Re: 과당 수송체 GLUT5 탐구!!

[문형철]

Am J Physiol Endocrinol Metab

. 2008 Apr 8;295(2):E227–E237. doi: 10.1152/ajpendo.90245.2008

Regulation of the fructose transporter GLUT5 in health and disease

Veronique Douard 1, Ronaldo P Ferraris 1

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PMCID: PMC2652499  PMID: 18398011

Abstract

Fructose is now such an important component of human diets that increasing attention is being focused on the fructose transporter GLUT5. In this review, we describe the regulation of GLUT5 not only in the intestine and testis, where it was first discovered, but also in the kidney, skeletal muscle, fat tissue, and brain where increasing numbers of cell types have been found to have GLUT5. GLUT5 expression‎ levels and fructose uptake rates are also significantly affected by diabetes, hypertension, obesity, and inflammation and seem to be induced during carcinogenesis, particularly in the mammary glands. We end by highlighting research areas that should yield information needed to better understand the role of GLUT5 during normal development, metabolic disturbances, and cancer.

초록

과당은

이제 인간 식단의 중요한 구성 요소로 자리 잡으면서

과당 운반체 GLUT5에 대한 관심이 증가하고 있습니다.

이 리뷰에서는

GLUT5의 조절 메커니즘을

장과 고환에서 처음 발견된 곳뿐만 아니라

신장, 골격근, 지방 조직, 뇌 등 다양한 세포 유형에서 GLUT5가 발견된 부위에서도 설명합니다.

GLUT5 발현 수준과 과당 흡수 속도는

당뇨병, 고혈압, 비만, 염증에 의해 크게 영향을 받으며,

특히 유방 조직에서 암 발생 과정에서 유도되는 것으로 보입니다.

마지막으로,

정상 발달, 대사 장애, 암에서 GLUT5의 역할을 이해하는 데 필요한 정보를

제공할 연구 분야를 강조합니다.

Keywords: cancer, diabetes, diet, hypertension, inflammation, metabolic syndrome

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for thousands of years, humans consumed about 16–24 g of fructose each day, mainly as fruits and honey obtained from foraging and agricultural activity. Recent modernization and specialization in agricultural and food processing methods initiated in Europe and North America have altered consumption patterns. Today, the per capita amount of fructose consumed each day ranges from 8 to 100 g, and the average is ∼80 g/day in the United States (16, 56, 86, 130). Most of the increase in consumption is derived from refined or processed fructose (63).

The chemical process for the rapid commercial conversion of glucose to fructose was developed in 1957 (99), and this technological advance led to the gradual increase in the manufacture and consumption of high-fructose corn syrup (HFCS) (11). HFCS typically contains 42, 55, or 90% fructose (68). Fructose is the sweetest of all natural sugars, and this is the primary reason why glucose is converted to fructose and why HFCS is used in the formulation of food and beverage products. About 330–380 kcal/day of the energy intake of average Americans (corresponding to 17–20% of daily energy intake) is derived from fructose (48). Recent studies have shown that there seems to be a direct relationship between increases in consumption of fructose and increases in incidence of obesity and type 2 diabetes (12, 69, 114, 120). High-fructose diets may also lead to the development of “metabolic syndrome,” which precedes the onset of type 2 diabetes and is a cluster of symptoms associated with insulin resistance, including dyslipidemia, insulin resistance, impaired glucose homeostasis, increased body fat, and high blood pressure [per reviews (8, 48, 78, 86, 130)].

The myriad effects of fructose are possible only if fructose reaches physiologically significant concentrations in the plasma and extracellular fluids and if subsequently transported into cells of various organ systems, thereby potentially altering normal metabolism in those organs. There are marked variations in estimates of blood fructose concentrations arising from differences in methods of collection and analysis. In normal humans, serum fructose concentration was estimated to be 0.008 mM (80), while plasma fructose was 0.030 mM (92). These variations can also arise from differences in fructose consumption, which is a potent regulator of intestinal fructose transport. In rats fed a diet containing glucose as the only carbohydrate source, serum fructose concentrations were <0.01 mM, but in those consuming fructose or sucrose, serum fructose concentrations reached 0.10–0.30 mM (19). In healthy humans consuming high-fructose or -sucrose diets, serum fructose can reach 0.2–0.5 mM (92), but this concentration is still very low compared with normal blood glucose levels (5.5 mM). This low fructose level results from rates of intestinal absorption lower than that of glucose and from efficient clearance of blood fructose mainly by the liver (50–70%) and, to a lesser extent, (20%) by the kidneys (103).

수천 년 동안 인간은

주로 채집과 농업 활동으로 얻은 과일과 꿀을 통해

하루에 약 16–24g의 과당를 섭취해 왔습니다.

유럽과 북미에서 시작된 농업 및 식품 가공 방법의 현대화와 전문화는

소비 패턴을 변화시켰습니다.

현재 1인당 하루 과당 섭취량은 8~100g이며,

미국에서는 평균 약 80g/일입니다 (16, 56, 86, 130).

섭취량의 대부분은

정제되거나 가공된 과당에서 유래합니다 (63).

글루코스를

과당으로 빠르게 상업적으로 전환하는 화학 공정은

1957년에 개발되었습니다(99),

이 기술적 진보는

고과당 옥수수 시럽(HFCS)의 제조 및 소비가 점차 증가하는 결과를 초래했습니다(11).

HFCS는

일반적으로 42%, 55%, 또는 90%의 과당을 함유합니다(68).

과당은

자연에 존재하는 모든 당류 중 가장 달콤하며,

이것이 글루코스를 과당으로 전환하고

HFCS를 식품 및 음료 제품의 제조에 사용하는 주요 이유입니다.

평균 미국인의 에너지 섭취량 중

약 330–380 kcal/일(일일 에너지 섭취량의 17–20%에 해당)이

과당에서 유래합니다(48).

최근 연구들은

과당 섭취량의 증가와 비만 및 제2형 당뇨병 발생률의 증가 사이에

직접적인 관계가 있는 것으로 나타났습니다(12, 69, 114, 120).

고과당 식단은

제2형 당뇨병 발병 전에 나타나는 '대사 증후군'의 발병을 유발할 수 있으며,

이는 인슐린 저항성과 관련된 증상군으로,

이상지질혈증, 인슐린 저항성, 혈당 조절 장애, 체지방 증가, 고혈압 등을 포함합니다 [참고 문헌 (8, 48, 78, 86, 130)].

과당의 다양한 효과는

과당이 혈장 및 세포외액에서 생리적으로 유의미한 농도에 도달하고

이후 다양한 장기 시스템의 세포로 운반되어

해당 장기에서 정상 대사 과정을 변화시킬 수 있을 때만 가능합니다.

혈중 과당 농도 추정치는

수집 및 분석 방법의 차이로 인해 큰 변이를 보입니다.

정상 인간에서 혈청 과당 농도는

0.008 mM (80)로 추정되었으며,

혈장 과당 농도는 0.030 mM (92)로 보고되었습니다.

