Aquaporins in lipid metabolism: functions and regulation in health and disease

Abstract

Aquaporins (AQPs), mainly divided into classical AQPs, aquaglyceroporins, and superaquaporins, constitute a channel protein family facilitating the movement of small molecules, such as H₂O, H₂O₂, and glycerol, across cell membrane. AQPs are widely found in kidneys, pancreas, liver, muscle, skin, brain, fatty tissues, and other tissues related to lipid metabolism, playing important roles in lipid metabolism in these tissues by affecting glycerol’s cell membrane permeability or indirectly through secondary pathways. This review provides a comprehensive analysis of AQP expression patterns across various tissues and elucidates their correlation with lipid metabolism, with the purpose of ascertaining the possible clinical significance of these proteins. This investigation provides novel insights and perspectives for future research on lipid metabolism disorders, with a specific focus on AQPs as therapeutic targets to support metabolic health and sustainable disease management strategies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12944-025-02727-y.

Introduction

Classification

Aquaporins (AQPs) constitute a channel protein family mediating the movement of low-molecular-weight soluble substances and water across cell membrane. Researchers have so far discovered over 300 AQP members, among which AQP0–AQP12 display widespread expression within mammalian organs and tissues [1]. Up till now, three molecular structure subcategories of these proteins have been characterized. Classical AQPs, including AQPs 0, 1, 2, 4–6, and 8, mainly mediate water diffusion [2]. Aquaglyceroporins, comprising AQPs 3, 7, 9 and 10, are related to small-molecule solute (involving glycerol, urea, and H₂O₂) movement, besides their functions in facilitating water diffusion [3]. Unorthodox aquaporins and superaquaporins, including AQPs 11 and 12, share low homology with classical AQPs [4]. In addition to phylogenetic classification, AQPs can be Functionally categorized based on their substrate permeability. Certain members, e.g. peroxiporins AQPs 3 and 8, facilitate H₂O₂ diffusion. Others, such as AQP8 and AQP9, function as ammoniaporins, allowing the passage of ammonia (NH₃/NH₄⁺). Moreover, some AQPs mediate the facilitation of gases, including O₂, CO₂, and NO, further broadening their physiological roles. Incorporating these functional classifications reveals AQP diversity more comprehensively [3].

Structures

AQPs are tetramers composed of identical 30-kD monomeric subunits functioning independently as transmembrane channels. For each of the monomeric subunit, five inter-helical loops (A-E) connect six transmembrane helices (H1-6), with aquaphilic N- and C-terminal domains consistently positioned within the cytoplasm [5]. Among the five inter-helical loops, A, C, and E are located extracellularly, whereas B and D are positioned intracellularly. Besides these structures, each AQP monomer also features a largely conserved promoter containing two repetitive Asn-Pro-Ala (NPA) motifs (NPA box) tandemly arranged on the B and E loops, whose spatial locations are maintained through forming ion pairs and hydrogen bonds with neighboring helical domains. One sequence is “AEFL” and the other is the “HW [V/I] [F/Y] WXGP” (Fig. 1) [6]. However, classical AQPs do not have the same structure as aquaglyceroporins. The structural differences between classical AQPs and aquaglyceroporins include additional sequence features beyond the NPA motifs, resulting in variations in the monomer length and domain architecture [7]. Two additional peptides appear after the second NPA promoter of the C and E loops in aquaglyceroporins [8]. Besides NPA boxes, the aromatic/arginine (ar/R) region, comprising four residues located in helices H2, H5, and loop E, functions as a crucial filter that defines AQP pore size and chemical characteristics, conferring these proteins selectivity among their substrates. In aquaglyceroporins, a wide ar/R filter permits the movement of various solutes including glycerol, whereas in classical AQPs, permeation is primarily restricted to water [8]. Researchers are actively exploring whether these structural differences underlie the distinct functional roles of classical AQPs and aquaglyceroporins.

Fig. 1.

A schematic of AQP monomer showcasing positions of the intracellular N and C termini, membrane-spanning helices, loops, and NPA motifs. NPA: Asn-Pro-Ala

However, despite increasing recognition of the involvement of AQPs in lipid metabolism, the existing literature remains fragmented, with limited integration across tissue types and metabolic pathways. Moreover, the potential clinical significance of targeting AQPs for management of metabolic diseases is yet to be systematically explored. This review aims to address these gaps by providing a comprehensive analysis of AQP expression patterns and their functional roles in lipid metabolism, with the central hypothesis that specific AQPs serve as key modulators of lipid homeostasis and represent promising targets in treating and preventing metabolic abnormalities.

Lipid metabolism and AQPs

The AQP-facilitated glycerol transmembrane movement is a central component of Lipid metabolism. In adipose tissue, glycerol produced during Lipolysis is moved out of adipocytes through AQPs 3 and 7, and subsequently subjected to AQP9-mediated hepatocyte uptake for gluconeogenesis and triglyceride (TG) synthesis [9, 10] (Fig. 2). Under normal physiological circumstances, the energy consumed by cardiac and skeletal muscles comes mainly from free fatty acids (FFAs), which represent almost the sole energy source in the context of low temperature stress and exercise. Therefore, regulating the release of FFAs and glycerol from adipocytes is of significant importance.

