Biophysical assessment of aquaporin‐9 as principal facilitative pathway in mouse liver import of glucogenetic glycerol

Calamita, Giuseppe; Gena, Patrizia; Ferri, Domenico; Rosito, A.; Rojek, Aleksandra; Nielsén, Sören; Marinelli, Raúl A.; Frühbeck, Gema; Svelto, María

doi:10.1111/boc.201100061

Cited by 95 publications

(107 citation statements)

References 32 publications

(57 reference statements)

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“…In contrary, there was no NMD in our study, and reviewed the other split-site mutations previously reported, no NMD was found too [4,5]. Fourth, some studies demonstrated that glycerolutilization by the cells (especially, hepatocytes) is rate-limited by the membrane permeation step, rather than the GK step [13][14][15]. AQP9, an aquaglyceroporin, has been reported to be of great significance in glycerol membrane permeation step [13][14][15].…”

Section: Citation: Zeng L Mei L Tan H Li H Lv W Et Al (2017) a contrasting

confidence: 64%

“…Fourth, some studies demonstrated that glycerolutilization by the cells (especially, hepatocytes) is rate-limited by the membrane permeation step, rather than the GK step [13][14][15]. AQP9, an aquaglyceroporin, has been reported to be of great significance in glycerol membrane permeation step [13][14][15]. Expression of AQP9 is influenced by gender and disease state.…”

Section: Analysis Of Gk Expression By Real-time Quantitative Pcrmentioning

confidence: 99%

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A Novel Splice-Site Mutation of the Gk Gene in a Chinese Patient with Isolate Glycerol Kinase Deficiency

Wu¹

2015

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What is already known on this topic?Glycerol Kinase Deficiency (GKD) [OMIM 307030] is a rare X-linked recessive metabolic disorder, which is characterized biochemically by hyperglycerolaemia and glyceroluria. Mutations in the GK gene are the major causes of isolate GKD. What this study adds?We report a novel splice-site mutation (c.1340 -2A>G) identified at GK gene analysis. IntroductionGlycerol Kinase Deficiency (GKD) [OMIM 307030] is a rare X-linked recessive metabolic disorder, which is characterized biochemically by hyperglycerolemia and glyceroluria [1]. The clinical spectrum varies from asymptomatic and Central Nervous System (CNS) deterioration to severe developmental delay, and is found to be related with GK gene mutation. The gene (GK) is located on Xp21 and encodes a key enzyme in regulation of glycerol uptake and metabolism that catalyzes the phosphorylation of glycerol [2].GKD can be categorized into three types: Infantile GKD, Juvenile GKD and Adult GKD. The Infantile GKD, also called the complex GKD or Xp21 contiguous gene deletion syndrome, is the most common type of GK mutation, which is caused by a deletion of GK gene or the neighboring genes, the clinical manifestations depends on the deletion of the genes [3]. The juvenile GKD is called symptomatic GKD, with symptoms like episodic vomiting, acidemia and Central Nervous System (CNS) deterioration. The adult GKD is called asymptomatic GKD, which detected incidentally with pseudohypertriglyceridemia. The juvenile and adult GKD are also called isolated GKD, which mainly caused by point mutations in GK gene.In this case report, a Chinese patient clinically diagnosed with isolated glycerol kinase deficiency is detected to have a novel splice-site mutation in the GK gene, which leads to a skip of exon 17. Case Report General information and clinical manifestationsA 3-month-old male term infant was referred to hospital due to no weight gain for three months. He was born with uterine-incision delivery route due to malpresentation after a first pregnancy of a 27-year-old mother at 38 weeks of uncomplicated gestation. His Apgar score was 9 points at 5min, with birth weight 3250g and head circumference 32cm. The parents were nonconsanguineous. Laboratory testsThe infant's serum triglyceride was 11.17mmol/l (normal range: 0.52-1.56mmol/l), and his urine analysis revealed increased urine glycerol. His serum cortisol level was 1.00μg/dl (normal range: 3.7-19.4μg/dl (8 am); 2.9-17.3μg/dl (4 pm)), testosterone was 1.02ng/ml (normal range:1.42-9.23ng/ml), lactate dehydrogenase was 275.5U/l (normal range: 109-245U/l), and creatine kinase was 77.0U/l (normal range: 24-190U/l). Molecular studiesThe clinical and laboratory findings were consistent with the clinical diagnosis of isolated glycerol kinase deficiency. The proband and his mother were recruited at the Hunan Jiahui genetics hospital. The study was approved by the Ethics Committee of the State Key AbstractGlycerol Kinase Deficiency (GKD) is a rare X-linked recessive metabolic disorder. Mutations in the G...

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Section: Citation: Zeng L Mei L Tan H Li H Lv W Et Al (2017) a contrasting

confidence: 64%

Section: Analysis Of Gk Expression By Real-time Quantitative Pcrmentioning

confidence: 99%

A Novel Splice-Site Mutation of the Gk Gene in a Chinese Patient with Isolate Glycerol Kinase Deficiency

Wu¹

2015

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“…This 10-fold increase was accompanied by a two-fold increase in hepatocyte plasma membrane glycerol permeability, which was reversed by addition of phloretin (an apple polyphenol that inhibits AQP9, AQP3 and several non-AQP membrane channel proteins including the SGLT1&2 glucose transporters and UT-A urea channels [74]). The increase was abolished in AQP9 -/-mice [75]. Fasted AQP9 -/-mice have elevated plasma glycerol compared to wild-type [75,76].…”