이러한 차이는

과당 섭취량의 차이에서도 발생할 수 있으며,

과당은 장 내 과당 운반의 강력한 조절인자입니다.

글루코스만을 탄수화물원으로 섭취한 쥐에서 혈청 과당 농도는 <0.01 mM이었지만,

과당이나 설탕을 섭취한 쥐에서는

혈청 과당 농도가 0.10–0.30 mM에 달했습니다(19).

건강한 인간이 고과당 또는 고설탕 식이를 섭취할 경우

혈청 과당 농도는 0.2–0.5 mM (92)에 달할 수 있지만,

이는 정상 혈당 수준(5.5 mM)과 비교할 때 여전히 매우 낮은 수준입니다.

이 낮은 과당 농도는

장 흡수 속도가 포도당보다 느리고,

혈중 과당이 주로 간(50–70%)과 신장(20%)을 통해

효율적으로 제거되기 때문입니다(103).

The Main Fructose Transporter GLUT5

How does fructose move from the intestinal lumen to the blood and from there to various tissues? Fructose is transported passively across membranes by a member of the facilitative glucose transporter (GLUT) family, named GLUT5 (19, 20, 72, 98, 137). The GLUT family consists of 14 members divided into three major classes based on sequence homology and substrate selectivity, as described in recent reviews (97, 149). The structure and kinetic properties of GLUT5 and other GLUTs will not be reviewed here, nor will fructose transport studies not clearly linked to GLUT5 and GLUT2. Among the seven members able to transport fructose, GLUT5 is the sole transporter specific for fructose with no ability to transport glucose or galactose. It is also insensitive to phloretin and cytochalasin B (79, 97). The second major fructose transporter is GLUT2, a low-affinity transporter that is also capable of recognizing glucose and galactose, and is inhibitable by phloretin and cytochalasin B (97). GLUT2 in a bidirectional manner is involved mainly in fructose uptake across the hepatic plasma membrane into the liver (154) and in the basolateral membrane of the intestinal and renal epithelial cells (88). Five other GLUTs may possess varying degrees of fructose selectivity based on sequence homology with GLUT5: GLUT7, GLUT9a/b, GLUT8, GLUT11, and GLUT12 (43, 90, 96).

GLUT5 was cloned almost 20 years ago and was initially described as a glucose transporter (9) until its specificity for fructose in the intestine and sperm was clearly demonstrated (20). Modest to significant levels of GLUT5 mRNA and/or protein have now been demonstrated in kidney, fat, skeletal muscle, and brain (55, 65, 66, 76, 81, 91, 101, 135).

Paralleling the increasing concern about the role of fructose in various diseases, the number of studies on GLUT5 has increased dramatically in the last three years (∼70 studies from 2004 to 2007). Here, we review the evidence demonstrating the presence of GLUT5 in an increasing variety of organs and tissues and then describe its regulation under physiological and pathophysiological conditions.

주요 과당 운반체 GLUT5

과당은 장 내강에서 혈액으로,

그리고 거기서 다양한 조직으로 어떻게 이동하나요?

과당은 용이한 포도당 운반체(GLUT) 가족의 일원인

GLUT5(19, 20, 72, 98, 137)에 의해 막을 통해

수동적으로 운반됩니다.

GLUT 가족은 서열 유사성과 기질 선택성에 따라

세 가지 주요 클래스로 나뉘어진 14개의 구성원으로 이루어져 있으며,

최근 리뷰(97, 149)에서 설명된 바와 같습니다.

GLUT5 및 기타 GLUT의 구조와 동역학적 특성은

여기에서 검토되지 않으며,

GLUT5 및 GLUT2와 명확히 연관되지 않은 과당 운반 연구도 포함되지 않습니다.

과당을 운반할 수 있는 7개 구성원 중

GLUT5는 과당에 특이적인 유일한 운반체로,

포도당이나 갈락토스를 운반할 수 없습니다.

또한 플로레틴과 사이토칼라신 B에 민감하지 않습니다(79, 97).

두 번째 주요 과당 운반체는 GLUT2로,

글루코스 및 갈락토스를 인식할 수 있는 저친화성 운반체이며,

플로레틴과 사이토칼라신 B에 의해 억제됩니다(97).

GLUT2는

간 혈장막을 통해 간으로 과당을 흡수하는 과정(154)과 장 및 신장 상피 세포의 기저측막에서

주로 관여합니다(88).

GLUT5와의 서열 유사성에 따라

과당 선택성이 다양한 5개의 다른 GLUT가 존재합니다:

GLUT7, GLUT9a/b, GLUT8, GLUT11, 및 GLUT12 (43, 90, 96).

GLUT5는

약 20년 전에 클로닝되었으며,

처음에는 포도당 운반체로 기술되었습니다(9).

그러나

장과 정자에서의 과당 특이성이 명확히 입증된 후(20)

현재의 명칭으로 변경되었습니다.

현재 신장, 지방, 골격근, 뇌에서 GLUT5 mRNA 및/또는 단백질의 적정 수준에서

상당한 수준까지 발현이 확인되었습니다(55, 65, 66, 76, 81, 91, 101, 135).

과당과 다양한 질환 간의 역할에 대한 우려가 증가함에 따라,

GLUT5에 대한 연구는

지난 3년간 급격히 증가했습니다(2004년부터 2007년까지 약 70건의 연구).

본 논문에서는

GLUT5가 점점 더 다양한 장기 및 조직에서 존재한다는 증거를 검토한 후,

생리적 및 병리생리적 조건 하에서의 조절 메커니즘을 설명합니다.

Physiology and Function

Small intestine.

The small intestine regulates fructose absorption from dietary sources and, therefore, the availability of fructose to other tissues. It is also the organ system expressing the greatest amount of GLUT5 in human (13, 20, 47, 79, 81), rat (24, 35–38, 45, 72, 75, 84, 108, 112, 113, 139, 140, 147), mouse (22, 33, 83, 107), rabbit (109), chicken (60), and horse (104). In cattle, GLUT5 expression‎ in the intestine is significantly lower than in skeletal muscle (159), probably because this species is a foregut fermenter, and it is possible that fructose-like cellulose and other carbohydrate products are fermented in the stomach and little sugar reaches the intestinal lumen.

After apical transport mediated by GLUT5, fructose is transported across the basolateral membrane by GLUT2. Recent work by Kellett and Brot-Laroche (82) proposes that GLUT2 is also involved in the apical transport of fructose (see also 5, 15, 136). The Km for fructose measured in oocytes expressing the human isoform of GLUT5 or in the brush border membrane vesicles from rat and human intestine ranges from 11 to 15 mM (20, 79, 100). This Km is therefore similar to daytime intestinal luminal fructose concentrations in rats fed dietary fructose, ∼26 mM (75). The Vmax for GLUT5 measured in brush border membrane vesicles from rat intestine is ∼200 pmol/s per milligram of protein (100). In rodents, cattle, and horses, the distribution of GLUT5 is greater in the proximal (duodenum and proximal jejunum) compared with the distal segments (distal jejunum and ileum) (104, 160). In addition to regional expression‎ patterns, GLUT5 gene expression‎ appears to be tightly regulated by developmental, nutritional, hormonal, and circadian influences. The mechanisms involved in these regulatory processes are detailed in the following paragraphs.