Fig. 2.

Coordination between adipocyte AQPs 3/7 and hepatocyte AQP9 during lipolysis

The schematic showcasing the implication of AQPs with Lipolysis. AQPs 3 and 7 expressed on adipocytes mediate the release of glycerol, which is transported through the hepatic portal vein into the liver and uptaken by hepatocytes possibly via AQP9. Glycerol represents a substrate for biosynthesis of glucose and TG in the liver. AQP: aquaporin; TG: triglyceride; FFA: free fatty acid.

Aquaglyceroporins are important pathways that control glycerol in and out of cells. All aquaglyceroporins are expressed in adipose tissue and knockout mouse models for all aquaglyceroporins are currently available [11–14]. A previous investigation found that AQP3 is expressed in the murine kidneys and hypothesized that it facilitates glycerol movement [15]. After AQP7 overexpression in African Xenopus oocytes, cellular permeability to water, glycerol, and urea were significantly increased [16]. Hkuriyama et al. identified AQP9 in the adipose tissue for the first time and confirmed that it participates in glycerol transfer in adipose cells [17]. AQP10 is crucial in the regulation of glycerol homeostasis within adipocytes, thereby maintaining physiological glycerol concentrations [18]. Additionally, some classical AQPs (including AQP5 and AQP8) and superaquaporins are involved in lipid metabolism.

AQPs and lipid metabolism

Classical AQPs influence lipid metabolism

Although most classical AQPs only facilitate water metabolism, there is evidence that AQP5 and AQP8 are involved in lipid metabolism. Although they do not directly engage in lipid metabolism, they indirectly influence it. In the hypothalamus, AQP5 was identified to be connected to 169 adipose genes within tissue-to-tissue co-expression gene networks, highlighting this interaction [19]. A phospholipid molecule was observed to occlude the central pore of human AQP5, as revealed by X-ray crystallography, thereby preventing the formation of small molecules, such as gases or ions [20]. Currently, this is the only reported example of lipid-induced occlusion in the AQP family. This structural feature may explain why AQP5 does not function as a direct channel of lipids or lipid-related molecules, although it May still influence Lipid metabolism through indirect mechanisms, such as gene regulatory networks. Previous research utilizing 3T3-L1 adipocytes indicated that AQP5 depletion could reduce lipid droplet (LD) content and inhibit adipocyte differentiation without affecting water-facilitated function [21]. In an in vivo assay, AQP5 knockout mice exhibited a 10–15% body weight reduction relative to their wild-type counterparts [22].

AQP8, which is mainly responsible for moving water [23, 24], ammonia [23, 25] and H₂O₂ [26, 27], is also involved in cholesterol metabolism in addition to AQP5. Initially, genome-wide analysis suggested that mouse hepatocyte AQP8 represents a cholesterol-related protein located on mitochondrial inner membrane [28]. Then several studies showed that AQP8 targeted sterol regulatory element-binding proteins (SREBPs) and mitochondrial AQP8 (mtAQP8) could regulate the biosynthesis of cholesterol in hepatocytes via H₂O₂ [29, 30], showcasing the SREBPs-dependent regulatory effects of cholesterol on mtAQP8 transcription in human hepatocytes. This result was also verified in microarray analyses, which identified that cholesterol feeding in mice downregulated several liver genes, including AQP8 [31, 32]. Another study showed that mtAQP8 gene expression in human hepatocytes regulates de novo cholesterol and fatty acid synthesis by controlling the abundance of crucial enzymes catalyzing Lipogenesis, involving fatty acid synthase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR) [33]. Collectively, AQP8 is important for cholesterol regulation and might be associated with cholesterol-related metabolic diseases.

Aquaglyceroporins influence lipid metabolism

Aquaglyceroporins are closely related to lipid metabolism as they are involved in glycerol facilitation. The distribution and function of the main AQPs related to lipid metabolism in tissues and organs are shown in Table 1.

Table 1.

Distribution and functions of Aquaporins in various tissues involved in lipid metabolism

