J Phys Fitness Sports Med, 2(4): 409-416 (2013) DOI: 10.7600/jpfsm.2.409 JPFSM: Review Article Role of nutrient transporters in lifestyle-related diseases

Yutaka Taketani*, Hisami Yamanaka-Okumura, Hironori Yamamoto and Eiji Takeda

Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan

Received: August 12, 2013 / Accepted: August 30, 2013 Abstract Nutrient transporters play significant roles in physiological hormonal and cellular functions as well as in the maintenance of nutrient metabolism. Lifestyle-related disease can be defined as caused by a disturbance in nutrient metabolism as found in diabetes, dyslipidemia, arteriosclerosis, etc. Therefore, deterioration of nutrient transporters by a genetic mutation or abnormal regulation would cause various lifestyle-related diseases. For instance, dysregulation of muscular glucose transport causes hyperglycemia, and impairment of pancreatic glucose transport can be related to inadequate insulin secretion. These deleterious changes in glucose transport can be a cause of diabetes mellitus. Here, we introduce some examples that indicate the relationship between impairment of nutrient transporters and development of lifestyle- related diseases. Keywords : transporter, nutrient homeostasis, polymorphism, lifestyle-related disease

entire body and cellular microenvironment (Fig. 1). Introduction Disturbance of nutrient transporter(s) can cause vari- Vertebrates, including humans, must take nutrients ous diseases, including congenital diseases and lifestyle- from food to maintain life. Any nutrient (i.e., glucose, related diseases. For instance, a genetic defect in the amino acids, fatty acids, vitamins and minerals) has to be sodium-dependent (SGLT1) causes absorbed in the intestine and distributed to cells. Excess glucose-galactose malabsorption1). In some cases, a slight amounts of some nutrients can be excreted into urine or modification of transporter function by polymorphism or bile. However, most nutrients, per se, cannot be transport- epigenetics does not cause severe dysfunction of trans- ed across the plasma membrane of the cells. In addition, port activity, but can slightly change nutrient metabo- nutrients can also be transcellularly transported from the lism. Such a modification of transporter function can be lumen side to the blood stream, which is called transcel- involved in the disturbance of homeostasis of nutrient lular transport. Thus, our bodies have developed various metabolism leading to lifestyle-related diseases such as transporters for absorption, distribution, and excretion of diabetes mellitus, hypertension, atherosclerosis, etc. nutrients. In this review, we describe the roles of nutrient trans- Roles of nutrient transporters in our body can be di- porters in the onset of some major lifestyle-related dis- vided into 6 categories as shown in Table 1. Intestinal eases. absorption is an important function of some transport- ers. Those transporters perform the rate-limiting step of Type 2 diabetes mellitus (T2D) and transporters nutrient absorption from digested food in the gut, supply those nutrients to the body and maintain the nutrient pool. T2D has become a common disease in most advanced Absorbed nutrients are transferred to cells by blood or nations, and recently there also has been an increase in lymph and are taken into cells by transporters. In contrast, T2D in some developing countries. T2D is representa- some nutrients and their metabolites can be exported from tive of lifestyle-related diseases (multifactorial diseases) the cells to the blood stream. Excess amounts of some caused by both multiple genetic factors as defined by nutrients can be excreted through the kidney or liver, with polymorphisms and lifestyle factors, including dietary specific transporters performing this excretion step. The and exercise habits. Those factors cause deterioration of blood brain barrier allows specific transporters to transfer glucose metabolism, especially insulin sensitivity and limited molecules necessary to protect brain cells. Intes- secretion, resulting in abnormal glucose tolerance and hy- tinal absorption, exchange between the blood stream and perglycemia. Impairment of some transporters may cause cells, and excretion from the kidney and liver play impor- dysregulation of glucose metabolism and contribute to the tant roles in the maintenance of the nutrient pool in the development of T2D. Glucose is an essential nutrient as a primary energy *Correspondence: [email protected] source in all cells, especially those in the brain. Dietary 410 JPFSM: Taketani Y, et al.