생리학 및 기능소장.

소장은 식이원에서 과당 흡수를 조절하며,

따라서 다른 조직에 공급되는 과당의 가용성을 조절합니다.

또한

인간에서 GLUT5를 가장 많이 발현하는 기관 시스템입니다(13, 20, 47, 79, 81), 쥐(24, 35–38, 45, 72, 75, 84, 108, 112, 113, 139, 140, 147), 쥐(22, 33, 83, 107), 토끼(109), 닭(60), 말(104)에서 가장 많은 GLUT5를 발현하는 기관 시스템입니다.

소에서는 장에서의 GLUT5 발현이 골격근보다 유의미하게 낮으며 (159),

이는 이 종이 전장 발효 동물이기 때문일 가능성이 있으며,

과당과 유사한 셀룰로오스와 다른 탄수화물 제품이 위에서 발효되어

장 내강으로 도달하는 당분이 적기 때문일 수 있습니다.

GLUT5에 의해 매개되는

아피칼 수송 후,

과당은 GLUT2에 의해 기저측막을 통해 수송됩니다.

Kellett과 Brot-Laroche(82)의 최근 연구는 GLUT2가 과당의 아피칼 수송에도 관여한다고 제안합니다(5, 15, 136 참조). 인간 GLUT5 이소형을 발현하는 난자 또는 쥐와 인간의 장 브러시 경계막 소체에서 측정된 과당의 Km 값은 11~15 mM 사이입니다(20, 79, 100). 이 Km 값은 식이 과당을 섭취한 쥐의 장 내강 과당 농도(약 26 mM)와 유사합니다(75). 쥐 장의 브러시 경계막 소포에서 측정된 GLUT5의 Vmax는 단백질 1mg당 약 200 pmol/s입니다(100). 쥐, 소, 말에서 GLUT5의 분포는 근위부(십이지장과 근위부 공장)에서 원위부(원위부 공장과 회장)보다 더 높습니다(104, 160). 지역적 발현 패턴 외에도 GLUT5 유전자 발현은 발달, 영양, 호르몬, 생체 리듬 요인에 의해 엄격히 조절됩니다. 이러한 조절 과정에 관여하는 메커니즘은 다음 단락에서 자세히 설명됩니다.

Developmental patterns.

Under normal conditions, in the prenatal and suckling periods of rat, rabbit, and human development (<14 days in rodents), intestinal GLUT5 mRNA levels and fructose transport rates are very low (17, 51) (Fig. 1). Consumption of honey and fruit juice containing much fructose elicit marked increases in breath hydrogen (a marker of carbohydrate malabsorption) in children less than 1 yr of age, but not in those 2 or more yr old, suggesting fructose-induced intestinal malabsorption in very young humans possibly expressing low GLUT5 levels (116). Fructose malabsorption in 5-mo-old infants is associated with infantile colic (46) and increases their energy requirements (150). In rats, baseline GLUT5 expression‎ and activity remain low (51, 75) throughout postnatal development until the weaning stage (Fig. 1) and then increase only after completion of weaning when solid foods are consumed. The increase in activity at 28 days of age is thought to be hardwired (148) and may not require the presence of luminal fructose. This increase in GLUT5 expression‎ and activity can be advanced developmentally in younger, weaning pups. Between 14 and 28 days of age, GLUT5 is dramatically stimulated by early introduction of dietary fructose or by gavage feeding fructose solutions into the gastric lumen (35, 42, 45, 75, 112, 139). At this age range, the nutritional regulation of GLUT5 by fructose is clearly genomic (75) and requires the presence of fructose in intestinal lumen (140). GLUT5 response to luminal fructose occurs rapidly as the mRNA abundance in all enterocytes lining the villus increases simultaneously within 4 h (74). In contrast to GLUT5, both intestinal GLUT2 and SGLT1 (the Na+-dependent glucose transporter) are expressed at high levels throughout development, even in the prenatal stage of mammals (17). From the prenatal to the weaning stages, rat SGLT1 does not seem to be regulated by sugars (139), whereas rat GLUT2 appears to be regulated by luminal and systemic glucose or fructose (36).

발달 패턴.

정상 조건에서

쥐, 토끼, 인간 발달의 태아기 및 수유기(쥐에서는 14일 미만) 동안

장 내 GLUT5 mRNA 수준과 과당 운반 속도는 매우 낮습니다(17, 51) (그림 1).

과당을 많이 함유한 꿀과 과일 주스를 섭취하면

1세 미만의 어린이에서 호흡 수소 농도(탄수화물 흡수 장애의 지표)가 현저히 증가하지만,

2세 이상의 어린이에서는 그렇지 않습니다.

이는 매우 어린 인간에서 과당에 의한 장 흡수 장애가 발생할 수 있으며,

이는 낮은 GLUT5 발현과 관련될 수 있음을 시사합니다(116).

5개월령 영아의 과당 흡수 장애는

영아 복통(46)과 연관되며 에너지 요구량을 증가시킵니다(150).

쥐에서 GLUT5 발현 및 활성은

출생 후 발달 기간 동안 젖을 떼는 단계까지 낮게 유지됩니다(51, 75)(그림 1)이며,

고체 음식을 섭취하기 시작하는 젖을 떼는 단계 이후에야

증가합니다.

28일령에서의 활성 증가가 선천적으로 결정되어 있으며(148) 장내 과당 존재가 필요하지 않을 수 있습니다. GLUT5 발현 및 활성의 이 증가 현상은 젖을 뗀 어린 쥐에서 발달적으로 조기화될 수 있습니다. 14일에서 28일령 사이에는 식이 과당의 조기 도입이나 위강 내 과당 용액 투여(35, 42, 45, 75, 112, 139)에 의해 GLUT5가 급격히 자극됩니다. 이 연령대에서는 과당에 의한 GLUT5의 영양 조절은 명확히 유전적(75)이며, 장 내강에 과당이 존재해야 합니다(140). 장 내강 과당에 대한 GLUT5 반응은 모든 장 상피 세포에서 동시에 mRNA 농도가 4시간 이내에 증가하는 방식으로 신속히 발생합니다(74).

GLUT5와 달리,

장 내 GLUT2와 SGLT1(Na+ 의존성 포도당 운반체)은

발달 전반에 걸쳐 높은 수준으로 발현되며,

포유류의 태아기 단계에서도 마찬가지입니다(17).

태아기부터 젖떼기 단계까지 쥐의 SGLT1은

당분에 의해 조절되지 않는 것으로 보입니다(139),

반면 쥐의 GLUT2는

장 내 및 체내 포도당 또는 과당에 의해 조절되는 것으로 나타났습니다(36).

Fig. 1.