Tissue/Organ	Main expressed AQPs	Functions in lipid metabolism
Adipose tissue	AQP3, AQP7, AQP9, AQP10, AQP11	Glycerol efflux during lipolysis; AQP3 glycerol metabolism; AQP7 deficiency promotes TG accumulation and obesity; AQP11 modulates ER stress impacting lipid metabolism
Liver	AQP9, (controversial AQP7)	Glycerol uptake for gluconeogenesis; AQP9 downregulation compensates for NAFLD; AQP8 regulates cholesterol synthesis
Kidney	AQP7	Glycerol reabsorption in the proximal tubule; AQP7 mutations linked to glyceroluria
Skeletal muscle	AQP3, AQP4, AQP7	Glycerol uptake for energy metabolism; AQP3/AQP7 upregulated in obesity/diabetes; AQP3 linked to exercise capacity and muscular dystrophy
Heart	AQP7	Glycerol metabolism supports cardiac ATP production; AQP7 deficiency leads to hypertrophy and worsened ischemic injury
Pancreas	AQP7	Modulates insulin secretion, TG synthesis; AQP7 deficiency linked to obesity, insulin resistance; role remains controversial
Skin	AQP3, AQP7 AQP10	Glycerol movement supports skin hydration and barrier function; linked to skin disorders; expression restricted to hypodermal adipocytes
Brain	AQP7, AQP9	Moves glycerol and lactate; supports astrocytic and neuronal metabolism under ischemia and normal conditions; mainly functions to move glycerol in fatty tissues
Genital system	AQP1, AQP9	In epididymis and Sertoli cells; implicated in sperm maturation, fertility, and glycerol homeostasis
Placental	AQP3, AQP9	Moves water and small solutes (glycerol and L-lactate), integral to placental lipid metabolism and fetal nutrient supply

TG Triacylglycerol, ER Endoplasmic reticulum, NAFLD Non-alcoholic fatty liver disease, ATP Adenosine triphosphate

AQP3

Skin

AQP3, which exhibits expression on mouse [34] and human [35] epidermal cells, mediates the transmembrane movement of glycerol. It is substantially important for the hydration of the epidermal layer [36, 37]. The skin of AQP3-knockout mice showed impaired wound-repairing capability, barrier function, elasticity, and hydration, which are likely associated with decreased stratum corneum and epidermal abundance of glycerol [38]. These changes could be corrected using glycerol replacement therapy, revealing the crucial function of AQP3 during cutaneous glycerol movement and other related processes. An in vitro study showcased that glycerol represents an important substrate for phospholipase D2 (PLD2)-mediated phosphatidylglycerol (PG) biosynthesis within intact epidermal keratinocytes [39]. Additionally, PLD2 and AQP3 co-localize and physically interact with each other within lipid rafts [40]. This complex constitutes a functional machinery that makes use of the proximity between AQP3 and PLD2 to facilitate the movement and utilization of glycerol, thereby promoting PG synthesis. Elevated extracellular calcium concentrations enhance PG production, consequently promoting keratinocyte differentiation and inhibiting cell proliferation. Furthermore, modulating this functional machinery through supplying glycerol exogenously to, overexpressing AQP3 in, or directly administrating PG administration to cells undergoing division rapidly hinders their multiplication and triggers differentiation [39, 41]. For keratinocytes, p53 transcription factor and histone deacetylase 3 (HDAC3) are key factors regulating AQP3 expression, with HDAC3 inhibiting AQP3 expression and p53 augmenting AQP3 activity [42]. Additionally, peroxisome proliferator-activated receptors (PPARs) have been implicated in the up-regulatory effects of HDAC inhibitor on AQP3 expression, as evidenced by the capacity of PPAR antagonists to abrogate HDAC inhibitor-dependent increases in AQP3 abundances. Specifically, increased abundances of AQP3 protein and mRNA resulting from inhibition of HDAC were implicated with enhanced PPARγ expression [43]. AQP3 is often dysregulated in common inflammatory dermatological diseases, suggesting that it is a novel therapeutic target for cutaneous lesion management [44].

Adipose tissue

Within adipocytes, aquaglyceroporins are primarily responsible for regulating glycerol influx and efflux, thereby governing the central pathways of TG synthesis and cellular metabolism [45]. As the major glycerol-generating tissue, adipose tissue is modulated by energy homeostasis. Although the adipocyte-specific glycerol-moving role of AQP7 has been recognized, AQP3 also exhibits similar functionalities in fatty tissues [46, 47]. The expression of AQP3 was mainly detected in the viscera, subcutaneous fat layer, and omentum [47]. Knockout of AQP3 in porcine intermuscular adipose tissue could inhibit Akt phosphorylation, the expression of genes involved in lipogenesis (e.g. PPARγ), and the accumulation of lipid, which indicates its function in the promotion of lipogenic differentiation of adipocytes [48].

Under physiological conditions, insulin modulates aquaglyceroporin expression, thereby regulating the glycerol flux in adipocytes [49]. Mechanistically, insulin stimulates the PI3K/Akt/mTOR signaling pathway to enhance the abundances of AQPs 3, 7, and 9 proteins [47]. During nutrient intake or physical activity, hormone-sensitive lipase (HSL) and adipose triglyceride lipase catalyze the hydrolysis of TGs to yield FFA and glycerol, which are released into the blood circulation. Catecholamines regulate lipolysis via lipolytic β-adrenergic and antilipolytic α2-adrenergic receptors [50]. β-adrenergic receptors couple to G-protein, which activates adenylyl cyclase, leading to increased cyclic adenosine monophosphate production. This activates protein kinase A, which phosphorylates HSL to trigger its migration into LDs from cytoplasm to enhance TGs catabolism. Upon lipolytic stimulation induced by the β-adrenergic agonist, isoproterenol, AQP3 facilitates the movement of glycerol out of adipocytes [47, 51, 52].

