Edited by: Graça Soveral, Universidade de Lisboa, Portugal
Reviewed by: Janne Lebeck, Danish Diabetes Academy, Denmark; Amaia Rodríguez, Universidad de Navarra, Spain
This article was submitted to Membrane Physiology and Membrane Biophysics, a section of the journal Frontiers in Physiology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Aquaporins (AQPs) are a family of transmembrane channel proteins facilitating the transport of water, small solutes, and gasses across biological membranes. AQPs are expressed in all tissues and ensure multiple roles under normal and pathophysiological conditions. Aquaglyceroporins are a subfamily of AQPs permeable to glycerol in addition to water and participate thereby to energy metabolism. This review focalizes on the present knowledge of the expression, regulation and physiological roles of AQPs in adipose tissue, liver and endocrine pancreas, that are involved in energy metabolism. In addition, the review aims at summarizing the involvement of AQPs in metabolic disorders, such as obesity, diabetes and liver diseases. Finally, challenges and recent advances related to pharmacological modulation of AQPs expression and function to control and treat metabolic diseases are discussed.
Mammalian aquaporins (AQPs) are a family of 13 integral membrane channel proteins termed AQP0–AQP12, facilitating the transport of water, small solutes, and gasses across biological membranes (
AQPs also allow movement of gasses such as CO2 (AQP1, AQP4, and AQP5), NO (AQP1, AQP4) or O2 (AQP1, AQP4) (
The expression of aquaglyceroporins has been documented in many body locations including adipose tissue, liver, and pancreas where they are reported to play important metabolic functions (
Considering the role of aquaglyceroporins in adipose tissue has been subjected to extensive reviews (see
In adipocytes, aquaglyceroporins display different subcellular localizations and are subjected to trafficking in response to hormonal stimulation, including insulin and cAMP-inducing hormones (
From a metabolic point of view, adipose tissue is a major source of triacylglycerols (TAG) storage during feeding, as well as a major source of plasma glycerol during fasting (
Experiments using differentiated adipocytes (
In mouse 3T3-L1 cells differentiated into adipocytes, hormones activating the cAMP pathway induced the translocation of AQP3 and AQP7, localized within intracellular vesicles, to the plasma membrane, while the plasma membrane localization of AQP9 was unchanged (
Glycerol metabolism: working model of the interplay between the liver and adipose tissue in fed and starved states in mouse. During fasted state, glucagon secretion is induced, TAG are hydrolyzed to glycerol and free fatty acids in adipocytes, and both AQP7 and AQP3 traffic to the plasma membrane and participate with AQP9 to glycerol efflux. AQP9 allows plasma glycerol entry in hepatocytes. Glycerol is then converted to glycerol-3-phosphate by glycerol kinase, and thereby participates to gluconeogenesis. During fed state inducing insulin secretion, glucose metabolites, glycerol-3-phosphate (obtained from glycerol by glycerol kinase enzymatic activity) and free fatty acids are used to produce TAG in both liver and adipose tissue. In response to insulin in adipocytes, AQP3 and AQP7 traffic from the plasma membrane to intracellular compartments. Glycerol most likely mainly enters adipocytes via AQP9. During lipogenesis, adipose glycerol uptake is likely low due to the weak activity of the glycerol kinase. In hepatocytes, glycerol likely enters via AQP7 and AQP9. ATGL, adipose triglyceride lipase; GK, glycerol kinase; Glut2, glucose transporter 2; Glut4, glucose transporter 4; G3P, glycerol-3-phosphate; FFA, free fatty acids; HSL, hormone sensitive lipase; TAG, triacylglycerols; broken arrows: trafficking.
In adipose tissue, the role of aquaglyceroporins in metabolic diseases, and more especially in obesity and metabolic syndrome, has extensively been reviewed (
Depending on their genetic background,
As human
Reported species-related expression and suggested physiological and pathophysiological relevance of adipose tissue aquaglyceroporins.