Section: Aqp9mentioning

confidence: 82%

“…The increase was abolished in AQP9 -/-mice [75]. Fasted AQP9 -/-mice have elevated plasma glycerol compared to wild-type [75,76]. In addition, plasma glucose concentration was decreased [76], indicating a gluconeogenetic deficiency.…”

Section: Aqp9mentioning

confidence: 87%

Beyond water homeostasis: Diverse functional roles of mammalian aquaporins

Kitchen

Day

Salman

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

130

115

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BACKGROUND: Aquaporin (AQP) water channels are best known as passive transporters of water that are vital for water homeostasis. SCOPE OF REVIEW:AQP knockout studies in whole animals and cultured cells, along with naturally occurring human mutations suggest that the transport of neutral solutes through AQPs has important physiological roles. Emerging biophysical evidence suggests that AQPs may also facilitate gas (CO2) and cation transport. AQPs may be involved in cell signalling for volume regulation and controlling the subcellular localization of other proteins by forming macromolecular complexes. This review examines the evidence for these diverse functions of AQPs as well their physiological relevance. MAJOR CONCLUSIONS:As well as being crucial for water homeostasis, AQPs are involved in physiologically important transport of molecules other than water, regulation of surface expression of other membrane proteins, cell adhesion, and signalling in cell volume regulation. GENERAL SIGNIFICANCE:Elucidating the full range of functional roles of AQPs beyond the passive conduction of water will improve our understanding of mammalian physiology in health and disease. The functional variety of AQPs makes them an exciting drug target and could provide routes to a range of novel therapies.3

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“…Aquaporin 9 (AQP9) is a broad-selectivity neutral solute channel that facilitates the hepatic uptake of glycerol (3,29,32,33). The importance of AQP9 as a facilitator of hepatic glycerol uptake is illustrated by the increased plasma glycerol levels found in AQP9 KO mice (29).…”

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confidence: 99%

Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment

Lebeck

Cheema

Skowroński

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Lebeck J, Cheema MU, Skowronski MT, Nielsen S, Praetorius J. Hepatic AQP9 expression in male rats is reduced in response to PPAR␣ agonist treatment. Am J Physiol Gastrointest Liver Physiol 308: G198 -G205, 2015. First published December 4, 2014 doi:10.1152/ajpgi.00407.2013.-The peroxisome proliferator receptor ␣ (PPAR␣) is a key regulator of the hepatic response to fasting with effects on both lipid and carbohydrate metabolism. A role in hepatic glycerol metabolism has also been found; however, the results are somewhat contradictive. Aquaporin 9 (AQP9) is a pore-forming transmembrane protein that facilitates hepatic uptake of glycerol. Its expression is inversely regulated by insulin in male rodents, with increased expression during fasting. Previous results indicate that PPAR␣ plays a crucial role in the induction of AQP9 mRNA during fasting. In the present study, we use PPAR␣ agonists to explore the effect of PPAR␣ activation on hepatic AQP9 expression and on the abundance of enzymes involved in glycerol metabolism using both in vivo and in vitro systems. In male rats with free access to food, treatment with the PPAR␣ agonist WY 14643 (3 mg·kg Ϫ1 ·day Ϫ1 ) caused a 50% reduction in hepatic AQP9 abundance with the effect being restricted to AQP9 expressed in periportal hepatocytes. The pharmacological activation of PPAR␣ had no effect on the abundance of GlyK, whereas it caused an increased expression of hepatic GPD1, GPAT1, and L-FABP protein. In WIF-B9 and HepG2 hepatocytes, both WY 14643 and another PPAR␣ agonist GW 7647 reduced the abundance of AQP9 protein. In conclusion, pharmacological PPAR␣ activation results in a marked reduction in the abundance of AQP9 in periportal hepatocytes. Together with the effect on the enzymatic apparatus for glycerol metabolism, our results suggest that PPAR␣ activation in the fed state directs glycerol into glycerolipid synthesis rather than into de novo synthesis of glucose. aquaporin-9; immunohistochemistry; WY 14643; hepatocytes; glycerol metabolism PEROXISOME PROLIFERATOR RECEPTOR ␣ (PPAR␣) is a ligandactivated transcription factor that belongs to the superfamily of nuclear hormone receptors (39). After binding of ligands such as free fatty acids and fibrates, PPAR␣ and its coactivators influence the transcription of target genes either by binding to response elements in the corresponding promoter region (PPREs) or by interfering with other transcription factors (39). Fibrates are used in the treatment of hypertriglyceridemia and PPAR␣ regulates the expression of several proteins involved in lipid metabolism that promotes the removal of triglycerides (TG) from the circulation and enhances ␤-oxidation and ketogenesis in the liver (11). The induction of these pathways is particularly vital during starvation and PPAR␣ knockout (KO) mice respond to fasting with hypoketonemia, hypothermia, and hypoglycemia (12). Several mechanisms have been proposed to explain the fasting-induced hypoglycemia, including decreased hepatic glucose production (12, 21) as well as increased extr...

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Biophysical assessment of aquaporin‐9 as principal facilitative pathway in mouse liver import of glucogenetic glycerol

Cited by 95 publications

References 32 publications

A Novel Splice-Site Mutation of the Gk Gene in a Chinese Patient with Isolate Glycerol Kinase Deficiency

A Novel Splice-Site Mutation of the Gk Gene in a Chinese Patient with Isolate Glycerol Kinase Deficiency

Beyond water homeostasis: Diverse functional roles of mammalian aquaporins

Hepatic AQP9 expression in male rats is reduced in response to PPARα agonist treatment

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