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Figure - PMC

그래프의 세부 설명:

• X축 (쥐의 나이 - 일): 쥐의 발달 단계(출생부터 수유기, 젖 떼기, 성체기까지)를 보여줍니다.
• Y축 (GLUT5 발현 또는 활동 (%)): GLUT5 발현 또는 활동의 상대적 수준을 나타내며, 기준 수준이 표시되어 있습니다.

그래프는 GLUT5 발현/활동의 여러 발달 경로를 보여줍니다:

1. 정상 발달 (붉은 선):
2. 글루코코르티코이드 + 루멘 과당 투여 시 조기 증강 (녹색 선):
3. 장내 과당 단독 투여 시 조기 증강(파란 선):
4. 정상 발달 + 장내 과당 (오렌지 선):

요약: 그래프는 GLUT5 발현/활성이 발달적으로 조절되며, 젖을 떼는 시점 주변에서 자연스럽게 증가함을 보여줍니다. 그러나 장내 과당의 조기 도입은 특히 글루코코르티코이드와 결합할 때 GLUT5의 상향 조절을 크게 가속화하고 강화할 수 있습니다. 이는 식이 요인이 장 과당 흡수 프로그래밍에 결정적인 역할을 한다는 것을 시사합니다. 성인 쥐에서도 장내 과당에의 만성 노출은 GLUT5 수준을 추가로 증가시킬 수 있습니다.

Under normal conditions (red line), the intestinal fructose transporter GLUT5 is expressed at low baseline levels throughout suckling (0–14 days of age) and weaning (14–28 days) stages in neonatal rats. GLUT5 expression‎ and activity increase normally after weaning has been completed and then can be enhanced by increases in consumption of dietary fructose (orange). Between 14 and 28 days old (blue), GLUT5 expression‎ and activity are dramatically enhanced by precocious introduction of its substrate fructose into the intestinal lumen. GLUT5 cannot be enhanced by luminal fructose in rats <14 days old unless the gut is primed with dexamethasone (green).

정상 조건(붉은 선)에서 신생 쥐의 수유기(0–14일령)와 젖 떼기 단계(14–28일령) 동안 장 포도당 운반체 GLUT5는 낮은 기본 수준에서 발현됩니다. 젖 떼기가 완료된 후 GLUT5 발현과 활성은 정상적으로 증가하며, 식이 포도당 섭취 증가에 의해 강화될 수 있습니다(주황색). 14일에서 28일령(파란색) 사이에는 장 내강에 프럭토스가 조기 도입될 경우 GLUT5 발현과 활성이 급격히 증가합니다. 14일령 미만의 쥐에서는 장이 데ksametason으로 사전 처리되지 않은 경우 장 내강 프럭토스에 의해 GLUT5가 증가하지 않습니다(녹색).

Role of glucocorticoid and thyroid hormones.

In suckling rats younger than 14 days, gavage feeding or perfusion in vivo of fructose has no effect on the already low levels of GLUT5 expression‎ and activity (Fig. 1) (38, 45, 74). This is understandable since milk is fructose free and there is no luminal signal that can stimulate GLUT5. However, GLUT5 in weaning rats (>14 days old) with no access to solid food, or even those with access to fructose-free pellets, can be enhanced by fructose. What developmental factors control the dramatic difference in GLUT5 regulation between suckling and weaning stages? Cui et al. (38) and Douard et al. (45) used microarray approaches to identify in vivo intestinal regulatory genes that modulate fructose sensitivity by tracking changes in expression‎ as a function of age and of perfusion solution. When the microarray results revealed that a significant number of age- and fructose-responsive genes were modulated by glucocorticoids, they hypothesized that corticosteroids play a major role in regulating intestinal GLUT5. By priming the gut with dexamethasone (a glucocorticoid analog), fructose was suddenly able to markedly stimulate GLUT5 even in suckling pups younger than 14 days (45). Dexamethasone also has similar stimulatory effects on the development of another intestinal membrane protein, sucrase-isomaltase, in similar-age pups, except that dexamethasone can directly upregulate sucrase-isomaltase without its substrate sucrose (2).

The glucocorticoid receptor, which binds dexamethasone, may be one of the transcription factors involved in the glucocorticoid-mediated enhancement of GLUT5 by fructose (44). Another candidate transcription factor discovered by microarray as significantly and simultaneously fructose and dexamethasone responsive is karyopherin-α2 (45), a nuclear importin known to be involved in the trafficking of nuclear factors stimulating the transcription of sugar-responsive genes (23). The expression‎ of karyopherin-α2 is stimulated by fructose at 20 days, an age when fructose can stimulate GLUT5, but not at 10 days, when fructose alone does not stimulate GLUT5 (45).

In older pups, ∼20–28 days of age, glucocorticoids may no longer be involved in the fructose stimulation of GLUT5, since adrenalectomy of pups at 10 days of age does not prevent dietary fructose from enhancing GLUT5 expression‎ (112). However, in this experiment, adrenalectomized pups received aldosterone every day to prevent salt wasting. Because aldosterone and corticosterone can both bind the glucocorticoid receptor with high affinity, this receptor may have mediated the effect of aldosterone on GLUT5 in the presence of fructose and confounded the effect of adrenalectomy on GLUT5 development.

The role of thyroid hormones, known to mediate the development of hydrolytic enzymes in the intestine, in the developmental regulation of GLUT5 has also been examined. l-triiodothyronine enhances GLUT5 expression‎ in Caco2 cells (102, 110, 111). In fact, thyroid hormone response elements were identified in the −338/−272 bp promoter region of GLUT5 (102, 111). However, the role of thyroid hormones in GLUT5 regulation so clearly demonstrated in cell culture may not be physiological because in vivo studies suggest that thyroxine does not regulate GLUT5. In normal pups, thyroxine concentrations increase significantly during the transition from suckling to weaning, and thyroxine may therefore be an ideal regulator of GLUT5 development (70). However, in weaning pups made hypothyroid from birth, dietary fructose can still enhance intestinal fructose uptake and GLUT5 mRNA expression‎ even though thyroxine levels in the serum are very low (113).

글루코코르티코이드 및 갑상선 호르몬의 역할.

생후 14일 미만의 수유기 쥐에서 포도당을 경구 투여하거나 체내 투여해도

이미 낮은 수준의 GLUT5 발현 및 활성에 영향을 미치지 않습니다(그림 1) (38, 45, 74).

이는 우유에 프럭토스가 포함되지 않으며

GLUT5를 자극할 수 있는 장내 신호가 없기 때문에 이해할 수 있습니다.

그러나

고체 음식에 접근할 수 없는 14일 이상 된 젖을 뗀 쥐나

프럭토스가 포함되지 않은 펠렛에 접근할 수 있는 쥐에서도

프럭토스가 GLUT5를 증가시킬 수 있습니다.

수유기와 젖을 뗀 단계 사이에서

GLUT5 조절의 극적인 차이를 조절하는 발달 요인은 무엇일까요?