Muscular tissue

Skeletal muscle fibers express not only AQPs 1, 4, and 7, but also AQP3 on the inner surface of cell membrane [53]. Muscle tissues can use AQP3 and AQP7 to absorb glycerol and oxidize it to glyceraldehyde through glycerol dehydrogenase or phosphorylate it to glyceraldehyde 3-phosphate (G3P) by glycerol kinase for use as energy [54]. Compared with normal mice, AQP3-knockout mice have decreased motor ability and increased glycerol concentration in the skeletal muscle during exercise, possibly because of obstructed movement of glycerol through AQP3 and decreased liver gluconeogenesis, thus affecting sustained exercise [55]. In addition, AQP3 and muscular dystrophy may be closely linked [56]. Notably, AQP3 deficiency exhibited association with several mechanisms, such as molecular programs related to impaired differentiation, progression into diseases invading muscle tissues, and ultimately metastasis (e.g. lymphovascular invasion) and reduced drug efficacy [57].

AQP3 in placental lipid metabolism

The placenta is a metabolically active organ that plays a central role in maternal-fetal nutrient exchange, including lipid and glycerol movement. Recent studies have demonstrated the expression and functional roles of aquaporins, particularly aquaglyceroporins, in placental tissues. Among them, AQP3 has garnered significant attention for its involvement in placental lipid metabolism.

AQP3 is localized to the apical membrane of syncytiotrophoblasts and facilitates the transcellular movement of water and glycerol from maternal circulation to the fetus. This function is critical for fetal energy supply and lipid accumulation [58]. AQP3 expression is hormonally regulated during pregnancy and may respond to maternal metabolic cues [59], suggesting a dynamic role in maintaining metabolic homeostasis. Importantly, dysregulation of placental AQP3 has been linked to pregnancy-related metabolic disorders. Altered AQP3 expression has been reported in placentas from gestational diabetes mellitus (GDM) cases, correlating with impaired glycerol movement and altered fetal growth patterns [60].

AQP7

AQP7 is an important aquaglyceroporin that moves ammonia, glycerol, hydrogen peroxide, urea, arsenite, and water [61]. The protein can be detected in human kidney, skeletal muscle, pancreas, and liver, with a notably high abundance in human fatty tissues [36]. AQP7 may also be a diagnostic basis and prognostic indicator for breast cancer [62].

Adipose tissue

Both adipose cells and vascular endothelial cells of brown and white adipose tissues display high abundances of AQP7 [18, 36]. As a type of tissue mainly responsible for storing fat, the endocrine significance of adipose tissue is being increasingly acknowledged [63]. Adipose cells regulate their TG content according to their energy requirements upon nerve and hormonal stimulation. In the presence of high energy requirements, adipocytes produce glycerol and FFA via TGs hydrolysis and supply these source substrates to other tissues faced with energy shortage. As a glycerol channel expressed on adipocytes, AQP7 determines the use of glycerol in adipose tissue and blood circulation, and affects intracellular lipid metabolism [64]. The glycerol concentration in AQP7-deficient mouse adipocytes is significantly increased, and a high glycerol concentration can increase glycerol kinase (GlyK) activity and promote TGs synthesis [12]. AQP7 is a representative lipid metabolism disorder gene implicated with obesity, whose downregulation is associated with insulin resistance [65]. Therefore, AQP7 downregulation induces fatty tissue TG accumulation and contributes to obesity occurrence.

Adipocytes possess dynamic mechanisms regulating AQP7 transcription. The promoter contains a peroxisome proliferator response element (PPRE) and an insulin-responsive element [66, 67]. Insulin suppressed AQP7 via PI3K signaling and fasting/refeeding-induced expression fluctuations align with lipid mobilization cycles [66]. In addition, AQP7 expression increased up to 2.2-fold in the white adipose tissue in diabetic mice induced through streptozotocin administration relative to that in the controls, and a 3-day fasting treatment significantly increased AQP7 expression, which was not observed following a 1-day fasting period [68]. PPARγ agonists enhanced AQP7 mRNA in adipocytes through PPRE binding, coordinating adipogenesis and glycerol metabolism [69, 70]. Leptin deficiency reduces AQP7 expression, which correlates with abnormal lipid profiles in both murine models and humans [47, 71]. Targeting glycerol movement function of AQP7 showed therapeutic potential; carboxymethyl-chitin modulated the AQP7-adenosine monophosphate-activated protein kinase axis to inhibit lipogenesis [72], while the adipokine apelin-13 upregulated AQP7 via PI3K to ameliorate lipid overload [73]. These observations reflect the potential of AQP7 as a therapeutic target for obesity.

