Hepatocyte and Sertoli Cell Aquaporins, Recent Advances and Research Trends

Abstract

Aquaporins (AQPs) are proteinaceous channels widespread in nature where they allow facilitated permeation of water and uncharged through cellular membranes. AQPs play a number of important roles in both health and disease. This review focuses on the most recent advances and research trends regarding the expression and modulation, as well as physiological and pathophysiological functions of AQPs in hepatocytes and Sertoli cells (SCs). Besides their involvement in bile formation, hepatocyte AQPs are involved in maintaining energy balance acting in hepatic gluconeogenesis and lipid metabolism, and in critical processes such as ammonia detoxification and mitochondrial output of hydrogen peroxide. Roles are played in clinical disorders including fatty liver disease, diabetes, obesity, cholestasis, hepatic cirrhosis and hepatocarcinoma. In the seminiferous tubules, particularly in SCs, AQPs are also widely expressed and seem to be implicated in the various stages of spermatogenesis. Like in hepatocytes, AQPs may be involved in maintaining energy homeostasis in these cells and have a major role in the metabolic cooperation established in the testicular tissue. Altogether, this information represents the mainstay of current and future investigation in an expanding field.

Keywords: Non-Alcoholic Fatty Liver Disease (NAFLD); bile formation; liver; male fertility; metabolic homeostasis; mitochondria; reactive oxygen species (ROS); spermatogenesis; testis.

Figure 1

Proposed model of glycerol uptake by Aquaporin 9 (AQP9) in hepatocytes. Glycerol is imported from the sinusoidal blood through the membrane facilitated pathway created by AQP9. Once in the cell interior, glycerol kinase (GK) phosphorylates glycerol (G-3-P) to sustain gluconeogenesis (GNG) or triacylglycerols’ (TAGs) synthesis. BC, bile canaliculus; FFA, free fatty acids; GLUT2, glucose transporter 2; PEP, phosphoenolpyruvate; Pyr, pyruvate; VLDL, very-low-density lipoprotein.

Figure 2

Working model of AQP-facilitated water movement in canalicular bile formation. AQP8 mediates osmotically-driven water secretion into the bile canaliculus (BC), whereas sinusoidal AQP9 contributes to the cellular uptake of water. The choleretic hormone glucagon, after binding to its receptor (in red), stimulates the microtubule-dependent canalicular targeting of AQP8-bearing vesicles located subapically (SAV, subapical vesicles). During the agonist-stimulated hepatocyte bile formation, the transcellular movement of water is coupled osmotically to the active transport of bile salts through pumps and exchangers. PKA, protein kinase A; ST, solute transporters. Black arrows indicate water transport; white arrows indicate solute transport.

Figure 3

Working model for the function of aquaglyceroporins in the onset of insulin resistance and Non-Alcoholic Fatty Liver Disease (NAFLD) in humans. Insulin and leptin are regulatory factors for the expression of adipocyte AQP3 and AQP7 and hepatocyte AQP9. Circulating insulin and leptin levels vary in accordance to the metabolic state and adiposity, respectively. Hence, the expression of aquaglyceroporins in fat tissue and hepatocytes augments or diminishes in function of the nutritional needs and excess adipose mass. In the setting of obesity-associated insulin resistance and NAFLD, despite the hyperleptinemia, adipocyte AQP3 and AQP7 undergo overexpression. This leads to the increase of glycerol output from fat cells and glycerol use for hepatic gluconeogenesis and lipid synthesis. The reduced levels of AQP9 and glycerol permeability in the liver of obese subjects with insulin resistance is speculated to be a counteracting mechanism to prevent a further aggravation in liver steatosis and hyperglycemia. ATGL, adipose tissue triacylglycerol lipase; GLUT2, Gcose transporter, type 2; HSL, hormone-sensitive lipase; FFA, free fatty acids; GK, glycerol kinase; TAGs, triacylglycerols.

Figure 4

Schematic diagram of the metabolic cooperation between Sertoli cells (SCs) and developing germ cells. The glucose taken up from the extracellular space enters SCs through glucose transporters (GLUTs). The glucose is then converted to pyruvate through glycolysis. Pyruvate can follow multiple pathways. However, in these cells, most glucose is used to produce, via lactate by lactate dehydrogenase (LDH). Lactate is then transported out of SCs by specific monocarboxylate transporters (MCT4). Germ cells take up the lactate produced by SCs through MCT2. Of note, as happens in other cells, pyruvate can also be converted into alanine (by alanine aminotransferase—ALT) or transported to mitochondria, forming acetyl-CoA (by pyruvate dehydrogenase—PDH). Acetyl-CoA is then converted into acetate that may be used by germ cells for lipid synthesis. PFK, phosphofructokinase.

Figure 5

Schematic diagram of the possible subcellular localizations of AQPs in Sertoli cells and their possible link to metabolism. SCs express multiple AQP homologues, AQP0, AQP4, AQP8 and AQP9. The basolateral plasma membrane is believed to contain AQP0, AQP4 and AQP9. Basolateral AQP9 may be relevant for testicular metabolic cooperation. The SC adluminal plasma membrane contains AQP4, AQP8 and AQP9. Adluminal AQP9 may mediate the extrusion of metabolic intermediates such as lactate, acetate and glycerol (in addition to water). The functional significance of adluminal AQP4, an AQP highly permeable to water, and AQP8, a homologue conducting water and some other molecules, remains elusive.