Cui 등 (38)과 Douard 등 (45)은

연령과 투여 용액에 따라 발현 변화를 추적하여

과당 민감성을 조절하는 장 내 조절 유전자를 식별하기 위해 마이크로어레이 접근법을 사용했습니다.

마이크로어레이 결과,

연령과 과당에 반응하는 유전자 중 상당수가 글루코코르티코이드에 의해 조절된다는 것이 밝혀지자,

그들은 코르티코스테로이드가 장 GLUT5 조절에 주요 역할을 한다는 가설을 제기했습니다.

데ksametason(글루코코르티코이드 유사체)로 장을 사전 처리한 후,

과당은 14일 미만의 수유기 쥐에서도 GLUT5를 현저히 자극할 수 있었습니다(45).

데카메타손은 유사 연령의 쥐에서 다른 장막 단백질인 수크레이스-이소말타제의 발달에도 유사한 자극 효과를 보이지만, 데카메타손은 기질인 수크로스가 없이도 수크레이스-이소말타제를 직접적으로 상향 조절할 수 있습니다(2).

데카메타손과 결합하는 글루코코르티코이드 수용체는 과당에 의한 글루코코르티코이드 매개 GLUT5 증강에 관여하는 전사 인자 중 하나일 수 있습니다(44). 마이크로어레이를 통해 과당과 데ksametason에 동시에 유의미하게 반응하는 또 다른 후보 전사 인자로 발견된 것은 핵 내수체 단백질인 karyopherin-α2 (45)입니다. 이 단백질은 당 반응성 유전자 전사를 자극하는 핵 인자의 이동에 관여하는 것으로 알려져 있습니다 (23). 카리오페린-α2의 발현은 과당이 GLUT5를 자극할 수 있는 20일령에서 과당에 의해 자극되지만, 과당 단독으로는 GLUT5를 자극하지 않는 10일령에서는 자극되지 않습니다(45).

더 나이 많은 쥐(약 20–28일령)에서는 글루코코르티코이드가 과당에 의한 GLUT5 자극에 더 이상 관여하지 않을 수 있습니다. 왜냐하면 10일령에 부신 절제술을 받은 쥐에서 식이 과당이 GLUT5 발현을 증가시키는 것을 부신 절제술이 방지하지 않았기 때문입니다(112). 그러나 이 실험에서는 부신 절제술을 받은 쥐가 염분 손실을 방지하기 위해 매일 알도스테론을 투여받았습니다. 알도스테론과 코르티코스테론은 모두 글루코코르티코이드 수용체에 높은 친화력으로 결합할 수 있으므로, 이 수용체가 과당 존재 시 알도스테론의 GLUT5에 대한 효과를 매개하고 부신 절제술이 GLUT5 발달에 미치는 효과를 혼란스럽게 했을 수 있습니다.

장 내 가수분해 효소의 발달을 조절하는 것으로 알려진 갑상선 호르몬이 GLUT5의 발달 조절에 미치는 역할도 조사되었습니다. l-트리요오드티로닌은 Caco2 세포에서 GLUT5 발현을 증가시킵니다(102, 110, 111). 실제로 GLUT5의 −338/−272 bp 프로모터 영역에서 갑상선 호르몬 반응 요소가 식별되었습니다(102, 111). 그러나 세포 배양에서 명확히 입증된 갑상선 호르몬의 GLUT5 조절 역할은 생리적이지 않을 수 있습니다. 왜냐하면 생체 내 연구는 티록신이 GLUT5를 조절하지 않는다는 것을 시사하기 때문입니다. 정상적인 쥐 새끼에서 티록신 농도는 수유에서 단유로 전환되는 과정에서 크게 증가하며, 따라서 티록신은 GLUT5 발달의 이상적인 조절인자일 수 있습니다(70). 그러나 출생 시 갑상선 기능 저하 상태로 만든 단유기 쥐 새끼에서 혈청 티록신 수치가 매우 낮음에도 불구하고 식이 과당은 장 내 과당 흡수 및 GLUT5 mRNA 발현을 여전히 증가시킬 수 있습니다(113).

Diurnal rhythm.

In adult rats, GLUT5 mRNA and protein expression‎ follow a distinct diurnal rhythm not found in neonatal rats (140). The rhythm occurs independent of food and fructose intake (34, 146), which in rats occur mostly and naturally at night (52). This diurnal rhythm consists of an anticipatory fourfold induction of intestinal GLUT5 mRNA and protein expression‎ occurring 3–4 h before the onset of peak feeding. Thus, GLUT5 can be regulated by factors not associated with feeding or with changes in luminal fructose concentrations. The same diurnal rhythm was also observed for intestinal GLUT2 (34, 146). Diurnal regulation of GLUT5, like fructose regulation of GLUT5 in weaning rats, seems modulated by paracrine and endocrine signals in the intestine, because diurnal variation of GLUT5 expression‎ is independent of the vagus nerve. In contrast, GLUT2 diurnal expression‎ is controlled by vagal signals (146).

Kidney.

After the small intestine, the kidney expresses the most GLUT5 in human, rat, and rabbit (4, 20, 28, 40, 81, 109, 126). GLUT5 mRNA is abundant in the cytosol, and protein is present in the apical plasma membrane of S3 proximal tubule cells (28, 145), where GLUT5 can potentially recapture fructose lost from glomerular filtration. Renal GLUT5 of rats has a Vmax of 106 pmol/s per milligram of protein and a Km of 12.6 mM, values relatively similar to those in the small intestine (101). The Km, however, seems much higher than physiological fructose concentrations in the blood (∼0.008–0.03 mM) and, presumably, glomerular filtrate. Fructose concentration in the urine of normal nondiabetic humans is 0.035 mM (personal communication, T. Kawasaki). Differences in fructose concentration between filtrate and intracellular compartment will determine the direction of fructose flux mediated by GLUT5. GLUT2 is also in the basolateral membrane of proximal tubular cells, and the role of these two relatively low-affinity GLUTs in renal fructose transport, in light of relatively low, apparently similar fructose concentrations in the blood and urine, needs to be elucidated. The transcript size and molecular weight of the protein are similar to those determined for GLUT5 in the intestine (33), in accord with the resemblance in kinetic features of this transport system from the two organs. Moreover, during the prenatal period, the levels of renal GLUT5 mRNA and protein are low but then rapidly increase during weaning when its expression‎ is also inducible by the fructose diet (19, 126), suggesting similar mechanisms of developmental regulation as those in the small intestine.

Testes and sperm.

GLUT5 has consistently been found in the spermatozoa of many species: human (3, 20), mouse (3, 33), rat (3), bull (3), pig (133, 134), and dog (127). Even if its role in sperm metabolism remains uncertain, it may confer to the spermatozoa the ability to use fructose as an energy source or as an activator of the fertilization process (3, 127). In humans, GLUT5 is expressed only in mature spermatids, suggesting a selective upregulation of GLUT5 expression‎ during germ cell development, from immature spermatogonia expressing low levels of GLUT5 through to elongated spermatids expressing high levels of GLUT5 (3, 20).