Table 1. Classification of roles of nutrient transporters in humans Type of transport------Role of transport in nutrient homeostasis 1. Absorption of nutrients from foods in the intestine------nutrient supply and maintenance of nutrient pool 2. Cellular uptake of cells ----- distribution of nutrients and maintenance of cellular microenvironment 3. Reabsorption of nutrients from glomerular filtrate in the renal tubules ---- recycle nutrients and maintenance of nutrient pool 4. Excretion of nutrients or their metabolites in the liver, kidney, or other organs ----- excretion of excess amount of nutrients and their metabolites, and maintenance of nutrient pool 5. Transport into the brain across blood brain barrier ---- distribution of nutrients specifically into the brain 6. Supplementation of cofactors for enzymes, receptors and hormones ---- maintenance of cellular function and systemic regulation of homeostasis

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Fig. 1 Transporters and lifestyle-related diseases

glucose can be absorbed in the small intestine via SGLT1, cose influx into the beta-cells on which insulin secretion localized in the apical membrane of intestinal epithelial depends4). Hepatic GLUT2 plays an important role in the cells, and GLUT2 localized in the basolateral mem- release of glucose resulting from gluconeogenesis in the brane2,3). SGLT1 is a secondary active transporter coupled liver in response to fasting4). Insulin can stimulate glucose with the sodium gradient between the extracellular fluid uptake in the muscle and adipose tissue by an increase in and intracellular fluid2). GLUT2, a facilitative glucose the translocation of GLUT4 from intracellular organelles transporter, can subsequently transport glucose from to the plasma membrane of the cells5). Other facilitative the intracellular to the extracellular space on the blood glucose transporters play an important role in the glucose side3). Absorbed glucose is uptaken by facilitative glucose supply in various tissues. For instance, GLUT1 is widely transporters (GLUT1, GLUT2, GLUT3, and GLUT4) expressed in human cells and tissues including eryth- into cells3). GLUT2 is also expressed in the liver and rocyte, brain, kidney, and liver3). In the kidney, SGLT2, pancreatic beta-cells. Pancreatic GLUT2 regulates glu- another type of sodium-dependent glucose transporter, JPFSM: Transporters and lifestyle-related diseases 411 performs the rate-limiting step in glucose reabsorption in ish Diabetes Prevention Study showed that moderate-to- the proximal tubules3). Therefore, genetic modification of vigorous physical activity could modify the risk of devel- these transporters and their regulating systems may affect oping T2D associated with the genetic variant of GLUT2 the transporter function and cause impaired glucose ho- in persons with impaired glucose tolerance14). GLUT2 meostasis and T2D. may be important not only in the maintenance of glucose At present, there has been evidence that the polymor- homeostasis, but also in the regulation of feeding behav- phisms of the various transporter , shown in Table ior and adaptation to physical activity to prevent life-style 2, are associated with the development of T2D, and these related diseases. associations have been investigated. In 1988, Li et al. GLUT4 is another important and well-characterized reported that a SNP (XbaI polymorphism) was identified facilitative glucose transporter3,5). It is expressed in the in the GLUT1 and that there was a difference in al- muscle and adipose tissue and its membrane localization lele frequency between diabetic patients and control sub- and activity are strictly regulated by insulin5,15). Numer- jects6). Recent studies have demonstrated that XbaI, Enh2 ous studies have investigated the regulation of GLUT4 and HaeIII SNPs in the GLUT1 gene may be related to by insulin. Insulin activates insulin receptors and down- a genetic susceptibility to diabetic nephropathy7), and stream signal transduction pathways, that is, both the APS that some SNPs in the GLUT1 gene are involved in the (adaptor with pleckstrin homology [PH] and Src development of non-alcoholic fatty liver disease due to a homology 2 [SH2] domains)-insulin signaling pathway decrease in the expression of GLUT1 in the liver8). and the PI3K (phosphoinositide 3-kinase)-dependent sig- A common SNP (rs5400) in the GLUT2 gene resulting naling pathway in myocytes and adipocytes5,15). Those ac- in a threonine to isoleucine amino acid substitution at tivated signals stimulate trafficking of GLUT4-containing codon 110 has been associated with the risk of T2D9-11). vesicles from submembrane space to the plasma mem- GLUT2 has a high Km value for glucose and can regulate brane. Eventually, GLUT4 appears on the cell surface glucose entry, and may regulate insulin secretion in pan- by means of the exocytosis system. GLUT4 performs a creatic beta-cells4). GLUT2 is also expressed in the liver large part of postprandial glucose uptake in muscle and and regulates glucose uptake/efflux, and this transport adipose tissue to maintain the blood glucose level within activity is important to maintain the blood glucose level. a narrow range. Thus, impairment of the regulation of Recent studies demonstrated that GLUT2 also plays a GLUT4 from insulin signaling to the exocytosis system key role in the preservation of beta-cell glucose compe- results in the development of peripheral insulin resistance tence12), and that a genetic variant of GLUT2 is associated and hyperglycemia. Some GLUT4 associated are with the higher intake of sugars13). Interestingly, the Finn- therapeutic targets for diabetes16).