Long-term starvation causes compensatory capillary AQP1 upregulation inside fatty tissues of mice lacking AQP7 expression, reflecting an adaptive response in water and glycerol facilitation under conditions of impaired AQP7 function [74].

Kidney

Previous immunohistochemical analyses confirmed that AQP7 exhibits specifically high expression on the brush border membrane of segment 3 (S3) of the renal proximal tubule, as well as in the spermatozoa and spermatids of male genital system [67, 68, 75]. In this case, it was rarely involved in water reabsorption. In contrast, AQP7-knockout mice show significant glyceruria, suggesting the crucial function of AQP7 in reabsorbing glycerol [76, 77]. Interestingly, although those mice displayed evident glyceruria symptoms, the contents of glycerol within their plasma were comparable to those of their wild-type counterparts [76]. The apparent loss of glycerol hinders lipid accumulation. The utilization of reabsorbed glycerol for glucose biosynthesis in kidney cells might modify glucose production pathways or favor the consumption of alternative gluconeogenic precursors [78]. Consistent with the aforementioned in vivo findings, a G264V homozygous missense mutation in AQP7 resulted in the phenotypes of normal plasma glycerol levels and signature glyceruria in three non-consanguineous children [79]. In conclusion, AQP7 possesses the crucial functions of reabsorbing glycerol and modulating gluconeogenic pathways inside kidney tissues.

Muscular tissue

AQP7 is expressed in both the skeletal [80] and myocardium [81] muscles. For skeletal muscles, the distribution of AQP7 was noted on myocyte membrane and capillary endothelial cells [68, 82]. The abundance of AQP7 in skeletal muscles of leptin-deficient ob/ob obese mice was higher than that in WT mice [83]. Consistent with this finding, Male type 2 diabetic sufferers also display significantly higher AQP7 abundance in their skeletal muscles relative to healthy male counterparts [84].

Glycerol may be crucial for cardiomyocyte lipid metabolism [85]. Similar to the skeletal muscle, AQP7 showcases confined expression on capillary endothelial cells of mouse myocardial tissues [68]. Previous research indicated that AQP7-deficient mice displayed markedly reduced consumption of glycerol in cardiomyocytes and significantly lower contents of adenosine triphosphate (ATP) relative to the wild-type controls [85], indicating that AQP7 has the function of regulating ATP generation and glycerol metabolism in cardiomyocytes. In addition, research utilizing various cardiac stress models demonstrated enhanced deathrates and higher likelihood of left ventricular hypertrophy in AQP7-knockout mice [85]. As a crucial enzyme catalyzing TG hydrolysis to yield FFA and glycerol, lipoprotein lipase (LPL) exhibits enhanced expression in the context of myocardial infarction (MI), and certain deficiencies of this enzyme promote cardiomyocyte apoptosis and post-MI cardiac dysfunction. Additionally, AQP7 deficiency would increase infarct size and ischemia-induced apoptosis; glycerol-3-phosphate dehydrogenase 2 (GPD2) could promote ATP synthesis from glycerol under physiological conditions, and GPD2 deficiency would aggravate post-MI cardiac dysfunction [86]. Collectively, these studies confirm the ability of AQP7 to control cardiac glycerol metabolism and induce lipid accumulation, and provide a basis for preventing myocardial ischemia-related complications.

Pancreas

Pancreatic beta cells, crucial endocrine cells involved in insulin production and the regulation of blood glucose uptake, also express AQP7. Investigations utilizing mouse models demonstrate that AQP7 could regulate the multiplication of endocrine cells, biosynthesis of TG, and production of insulin [87, 88]. Although the protein is localized within the cytoplasm, Matsumara et al. noticed enhanced glycerol concentration, increased GlyK activity, decreased beta cell volume, and increased insulin synthesis in islets of AQP7-knockout mice [88–90]. Typically, pancreatic cells display minimal activity of GlyK. However, the introduction of glycerol at the genetic level stimulates insulin synthesis and secretion [91], suggesting the significant contribution of GlyK activity to these events. In contrast, insulinemia was not observed when studying the functional role of pancreatic beta cells in AQP7-knockout mice. Additionally, adipocyte hypertrophy [92] and significant glyceruria [12] have been previously demonstrated. Further studies have found that AQP7 defects lead to glycerin-induced swelling damage and membrane potential changes in the beta cells of islets, suggesting another mechanism by which AQP7 affects insulin secretion [93]. Owing to various contradictions between studies, the effect of changes in AQP7 expression in the pancreas on insulin secretion requires Further research to elucidate the underlying molecular mechanisms. A recent study proposed that metformin treatment for type 2 diabetes may inhibit mitogen-activated protein kinase signaling to promote pancreatic AQP7 expression. AQP7 upregulation in turn facilitated glycerol transmembrane movement into β cells, thereby inducing insulin secretion [94]. Furthermore, AQP7 deficiency may cause hyperinsulinemia, insulin resistance, and obesity [88, 95, 96]. To summarize, understanding how pancreatic AQP7 expression affects insulin secretion remains challenging.