Testicular GLUT5 levels are also influenced by age as are those in the small intestine. Interestingly, changes in GLUT5 expression‎ in the whole testis as a function of ontogenetic development parallels changes in GLUT5 expression‎ as a function of spermatogenetic development. Testicular GLUT5 expression‎ increases threefold in 6-wk-old adults compared with that in 1-wk-old prepubertal mice (33). This implies a reproductive function for fructose and suggests that, even in a tissue that does not deal with or perceive the diet change at weaning, an intrinsic factor with wide-ranging effects seems to be responsible for the developmental regulation of GLUT5.

The pubertal timing for the increase in GLUT5 expression‎ in the testis reinforces the postulated relationship between steroid hormones and GLUT5 as previously described in the small intestine. The total transcript size of testicular GLUT5 is 2.8 kb and is significantly larger than the 2.1 kb size of intestinal and renal GLUT5 (33). The difference in transcript size may result from the existence of two distinct promoters, one type controlling GLUT5 transcription in somatic cells like intestinal epithelia and another type controlling transcription in germ cells, where GLUT5 contains an additional exon (33). The GLUT5 promoter in the intestine/kidney contains binding sites for the caudal homeobox gene (CdxA, a transcriptional factor involved in development of gastrointestinal tissues) (33). In addition to CdxA, the GLUT5 promoter in the testis also contains binding sites for the sex-determining region of Y (SRY, a transcriptional factor essential for the development of the testis), whose influence prevails over or supplements that of CdxA. These findings show how differences in promoter regions or in promoter activity may be responsible for the tissue-selective expression‎ of GLUT5.

Muscle/fat tissue.

GLUT5 is expressed in skeletal muscle of human (14, 40, 41, 66, 71, 81, 125, 137, 143, 144), rat (40), and mouse (131). In fact, GLUT5 is, along with GLUT4 and GLUT12, one of the more significantly expressed GLUTs in human skeletal muscle compared with the other members of the GLUT family (144). However, GLUT5 mRNA and protein levels in skeletal muscle are low compared with those of the intestine in humans (81) and rats (40). Adipocytes of rats (65, 91) and humans (137) also express GLUT5, but expression‎ seems less compared with that of the small intestine (81). GLUT5 expression‎ is strictly confined to the plasma membrane of adipocytes and to the sarcolemma of skeletal muscle where it is responsible for facilitating fructose uptake from the blood into these tissues (40, 65, 137). Since GLUT5 is facilitative and extracellular fructose concentration seems quite low (probably <0.5 mM), intracellular levels of fructose should be lower in order for it to enter the cell. This low intracellular fructose concentration is possible because fructose is rapidly metabolized and significantly contributes to glycogenolysis in muscle or lipogenesis in adipocytes (69, 161). In human adipocytes, a recent study demonstrated, hypoxia increases GLUT5 expression‎ (9-fold) (155). Because hypoxia becomes more common during the progression of obesity, it can be one of the factors leading to increases in GLUT5 expression‎ in adipocytes of young obese fa/fa rats (91).

In contrast to the intestine and kidney but like the testis, GLUT5 expression‎ is not substrate dependent in muscle (40) but may be modulated by hormones. Insulin is capable of increasing the abundance and functional activity of GLUT5 in skeletal muscle cells, and the insulin effect is most likely mediated via activation of the GLUT5 promoter (66). The contribution of skeletal muscles and of adipocytes in the clearance from the blood and in metabolism of fructose is minor compared with that of the liver and the kidney.

Brain.

Glucose is the principal substrate used by and is considered sufficient for the metabolic needs of the brain (142), so there is no requirement for additional energy sources. However, GLUT5 has been identified in different cell types such as human microglia (122), cerebellar Purkinje cells in human fetus (117), mouse cerebellum (55), human blood-brain barrier (98), and rat hippocampus (138). Because the GLUT5 transporter is commonly found in tissues that metabolize fructose (20), these brain cells may be capable of utilizing fructose as an energy substrate. However, the utility of fructose and function of GLUT5 remains uncertain in the brain. Since it is unlikely that the brain secretes fructose, the presence of GLUT5 in the blood-brain barrier indicates that fructose enters the brain, but radioalabeled fructose injected into rat arteries resulted in minimal accumulation of radio-labeled fructose in the brain, suggesting insignificant transport across the blood brain barrier (119) that is likely mediated by GLUT1. GLUT1 typically transports glucose across the blood brain barrier but has a very low affinity for fructose (39). In contrast to the finding that fructose does not enter the brain, a modest and transient upregulation of GLUT5 mRNA and protein levels in the brain has been demonstrated in rats consuming a high fructose diet (138) and following schemia (151). This suggests that fructose enters the brain because it is a potent and specific stimulator of GLUT5 transcription (51). Consistent with the controversial nature of this subject, a more recent study found that high fructose diets do not upregulate GLUT5 in the brain (106). Hence, the physiological role of GLUT5 and the effect of high-fructose diets in the brain still need to be investigated.

Regulation of Intestinal GLUT5 by Its Own SubstrateRegulation in vivo.

Here, we will focus primarily on the intestinal regulation of GLUT5 in adults or weaning pups older than 14 days in which GLUT5 responds to luminal fructose. GLUT5 expression‎ and function in weaning and postweaning rats can be enhanced markedly in vivo by consumption of high-fructose diets (42), gavage-feeding of fructose solutions (74), perfusion in vivo of the intestine with fructose (75), or incubation in vitro of isolated everted intestines in fructose solutions (85). Intestinal GLUT5 is therefore remarkably responsive to its substrate fructose. The response of GLUT5 is quite specific, as SGLT1 or GLUT2 expression‎ is similar among fructose, glucose, and nonmetabolizable glucose analogs. Fructose metabolism, partial or total, may be a key factor in the regulatory process because of the modest effect of the nonmetabolizable fructose analog 3-O-methylfructose on GLUT5 upregulation in 20-day-old rats (75). Fructose is supposedly metabolized via either of two pathways, the fructose 1-phosphate and/or the fructose 6-phosphate pathway. Although the fructose 1-phosphate pathway using fructokinase and aldolase B seems to be prominent in the liver, it is not clear whether intestinal cells are capable of fructose metabolism and, if they are, which of the two pathways would prevail (49, 103).

