity are through increased transcription and via changes in regulatory proteins (e.g., apolipoproteins, ANGPTL family members). Similarly, N-3 PUFA regulation of fatty acid transporters such as CD36 further support their ability to elicit a concerted response that favours lipid uptake into WAT. Collectively, these responses to N-3 PUFA increase postprandial TAG clearance and may provide an additional explanation for the TAG-lowering properties of N-3 PUFA. However, this area of research remains in its infancy and continued investigation is necessary to further clarify the mechanisms underlying N-3 PUFA mediated changes in WAT lipid uptake in both healthy and diseased states.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ANGPTL:

Angiopoietin-like Protein

APO:

Apolipoprotein

DHA:

Docosahexaenoic Acid

EPA:

Eicosapentaenoic Acid

eWAT:

Epidydimal White Adipose Tissue

FABP:

Fatty Acid Binding Protein

FAT/CD36:

Fatty Acid Translocase/Cluster of Differentiation 36

FATP:

Fatty Acid Transport Protein

iWat:

Inguinal White Adipose Tissue

LPL:

Lipoprotein Lipase

NEFA:

Non-esterified Fatty Acid

N-3 PUFA:

Omega-3 polyunsaturated fatty acid

PPARγ:

Peroxisome Proliferator Activated Receptor Gamma

PPRE:

PPAR Response Element

rpWAT:

Retro-peritoneal White Adipose Tissue

scWAT:

Subcutaneous White Adipose Tissue

TAG:

Triacylglycerol

TRL:

Triacylglycerol-rich Lipoprotein

TZD:

Thiazolidinedione

VLDL:

Very Low-density Lipoprotein

WAT:

White Adipose Tissue

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PVM is supported by an Ontario Graduate Scholarship (OGS).

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  1. Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada

    Patrick V. McTavish & David M. Mutch

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PVM and DMM conceptualized the review manuscript, collated relevant articles, and wrote the manuscript. PVM generated the figure. DMM provided oversight and mentorship.

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McTavish, P.V., Mutch, D.M. Omega-3 fatty acid regulation of lipoprotein lipase and FAT/CD36 and its impact on white adipose tissue lipid uptake. Lipids Health Dis 23, 386 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12944-024-02376-7

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Keywords

Lipids in Health and Disease

ISSN: 1476-511X