Liver

AQP7 is expressed in both human [97] and mouse [98] liver. However, it has also been reported that AQP7 is not expressed in mouse [99] and rat [42] livers, and has very low mRNA levels in human livers [100, 101]. In the human liver, AQP7 is mainly located in the cytoplasm of hepatocytes [102], and on the top membrane of the bile duct and endothelial cells [103]. Additionally, 17β estradiol (E2) can promote the expression of AQP7, inhibit GlyK activity and TG synthesis in HepG2 cells, and alleviate hepatocyte steatosis [104]. Nevertheless, owing to limited evidence, the mechanism of action of AQP7 in the liver needs to be further explored.

Genital system

AQP7 is expressed in the mouse testicles and human sperm [16]. A lack of AQP7 expression was observed in infertile male patients. Consistent with mounting evidence from prior investigations implicating AQP7 in male reproductive physiology, several studies have demonstrated that impaired AQP7-mediated glycerol movement mechanisms are significantly correlated with both asthenozoospermic manifestations and the regulation of metabolic processes during human sperm capacitation, particularly in relation to energy substrate use for hyperactivated motility [105, 106].

AQP9

Liver

The Liver plays a key role in 70–90% of glycerol metabolism in the body [107]. AQP9 is expressed in the liver of both humans and mice [108, 109] It is the most abundantly expressed aquaglyceroporin in the liver, located in the plasma membrane of hepatic sinuses facing the portal vein [110], and mainly involved in the movement of water, glycerol, and urea in the liver [111]. Among them, the permeability of AQP9 to glycerol and urea is much stronger than that to water, which promotes glycerol inflow and urea outflow of hepatocytes [112]. In addition, AQP9 in the liver mediates the entry of water from the sinusoidal side during primary bile formation [113]. The role of AQP9 in maintaining the physiological environment of the liver under basic conditions is important, especially in osmotic pressure regulation and energy metabolism [114, 115]. AQP9 participates in the lipid-lowering effect of silybin via autophagy and LD synthesis, thereby regulating liver lipid metabolism [116]. Additionally, AQP9 expression positively correlates with the severity of fatty liver disease [9, 117, 118]. It is considered a potential treatment for non-alcoholic fatty liver disease (NAFLD) because NAFLD is characterized by abnormal lipid metabolism and excessive accumulation of TGs stored in LDs, and TG synthesis is closely related to AQP9-mediated glycerol uptake. Therefore, decreased AQP9 expression can lead to decreased hepatocyte glycerol levels, which may be a new treatment for patients with NAFLD [100]. Further downregulation of AQP9 in insulin-resistant mice could constitute a defense mechanism against hyperglycemia and steatosis in patients with NAFLD [100]. After activating PPARα, the expression of the AQP9 protein in liver was significantly decreased, and efficiency of gluconeogenesis was weakened. AQP9 plays a role in glycerol uptake in liver lipid metabolism [119, 120]. Other studies have shown that the expression level of AQP9 in fasting mice significantly decreases after refeeding, indicating that AQP9-mediated gluconeogenic utilization of glycerol decreases after feeding [121]. Additionally, AQP9-null mice had increased plasma glycerol and TG levels, suggesting an important role for AQP9 in hepatic glycerol metabolism [11]. Collectively, these results suggest that AQP9 plays an important role in glycerol absorption in the liver and affects the gluconeogenic pathway, thus establishing its role as an important target in glycolipid metabolism.

Brain tissue

AQP9 plays a similar role in many neurological disorders owing to its wide distribution in the brain. The expression of AQP9 mainly occurs in three cell types: (i) glial cells, mainly astrocytes [122], (ii) endothelial cells [123], and (iii) neurons [124]. In astrocytes, AQP9 acts as a metabolic channel involved in glycerol and lactate outflow [125]. Under normal physiological conditions, human AQP9 moves electroneutral species of L-lactate. Changes in human physiological pH can affect the concentration of lactic acid, thereby affecting the permeability of AQP9 [126–128]. Under pathological conditions, the expression of AQP9 in the affected parts increases and astrocytes perform L-lactate metabolic uptake to maintain energy homeostasis. This further indicates that AQP9 in astrocytes is associated with reduced accumulation of extracellular lactate [125]. This is precisely because the mRNA expression of AQP9 increases under pathological conditions, suggesting that AQP9 can serve as an effective diagnostic marker. For example, in a study of human astrocytic tumors, the expression of AQP9 mRNA and protein was significantly higher than in normal brain tissue and was positively correlated with pathological staging. It has been proposed to AQP9 plays an important role in the malignant progression of astrocytic tumors and can be used for diagnosis [129].

Endothelial cells expressing AQP9 are mainly concentrated in the pia but not in the brain parenchyma [125]. Endothelial cells of the pia participate in the formation of the blood-brain barrier, which is permeable to glycerol [130]. Therefore, AQP9 may be involved in glycerol movement through the blood-brain barrier. AQP9 of neuron cells was also involved in the movement of lactate and glycerol, both of which serve as substrates for energy survival [131]. Although these studies suggest that the expression of AQP9 in the brain tissue may be related to lipid metabolism, direct evidence of a relationship between AQP9 and lipid metabolism is still lacking.