Along with GLUT5, the mRNA expression‎ of key gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-1,6-bisphosphatase (FBPase), increased significantly in fructose-perfused intestines, suggesting a link between gluconeogenesis on the one hand and fructose transport as well as intracellular fructose on the other (38). However, only the inhibition of FBPase activity using vanadate prevents the fructose-induced increase in GLUT5 mRNA expression‎ and fructose uptake (84). FBPase activity is indirectly regulated by cAMP, which increases in vivo in the intestinal mucosa (35) or in vitro in Caco2 cells (94) exposed to fructose compared with those exposed to glucose. It had been demonstrated in vivo that cAMP modulates fructose transport induced by fructose without affecting GLUT5 mRNA abundance (35), whereas in vitro, cAMP affects GLUT5 mRNA expression‎ levels (62). The reasons for these different effects of cAMP on the transcriptional and posttranscriptional regulation of GLUT5 by fructose remain unknown and may underlie the difference between in vitro and in vivo models. In fructose-perfused rats, the phosphatidylinositol 3-kinase/protein kinase B system (PI 3-kinase/Akt) also mediates the fructose-induced increase in fructose uptake but still has no effect on GLUT5 transcription (37). The signaling pathways in vivo related to the dramatic and specific fructose-induced increase in GLUT5 mRNA and activity remain to be elucidated, although several fructose-responsive genes identified from microarray comparisons of fructose- and glucose-perfused intestines suggest that 1) intracellular phosphate metabolism or transport, 2) several regulatory genes in the gluconeogenic pathway, and 3) alterations in ATP/ADP levels, may be involved (38).

Regulation in vitro in Caco2 cells.

The molecular regulation of GLUT5 in the intestine has also been studied using mostly Caco2 cells as a model. Among the numerous clones of Caco2, GLUT5 is expressed endogenously only in those clones exhibiting low rates of glucose consumption (Caco2-PD7, -TB10, -TC7, -TF3, or -TG6) and only in those cells that are differentiated (94). It is not clear why these clones have low rates of glucose metabolism, but endogenous expression‎ of GLUT5 suggests that they may be attempting to obtain additional sources of sugars. Interestingly, by use if glucokinase activity as an indicator of the rate of glucose metabolism, the intestine can be categorized more like a low-glucose-metabolizing tissue compared with the liver, brain, or adipose tissue in rats fed a carbohydrate diet (1). Although glucose under in vivo conditions does not alter GLUT5 mRNA and protein levels in enterocytes, both glucose and fructose are potent activators of GLUT5 in Caco2 cells (93, 94, 102, 105). Hence, under most conditions, GLUT5 regulation in Caco2 cells does not distinguish between glucose and fructose. Only if postconfluent cells are grown in culture media containing dialyzed fetal bovine serum and only in Caco2/PD7 or Caco2/TC7 clones can fructose modestly induce GLUT5 expression‎ to a greater extent than glucose (105).

Because fructose, compared with glucose, does not increase the activity of the human GLUT5 promoter in vitro, the modest fructose-induced increase of GLUT5 mRNA abundance in Caco2 cells appears to result from increased mRNA stability (62). Since cAMP is involved in GLUT5 regulation in Caco2 cells (93, 94, 105), increased mRNA stability may result from an inhibitory effect of cAMP on the formation of a complex between the GLUT5 3′ UTR area and PABP (polyadenylate-binding protein)-interacting protein (Paip2). PABP proteins are found in all eukaryotes and are implicated primarily in mRNA maturation, export, and turnover (141). Specifically, Paip2, a partner of PABP, is involved in the destabilization of the transcripts, and inhibition of Paip2 enhances mRNA stability. Two cAMP potential response elements had been identified in the GLUT5 promoter and now localized to −365/−358 and −332/−325 regions (94). Interestingly, GLUT5 expression‎ is also cAMP sensitive in primary cultures of rabbit proximal tubule cells (121).

Pathology and GLUT5

Diabetes/hyperinsulinemia.

It is not clear whether diabetes alters serum fructose concentration. Serum fructose concentration and urinary fructose excretion increased markedly in diabetic Japanese patients (80). On the other hand, serum fructose concentrations were similar among healthy Finnish volunteers and those with type 1 or 2 diabetes (124). What is clearer is that fructose may be profoundly involved in the development of metabolic syndromes important in the pathogenesis of diabetic complications (56, 63, 86, 120). Fructose is now the major sweetener in Western diets, and for a while was used in diabetes therapy because it did not result in acute hyperglycemia. GLUT5 is expressed in insulin-sensitive tissues like skeletal muscle and adipocytes of humans and rodents and may participate in the management of glycemia involving insulin. Despite the importance of dietary fructose in the development of diabetes, and that of GLUT5 in fructose transport, very few studies have investigated the link between diabetes and GLUT5 in these insulin-sensitive organ systems. The few studies that did so found interesting but inconsistent correlations between this transporter and diabetes, with inconsistencies arising from the fact that although GLUT5 may be affected by diabetes, GLUT5 is also particularly affected by levels of dietary fructose that may vary markedly among diabetes patients.

Patients with type 2 diabetes exhibited dramatic increases in GLUT5 mRNA and protein abundance in skeletal muscle (143). These increases were specific, because expression‎ of GLUT1, GLUT3, GLUT4, GLUT8, GLUT11, and GLUT12 did not change with diabetes and could be reversed if diabetic patients were treated for 8 wk with pioglitazone, a drug enhancing insulin action.

Several studies have also linked GLUT5 expression‎ in fat tissue of rodent models with diabetes or with diabetic complications. In rats with streptozotocin-induced diabetes, there was a dramatic, insulin-insensitive, glycemia-regulated decrease in levels of GLUT5 mRNA and in rates of fructose uptake in adipose cells (65). Type 2 diabetes may have different effects on GLUT5, and those effects may be age or insulin dependent. GLUT5 protein abundance and activity increased two- to fourfold in young obese fa/fa rats that were normoglycemic and hyperinsulinemic compared with lean controls. When insulin resistance (hyperinsulinemia and hyperglycemia) became established in aged obese fa/fa rats, GLUT5 protein and the rate of fructose uptake in adipocytes decreased 12-fold (91). These reductions in site density of adipocyte GLUT5 can contribute to increases in plasma fructose concentrations in diabetes. Because GLUT5 abundance and fructose transport in adipocytes are upregulated in highly insulin-responsive rats but are downregulated dramatically when these rats age and become insulin resistant, this suggests that changes in GLUT5 expression‎ in adipocytes of type 2 diabetics are dependent on insulin sensitivity. However, the exact role of insulin needs further study.

In the same aged fa/fa rats, there was no effect of insulin resistance on GLUT5 protein levels in the kidney (91), suggesting that the effect of insulin resistance on GLUT5 was primarily in adipocytes. However, two studies observed an increase of GLUT5 mRNA and protein levels in rat kidney after onset of streptozotocin-induced diabetes (4, 28). Streptozotocin-induced diabetes results in increases in levels of GLUT5 in the apical membrane of mesangeal cells in the glomerulus and of proximal convoluted tubular cells in the renal cortex. Changes in the levels of GLUT5 in the membrane of tubular cells may affect rates of fructose transport to/from the filtrate, depending on concentration gradients. Increases in levels of renal GLUT5 may mediate the threefold increase in urinary fructose excretion observed in type 2 diabetic patients (80).