Table 2. Genes that encode nutrient transporters whose polymorphisms are associated with type 2 diabetes mellitus. Name description GLUT1 (SLC2A1) facilitative glucose transporter GLUT2 (SLC2A2) facilitative glucose transporter GLUT4 (SLC2A4) facilitative glucose transporter GLUT9 (SLC2A9) facilitative glucose transporter GLUT10 (SLC2A10) facilitative glucose transporter SGLT2 (SLC5A2) sodium-dependent glucose transporter OCT1 (SLC22A1) organic cation transporter OCT2 (SLC22A2) organic cation transporter (SLC6A4) serotonin transporter ZnT8 (SLC30A8) zinc transporter Thiamine transporter (SLC19A2) thiamine transporter Na+/Cl- transporter (SLC12A3) Na+/Cl- OATP1B1 (SLC21A) organic anion transporter MATE (SLC47A1) proton-coupled organic cation antiporter FATP1 (SLC27A1) fatty acid transporter ABCA1 ATP-binding cassette transporter ABCC8 (SUR-1) ATP-binding cassette transporter 412 JPFSM: Taketani Y, et al.

SGLT2 performs a rate-limiting step of renal glucose re- Tangier disease, in which patients exhibit low levels of absorption in the proximal tubules2). A missense mutation serum HDL, hypercholesterolemia, and a high risk of car- of SGLT2 causes familial renal glucosuria17). An excellent diovascular disease28-30). ABCA1 is widely expressed in idea has been proposed that inhibition of renal glucose various tissues, and mainly transfers cholesterol from pe- reabsorption can decrease serum glucose levels in T2D ripheral tissue to pre-HDL, known as reverse cholesterol patients18). Up to the present, several specific inhibitors transport31,32). Thus, ABCA1 performs the first step of re- of SGLT2 have been developed and are under Phase III verse cholesterol transport and prevents accumulation of clinical trials. Canagliflozin, a selective SGLT2 inhibitor, an excess amount of cholesterol. There have been reports improved hyperglycemia, decreased body weight and was that a polymorphism of ABCA1 is associated with serum associated with a low incidence of hypoglycemia19). In cholesterol levels and susceptibility to coronary heart 2013, canagliflozin was approved by the U.S. Food and disease33-35). Another ABC transporter (ABCG1) is also Drug Administration (FDA)20). important in removing cholesterol from peripheral tissues Because the maturation of insulin requires two zinc ions and the formation and maturation of HDL32,33). to form a hexamer, a zinc transporter is also associated Excess amounts of cholesterol can be metabolized with glucose metabolism and development of diabetes21). into bile acid. CYP7A1 is a rate-limiting enzyme for A zinc transporter (ZnT8) is specifically expressed in the cholesterol catabolism and can convert cholesterol to pancreatic beta-cells and localized in the insulin-contain- 7-dehydrocholesterol, which is a precursor for bile acid. ing secretory granule membrane to transport Zn2+ from ABCB4, ABCB11, ABCC2, ABCG5, and ABCG8 coop- cytosol to the vesicles22). Genome-wide analysis demon- eratively work for the production of bile36). ABCB4 trans- strated that the R325W polymorphism of ZnT8 was as- ports phosphatidylcholine, ABCB11 transports bile acid, sociated with susceptibility to T2D23). In addition, autoan- ABCC2 can transport conjugated bile acid, and ABCG5/ tibodies of ZnT8 were shown to cause type 1 diabetes24). ABCG8 transports cholesterol on the cancalicular mem- Therefore, various transporters, other than glucose trans- brane (bile duct side) of hepatocytes36). These transporters porters, can also be directly or indirectly associated with play a role in the maintenance of cholesterol homeostasis the development of diabetes. by regulating hepatic cholesterol and bile acid efflux as well as production of bile. Benton