Aqua-glyceroporin | Cell type | Suggested physiological role | Suggested pathophysiological involvement |
---|---|---|---|
AQP3 | Adipocytes (h, m, r) | TAG synthesis; uptake of glycerol (low contribution) | |
Lipolysis; release of glycerol | |||
AQP7 | Adipocytes (h, m, r) | TAG synthesis; uptake of glycerol (low contribution) | Obesity; Insulin resistance; metabolic syndrome |
Lipolysis; release of glycerol | |||
Endothelial cells (h, m) | Unknown | ||
AQP9 | Adipocytes (h, m) | TAG synthesis; uptake of glycerol (low contribution) | |
Lipolysis; release of glycerol | |||
AQP10 | Adipocytes (h) | Unknown |
Glycerol is an intermediate metabolite of physiological relevance in energy metabolism. Indeed, glycerol is a direct source of glycerol-3-phosphate (G3P), an important substrate for hepatic gluconeogenesis during fasting and for TAG synthesis (
In rodents and human, AQP9 is expressed at the sinusoidal domain of the hepatocyte plasma membrane, facing the space of Disse (
Liver AQP9 has also considerable relevance to lipid metabolism as G3P also represents a key substrate for TAG synthesis (
In rat, the fasting-induced increase of liver AQP9 expression resulted a 2.6 times higher level in males than females (
Probably due to the broad selectively of its channel, hepatocyte AQP9 seems to be of pleiotropic relevance, as roles in bile formation (
In addition to AQP9, but to a lesser extent and undermined by conflicting results, human hepatocytes have been also reported to express the other three aquaglyceroporins, AQP3, AQP7, and AQP10 (
The reported localization and suggested physiological relevance of liver aquaglyceroporins are described in
Reported localization and proposed physiological and pathophysiological relevance of liver aquaglyceroporins.
Aquaglyceroporins | Cell type | Subcellular location | Suggested physiological role | Suggested pathophysiological involvement |
---|---|---|---|---|
AQP3 | Kupffer cells (h) | Undefined | Repopulation of Kupffer cells in liver regeneration | Kupffer cell migration and proinflammatory cytokine secretion |
Hepatocytes (h) | Undefined | Uptake of glycerol? | Insulin resistance? | |
Stellate cells (h) | Undefined | Cell activation | Hepatic steatosis (I148M variant) | |
AQP7 | Hepatocytes (h, m) | Cyt; others? | TAG synthesis; uptake of glycerol? | Insulin resistance |
Cholangiocytes (h) | APM | Unknown | ||
Endothelial cells (h) | APM | Unknown | ||
AQP9 | Hepatocytes (h, m, r) | BLPM | Uptake of portal glycerol (gluconeogenesis; TAG synthesis); import of water from portal blood (bile formation); urea extrusion; arsenic detoxification; liver regeneration | NAFLD; NASH; obesity; T2D; hepatocellular carcinoma |
Cholangiocytes (h) | Undefined | Unknown | ||
AQP10 | Hepatocytes (h) | Undefined | Exit of glycerol during lipolysis |
Consistent with their role in facilitating glycerol transport into and out of cells and the related control of fat accumulation and glucose homeostasis, hepatic aquaglyceroporins, in particular AQP9, are reported to be implicated in metabolic disorders affecting the liver (
The pathology of NAFLD is multifactorial and characterized by ectopic accumulation of TAG in the liver ranging from simple fatty liver (hepatic steatosis) to NASH and to cirrhosis (irreversible, advanced scarring of the liver) (
AQP9 seems to be of minor pathophysiological relevance in the fatty liver disease of alcoholic origin. A rapid increase in glycerol import and cell size was seen when rat primary hepatocytes were acutely exposed to acetaldehyde, an oxidation product derived from ethanol by the action of the hepatic enzyme alcohol dehydrogenase (
Contrary to liver steatosis, a recent work using subcutaneously xenografted liver tumors in nude mice showed that hepatic AQP9 overexpression inhibit hepatocellular carcinoma by upregulating forkhead-box protein O1 (FOXO1) expression (
A recent study showed that treatment with estrogen protects against ovariectomy-induced hepatic steatosis by increasing hepatocyte AQP7 expression (
Human HSC AQP3 was suggested to interact with the PNPLA3 I148M variant in causing hepatic steatosis, NASH, fibrosis and cancer (
Endocrine pancreas accounts for 10% of total pancreas and is made of islets of Langerhans dispersed within the pancreatic tissue. Islets of Langerhans are constituted of five types of cells: (1) β-cells producing insulin; (2) α-cells producing glucagon; (3) δ-cells producing somatostatin; (4) γ-cells producing pancreatic polypeptide; and (5) 𝜖-cells producing ghrelin (
To the best of our knowledge, the expression of aquaglyceroporins in human endocrine pancreas has not yet been documented. However, AQP7 is expressed in rat and mouse β-cells (
In β-cells, AQP7 has been shown to play a role in intracellular glycerol content and both insulin production and secretion (
Reported species-related expression and suggested physiological and pathophysiological relevance of pancreas aquaglyceroporins.