Genital system

The expression of AQP9 was observed within the cilia of epididymal duct and testicular interstitial cells in rat testes [132]. Furthermore, its presence was noted throughout the male reproductive tract, specifically within the epithelium of the efferent tubules, epididymis, and vas deferens, potentially implicating its involvement in sperm maturation, concentration, and storage [133]. AQP9 expression is regulated by testosterone and estrogen [134, 135]. This suggests that AQP9 in testicular stromal cells is involved in the rapid uptake and release of various small-volume lipids and cholesterol metabolites through the apical membrane.

In addition to their expression in the male reproductive tract, recent studies have demonstrated that several other AQPs, including AQP7, AQP8, and AQP9, are expressed in Sertoli cells, where they play important roles in testicular metabolism and spermatogenesis. AQP-mediated glycerol movement within Sertoli cells contributes to the maintenance of the intracellular energy balance and supports the metabolic needs of developing germ cells. Furthermore, the dysregulation of AQP expression in Sertoli cells has been linked to oxidative stress, disruption of the blood-testis barrier, and impaired spermatogenic function, which are key factors contributing to male infertility [136, 137]. These findings underscore the metabolic and pathophysiological relevance of Sertoli cell AQPs and suggest their potential as novel targets for the diagnosis and management of male reproductive disorders.

AQP9 in placental lipid metabolism

AQP9, another key aquaglyceroporin, is expressed in placental endothelial and trophoblast cells. It mediates the movement of small solutes such as glycerol and L-lactate, the latter being a key energy substrate under both physiological and hypoxic conditions [138]. Subsequent studies have further demonstrated its role in lactate movement and metabolic regulation, particularly in hepatic and immune cell contexts, thereby underscoring its broader physiological significance [139]. Such AQP9-mediated lactate movement may contribute to fetal energy metabolism, particularly when glucose availability is limited.

In summary, AQPs, particularly AQP3 and AQP9, are integral to placental lipid metabolism and fetal nutrient supply. Their expression and function may influence pregnancy outcomes, positioning them as potential biomarkers or therapeutic targets in gestational metabolic disorders.

AQP10

Adipose tissue

AQP10 is present in human white adipose tissue, localized in the plasma membrane of fat cells, and can be considered an alternative pathway for glycerol efflux, in addition to the previously demonstrated aquaglyceroporins. AQP7 and AQP10 are particularly important for maintaining normal or low glycerol content in adipocytes, thus protecting humans from obesity [18]. Gotfryd et al. demonstrated that, in human adipocytes, the decreased pH observed during lipolysis (fat burning) correlated with increased glycerol release and stimulation of AQP10 [140]. Glycerol flux across the plasma membranes of adipocytes (and likely duodenal enterocytes, where the reported pH was acidic) was stimulated by low pH and unarguably Linked to human aquaporin 10 (hAQP10) [140].

Intestine

AQP10 is highly expressed in the human duodenum, jejunum, and ileum, facilitating the absorption of intestinal water and glycerol [141, 142]. Immunohistochemistry and immunoelectron microscopy have shown that AQP10 is localized in the capillary endothelium of the villi of the small intestine [143]. AQP10 is the only human aquaglyceroporin stimulated by pH reduction and is controlled by pH-dependent glycerol-specific gating rather than classical selectivity filter control [140]. As the pH decreases, the fluxes of glycerol and water increase. hAQP10 is substantially relevant to glycerol flow in these cell types [18, 143, 144]. AQP10 immunostaining was interrupted at the opening of goblet cells and significantly reduced on the apical membrane of epithelial cells near the crypt at the base of the villi [141]. This indicated that AQP10 was strategically expressed in the upper villi to achieve maximum water or low-solute absorption. However, studies on the function of AQP10 are limited.

Skin

AQP10 was not found in human skin in previous studies, but Boury-Jamot et al. recently found that the mRNA of AQP10 was present in keratinocytes, indicating that AQP10 may be modulated by pH and elevated pH levels are likely to upregulate AQP10 activity [145]. However, little research has been conducted on the movement mechanism of AQP10 in the skin.

Superaquaporins influence lipid metabolism

AQP11 and AQP12, which serve as the third subfamily of AQPs, exhibit unique Asn-Pro-Cys motifs in AQP11 and Asn-Pro-Thr in AQP12 and are located in the membranes of intracellular organelles [146–148]. AQP11 was permeated with water [148], glycerol [149], and H₂O₂ [150]. Endoplasmic reticulum (ER) AQP11 was identified close to LDs in human adipocytes [148], indicating that it may be related to lipid metabolism. Based on this finding, Frühbeck et al. demonstrated that downregulation of AQP11 exacerbated transforming growth factor β1 (TGF-β1)-induced ER stress in visceral adipocytes [151]. These findings suggest that the pharmacological targeting of AQP11 to attenuate ER stress may represent a novel therapeutic strategy for obesity management. Studies on the association between AQP12 and lipid metabolism are not yet available and require further investigation.