et al. identified two SNPs of the ABCA1 gene and investigated their relation- Dyslipidemia and transporters ship with the risk of cardiovascular disease in a multi- Dyslipidemia is a common disease and is characterized ethnic study of atherosclerosis (MESA study)37). G1051A by a high level of serum low-density lipoprotein (LDL)- (R219K) is associated with higher HDL-cholesterol levels cholesterol, hypertriglyceridemia, or a low level of serum and lower prevalence of coronary artery calcification. An- high-density lipoprotein (HDL)-cholesterol. LDL trans- other SNP (-565C/T) in the promoter region is associated fers cholesterol from the liver to peripheral tissues; con- with carotid-media thickness. An SNP of the ABCG1 pro- versely, HDL transfers cholesterol from peripheral tissue moter showed a significantly decreased risk for coronary to the liver. Either an elevation of serum LDL-cholesterol artery disease in a Han Chinese population38). or a decrease in HDL-cholesterol is a potent risk factor for cardiovascular disease. Generally, homeostasis of Cardiovascular disease and transporters serum cholesterol levels can be maintained by intestinal absorption of cholesterol, hepatic de novo production of Other nutrient or drug transporters, aside from those for cholesterol from acetyl-CoA, or an efflux of cholesterol regulating lipid homeostasis, can also be related to the de- as bile acid from the liver to the gastrointestinal tract. velopment and prevalence of cardiovascular disease. For Cholesterol is lipophilic; thus it has been believed that instance, hyperphosphatemia is an independent risk fac- cholesterol can freely cross the lipid bilayer membrane. tor for cardiovascular disease in chronic kidney disease However, recent studies have unveiled various cholesterol patients39,40). Recent epidemiological studies suggested transporters. that elevated serum phosphate levels, even though within Niemann-Pick C1-Like 1 (NPC1L1) protein was identi- a normal range, were also associated with the prevalence fied as a target molecule for ezetimib, which is a potent of cardiovascular disease in a general population without inhibitor of intestinal cholesterol absorption25). NPC1L1 impaired kidney function40,41). Phosphorus is an essential has 13 transmembrane regions and a sterol sensing do- nutrient for bone formation, ATP synthesis, nucleic acid main, the same as Niemann-Pick C1 (NPC1). NPC1L1- synthesis, phospholipid synthesis, energy metabolism, etc. null mice had decreased levels of cholesterol absorption Phosphorus deficiency causes hypophosphatemic rickets and an ezetimib-insensitive phenotype26). Maeda et al. in childhood, osteomalacia in adulthood, and also muscle reported that an SNP of the NPC1L1 gene affected cho- weakness. Phosphorus homeostasis is strictly regulated by lesterol absorption in Japanese27). intestinal absorption, distribution into the bone, muscle The ATP-binding cassette (ABC) transporter A1 and other tissues, and renal excretion through specific (ABCA1) has been identified as a causative gene for transporters42). There are three types of sodium-dependent JPFSM: Transporters and lifestyle-related diseases 413 phosphate transporters as shown in Table 3. NaPi-IIa and fed with a high phosphorus diet (1.2% phosphorus) for NaPi-IIc perform the rate-limiting step of renal phos- 12 weeks had progressive glomerular sclerosis and pro- phate reabsorption, which is the most important step in teinuria due to podocyte injury and damaged glomerular determining the serum phosphorus level, and is a primary barriers47). Phosphorus overload and increased influx of target for phosphate regulating factors such as parathyroid phosphate in glomerular