Aqua-glyceroporin | Cell type | Suggested physiological role | Suggested pathophysiological involvement |
---|---|---|---|
AQP3 | Absent in β-cells (m, r) | ||
AQP7 | β-cells (m, r) | Insulin secretion | Obesity |
TAG synthesis; uptake of glycerol | |||
Lipolysis; release of glycerol | |||
Regulation of β-cell size and number | |||
AQP9 | β-cells (r)∗ | ||
AQP10 | Undefined |
Glycaemia was measured in several
In the current model of insulin secretion, the sequential mechanisms accounting for insulin secretion involve: glucose uptake ensured by the glucose transporter type 2 (GLUT2), metabolism of glucose, increase in intracellular ATP concentration, inhibition of ATP-sensitive potassium channels, membrane depolarization, opening of voltage-dependent calcium channels, increase in intracellular calcium concentration, and finally insulin vesicle degranulation (
Role of AQP7 in β-cell insulin secretion. Following glycerol entry via AQP7 in β-cell (1), β-cell undergo cell swelling (2) leading to the activation of volume-regulated anion channel (VRAC) with concomitant Cl- exit (3) and subsequent cell membrane depolarization (4). Cell membrane depolarization then activates voltage-sensitive calcium channels leading to intracellular calcium increase (5) provoking insulin exocytosis (6).
Based on the results from the literature, following an increase in circulating glycerol levels (in response to the induction of lipolysis in adipocytes), it is hypothesized that local β-cells intracellular glycerol concentration rises and induces activation of β-cells. In addition, β-cells activation, subsequent to intracellular glycerol concentration increase, may occur following a rise in insulin downregulating AQP7 expression (
Very little data are available in the literature concerning the expression and function of aquaglyceroporins in the endocrine pancreas in relation to metabolic diseases. One recent study, however, has shown that obese rats pancreas had increased
A variety of drugs have been identified as capable of modulating either the expression and/or the activity of aquaglyceroporins. The effects as well as the potential therapeutic use of aquaglyceroporin modulators are described with main focus on their relationship to metabolic diseases. More in general, most AQPs trigger strong interest for their pharmacological potentials in medical treatment of pathologies of high epidemiological impact such as the oxidative stress-related diseases (
Some gold(III)-base compounds have been shown to act as modulators of aquaglyceroporins. The gold(III) compound complex [Au(phen)Cl2]Cl (phen = 1,10-phenanthroline; Auphen) has been shown to be a very selective and potent blocker of AQP3 by binding to its selectivity filter domain, and to the side chain of Cys40 located close to the constriction pore (
Other gold compounds, including [Au(bipy)Cl2]+ (bipy = 2,2′-bipyridine; Aubipy), have been shown to also inhibit AQP3 (for review see
AQPs have been shown to contribute to cell migration, metastasis and angiogenesis (
The potential beneficial use of AQP3 inhibitors or modulators (decreasing AQP3 expression) remains to be evaluated for cancer treatment. In addition, radiolabeled glycerol could be used as a molecular probe targeting aquaglyceroporins to estimate their expression in different tissues
In adipose tissue, aquaglyceroporins, and in particular AQP7, represent potential drug target for the treatment of obesity and metabolic syndrome (
Metalloids, that are physiologically harmful to humans, are still being used in the form of arsenic or antimony containing drugs to treat certain diseases and forms of cancers (
Due to its permeability to glucogenic glycerol (
Troglitazone (a thiazolidinedione activating PPARγ) and tolbutamide (a sulfonylurea blocking potassium channels) were shown to significantly decrease AQP3 expression in Caco-2 cells, while metformin [belonging to the beguanide family and activating AMP-activated protein kinase (AMPK)] and tolbutamide did not alter AQP3 expression (
Phloretin, a natural antioxidant phenol acting as a potent inhibitor of glycerol fluxes (
Obese
A body of evidence indicates involvement of Adipose liver and endocrine pancreas aquaglyceroporins in the metabolic and energy control function exerted by these tissues. Metabolic relevance is also testified by the alterations in expression levels and regulation to which they undergo in clinical disorders associated with metabolic and energy dysfunction. While a number of reports have described aquaglyceroporins modulation by phytochemical compounds preventing or improving chronic metabolic diseases, investigation of their pharmacological potential is just picking up speed. New and more sustainable aquaglyceroporin inhibitors have been identified while others are subject to ongoing research. Development of therapeutic strategies targeting aquaglyceroporins may therefore offer promise for the management of a large spectrum of clinical disorders including metabolic and energy balance diseases. Overall, the study of biologically active phytochemicals and synthetic compounds as modulators of aquaglyceroporin expression or function is an emerging topic in which new and important achievements are anticipated.
CD wrote the first draft of the manuscript. GC, JP, and CD wrote sections of the manuscript. All authors contributed to manuscript revision, read and approved the submitted manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.