Strengths and limitations

This review provides a comprehensive synthesis of the current knowledge regarding the roles of AQPs in lipid metabolism, integrating findings across multiple organ systems, including adipose tissue, liver, muscle, kidney, pancreas, and brain. One particular strength lies in the inclusion of both well-studied aquaglyceroporins (AQP3, AQP7, and AQP9) and less-explored classical AQPs and superaquaporins (AQP5, AQP8, and AQP11), thereby offering a broad and nuanced perspective on the involvement of AQPs in lipid metabolic regulation.

Nevertheless, several limitations should be acknowledged. This review predominantly focuses on preclinical and animal model studies, with relatively limited human clinical data available to confirm the translational applicability of these findings. Furthermore, inconsistencies in the reported tissue distribution and functional roles of certain AQPs, such as AQP10 and AQP7, in the pancreas and liver warrant cautious interpretation. Technical challenges inherent to AQP research, including compensatory mechanisms in knockout models and limitations in distinguishing direct channel-mediated effects from systemic metabolic adaptations, further complicate the mechanistic understanding. Addressing these limitations is essential to advance AQP-targeted therapeutic strategies for the management of metabolic diseases.

Conclusions and future perspectives

The diverse functions of AQPs in lipid metabolism emphasize their importance in maintaining energy homeostasis. Specifically, aquaglyceroporins, including AQP3, AQP7, and AQP9, are critical for glycerol facilitation, thereby linking adipose tissue lipolysis to hepatic gluconeogenesis and muscular energy utilization. Dysregulation of these aquaglyceroporins has been implicated in metabolic disorders, such as obesity, insulin resistance, and NAFLD. For example, AQP7 deficiency in adipocytes results in elevated intracellular glycerol levels, which promote TG accumulation and obesity, whereas downregulation of hepatic AQP9 in NAFLD may represent a compensatory mechanism to mitigate steatosis. Similarly, the involvement of AQP3 in skin hydration and adipogenesis highlights its systemic metabolic effects.

Classical AQPs and super-aquaporins, which are not directly involved, modulate lipid metabolism through secondary pathways. Mitochondrial AQP8 regulates cholesterol synthesis via H₂O₂ signaling and ER-localized AQP11 modulates oxidative stress, a key factor in obesity-induced inflammation. These observations suggest that classical AQPs and superaquaporins may serve as potential therapeutic targets in addition to aquaglyceroporins.

However, there are several knowledge gaps in the literature. The physiological relevance of AQP10 in humans is not fully understood and reports on its tissue distribution are inconsistent. However, these contradictory roles of AQP7 in pancreatic insulin secretion require further investigation. Technical challenges, such as differentiating channel-specific effects from systemic metabolic adaptations in knockout models, complicate mechanistic studies. Future research should focus on tissue-specific AQP manipulation and exploration of their interactions with LD proteins or signaling kinases.

In conclusion, AQPs are integral to lipid metabolism and function as key regulators of the glycerol flux and redox balance. Their dual roles in health and disease render them promising candidates for the diagnosis and treatment of metabolic syndromes, thereby contributing to improved metabolic health and fostering sustainable and equitable approaches to healthcare.

Abbreviations

AQPs

Aquaporins

NPA

Asn-Pro-Ala

TGs

Triacylglycerols

FFA

Free fatty acids

LDs

Lipid droplets

SREBPs

Sterol regulatory element-binding proteins

mtAQP8

Mitochondrial AQP8

hAQP10

Human aquaporin 10

PLD2

Phospholipase D2

PG

Phosphatidylglycerol

HDAC3

Histone deacetylase 3

PPARs

Peroxisome proliferator-activated receptors

HSL

Hormone-sensitive lipase

G3P

Glyceraldehyde 3-phosphate

GlyK

Glycerol kinase

PPRE

Peroxisome proliferator response element

ATP

Adenosine triphosphate

MI

Myocardial infarction

LPL

Lipoprotein lipase

GPD2

Glycerol-3-phosphate dehydrogenase 2

MAPK

Mitogen-activated protein kinase

NAFLD

Non-alcoholic fatty liver disease

ER

Endoplasmic reticulum

TGF-β1

Transforming growth factor β1

PPARα

Peroxisome proliferator-activated receptor alpha

PPARγ

Peroxisome proliferator-activated receptor gamma

HMGCoAR

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Authors’ contributions

YB, SP and YL conceived the idea and prepare the outline and first draft of the manuscript; YB, QM and XY wrote the manuscript; JC and AS prepared figures for the manuscript; YB, XY and JW review the manuscript; All the authors read and approved the submission of the manuscript.

Funding

This work was supported by National Natural Science Foundation of China (No. 82173121).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.