cells such as podocytes are in- hormone, fibroblast growth factor 23 (FGF23) and an ac- volved in the cellular damage. Other studies, including tive form of vitamin D42). our investigation, demonstrated that elevation of extracel- FGF23 is a novel phosphaturic factor, and strongly in- lular phosphate levels could induce endothelial dysfunc- hibits the activities of NaPi-IIa and NaPi-IIc through its tion by an increase in oxidative stress and apoptosis, and specific receptor complex that consists of an FGF recep- a decrease in eNOS activity48,49). Inhibition of phosphate tor and Klotho, which is an aging-related gene43). Mice transport activity by phosphonoformic acid or siRNA that are null for either FGF23 or Klotho had the same can inhibit both calcification in vascular smooth muscle premature aging-like phenotypes such as short lifespan, cells44,50) and oxidative stress in endothelial cells48,49). ectopic calcification, arteriosclerosis, and growth retarda- Therefore, the phosphate transport activity of type III tion that are induced by hyperphosphatemia. Feeding a sodium-dependent phosphate transporters is important low phosphate diet or the simultaneous lack of the NaPi- in the development of vascular complications leading to IIa gene can normalize serum phosphorus levels and arteriosclerosis. However, recent findings suggest that cancel the premature aging-like phenotype of FGF23 phosphate transport activity is not necessary to induce or Klotho knockout mice43). It remains under investiga- vascular calcification and endothelial dysfunction51). Hy- tion how hyperphosphatemia causes a premature aging- perphosphatemia can stimulate the physical formation of like phenotype. Previously it was suggested that elevated calciprotein particles (CPP), which consist of calcium, serum phosphorus levels can be involved in increases in phosphate and fetuin-A; and calciprotein particles can in- oxidative stress and apoptosis, as well as induction of ec- duce vascular calcification and endothelial dysfunction52). topic calcification of arterial walls by trans-differentiation Together with previous findings, Professor Kuro-o indi- of vascular smooth muscle cells44-46). Type III sodium- cated that Pit-1 may function not only as a transporter, but dependent phosphate transporters (Pit-1 and Pit-2) play a also as a receptor for calciprotein particles53). pivotal role in the development of vascular complications Mutations in the Pit-2 gene in humans causes familial and impairment of renal function. idiopathic basal ganglia calcification (IBGC; also called Jono et al. reported that the elevation of extracellular Fahr’s disease), which is a rare neurodegenerative disor- phosphate induced the calcification of vascular smooth der characterized by calcification of the basal ganglia and muscle cells dependent upon phosphate influx into the other regions in the brain54,55). Such patients do not have cells via Pit-144). Sekiguchi et al. have established Pit- an abnormal phosphorus metabolism, but the respon- 1 transgenic rats. They found that Pit-1 transgenic rats sible mutation in the Pit-2 gene causes a loss of transport

Table 3. Mammalian sodium-dependent phosphate transporters

Gene symbol Protein Tissue distribution human gene locus

(Type I sodium-dependent phosphate transporter) SLC17A1 NaPi-1 (NPT1) kidney, liver 6p22.2

(Type II sodium-dependent phosphate transporter) SLC34A1 NaPi-IIa (NPT2a) kidney, osteoclast 5q35

SLC34A2 NaPi-IIb (NPT2b) small intestine, lung 4p15.2

SLC34A3 NaPi-IIc (NPT2c) kidney 9q34

(Type III sodium-dependent phosphate transporter) SLC20A1 Pit-1 (Glvr-1) widely expressed 2q13

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