Diabetes also profoundly affects GLUT5 expression‎ in the small intestine. Duodenal GLUT5 mRNA and protein levels increase three- to fourfold in type 2 diabetic subjects (47). Lowering hyperglycemia in certain patients reversed this intestinal upregulation of GLUT5, suggesting that blood glucose level or its consequences are involved in the GLUT5 regulation in the intestine of diabetic subjects (47). In contrast, in Zucker rats, considered a model of type 2 diabetes, the mRNA and protein levels of the intestinal sugar transporters SGLT1, GLUT5, and GLUT2 remained the same as those of lean controls (31). These differences may arise from species differences or from the different composition of diets consumed by control and diabetic patients in the human study. Interestingly, treating the diabetic rats with troglitazone (another drug enhancing insulin action) specifically downregulates GLUT5 protein levels, consistent with previous observations (143).

In streptozotocin-induced type 1 diabetes, findings on intestine are also contradictory. In streptozotocin-diabetic rats, dramatic increases in levels of GLUT5 mRNA, cytosolic protein, and brush border protein were demonstrated in the jejunum and ileum (18, 32). Diabetes also increased intestinal size and caused a premature expression‎ of hexose transporters by enterocytes along the crypt-villus axis, thereby causing a cumulative increase in enterocyte transporter protein during maturation. GLUT5 protein levels increased in parallel with a diminution of GLUT5 activity (32), suggesting less fructose transported per GLUT5. Unfortunately, in the same model of type 1 diabetic rats, another study observed a diabetes-induced reduction in intestinal GLUT5 expression‎ (108). In summary, the regulation of intestinal GLUT5 in diabetic subjects seems to be complex, and no clear picture has emerged due to contradictory findings. This multifaceted regulation also reflects the complexity of diabetes-induced metabolic changes (e.g., hyperinsulinemia, hyperglycemia, insulin-resistance, obesity, inflammation) that can affect GLUT5 expression‎.

Arterial hypertension and obesity.

Metabolic disorders like impairments in glucose metabolism and insulin resistance have also been reported in humans and mammals exhibiting arterial hypertension. In the ileum of spontaneously hypertensive (SHR) rats, the capacity to absorb fructose was reduced and levels of GLUT5 mRNA and protein decreased, suggesting a transcriptional downregulation of GLUT5 in the intestine of these rats (100). Levels of GLUT5 protein in renal brush border membrane vesicles of hypertensive rats compared with those from normotensive rats also decreased with hypertension (101). It is interesting to note that there exists another animal model for hypertension: young rats fed high levels of fructose. These young rats increase intestinal GLUT5 expression‎ and then eventually develop glucose intolerance and high blood pressure (10).

The mechanism by which dietary fructose induces hypertension is being investigated. In rodents, fructose, unlike other sugars, induces hyperuricemia (115, 132) which is a major risk factor for hypertension (50). Recent clinical studies using patient data from the Third National Health and Nutrition Examination Survey confirm‎ the link not only between hyperuricemia and hypertension in particular but also between serum concentrations of uric acid and the preval‎ence of metabolic syndrome in general (29, 53). In turn, consumption of sugar-sweetened soft drinks is substantially correlated with increasing levels of serum uric acid and frequency of hyperuricemia (30). This increase in levels of blood uric acid can result from fructose-induced reduction in the renal excretion of uric acid and from the stimulation of nucleotide catabolism (67). However, little else is known about GLUT5 regulation and its physiological significance in fructose induced hypertension in animal models or humans.

Intestinal inflammatory and infectious diseases.

Inflammatory or infectious conditions also lead to adaptive changes in intestinal absorptive function, including fructose transport. The link between inflammation or infection and fructose has been poorly explored, maybe because no inherited disorders of intestinal fructose transport have yet been reported. Isolated fructose malabsorption is rare and is not linked to protein-altering mutations in GLUT5, and the inheritance pattern is unknown (153). As a consequence, there are few studies on GLUT5 expression‎ and function under pathological conditions in the intestine. In general, GLUT5 expression‎ and activity decrease in inflammatory diseases. A patient with Helicobacter pylori infection exhibited a decrease in intestinal GLUT5 expression‎ (87). In rats, 2–8 days after iodoacetamide-induced colitis, GLUT5 protein and mRNA levels decreased in noninflamed small intestine, thereby paralleling the time course of inflammation manifested in the large intestine and suggesting that GLUT5 in noninflamed tissues may be sensitive to inflammation inducers or to inflammatory signals in the blood (77). In the case of sepsis induced by lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α) in rabbit, fructose absorption also decreased in the jejunum (57, 59). When injected intravenously, LPS, which is a component of the membrane of gram-negative bacteria, stimulates cytokine (including TNF-α) and glucocorticoid production. The decrease in rate of fructose absorption can be prevented by an inhibitor of TNF-α and can be explained mostly by decreases in GLUT5 protein levels in the enterocytes, indicating that the effect of inflammatory factors on GLUT5 is mainly specific. LPS treatment decreased GLUT5 levels by proteasome-dependent degradation. The regulatory mechanism underlying the inhibition of fructose absorption by LPS and TNF-α may involve cross talk among various protein kinase signaling pathways because specific inhibitors of PKC, PKA, and MAP kinases, p38 MAPK, JNK, and MEK1/2, protected fructose uptake from adverse LPS effects (58).

The role of bacteria and the adaptive immune responses it generates also seem to affect GLUT5 expression‎. Under nonpathological states but in the absence of both passive and adaptive immunity, a dramatic increase in expression‎ of GLUT5 is observed in the proximal small intestine of 18-, 21-, and 25-day-old rats (73). This increased expression‎ of GLUT5 in the immunodeficient host could be an adaptive response limiting the nutrients available for intestinal microflora in the more distal regions of the gut and indicate that when the immune system is compromised GLUT5 expression‎ is upregulated.

GLUT5 is also found in immune cells like the mature macrophages of peripheral organs (54, 95) and in the microglia of the brain (26, 128, 135, 151). When human monocytes differentiate into macrophages, differentiation is accompanied by marked changes in intracellular location of GLUT5 and by dramatic increases in GLUT5 mRNA levels and protein abundance and in fructose uptake rate (54, 95).

Breast cancer.

GLUT5 mRNA and protein expression‎ are affected by the development of tumors in certain organ systems. This surprising finding is not only consistent among different organ systems and cell types but also seems independent of associated metabolic or inflammatory diseases. In general, oncogene-transformed cells that portray cancerous characteristics will also exhibit an increase in glucose transport by overexpressing specifically sugar transporters like GLUT1 in breast, colorectal, lung, and ovarian carcinoma (21, 64, 118, 156), GLUT12 in breast cancer (129), or GLUT3 in lung, ovarian, and gastric cancers (157). This increase in glucose transport and metabolism may reflect a requirement by these rapidly growing cells for more sources of energy (27). Although GLUT5 is poorly expressed in normal mammary epithelial cells, the breast carcinoma cell lines MCF-7 and MDA-MB-231 possess high amounts of GLUT5 mRNA and protein and exhibit high rates of fructose transport (158). This finding from an earlier study was later on confirmed a number of times in later studies. In fact, GLUT5 knockdown by antisense oligonucleotide decreases rates of fructose uptake, thereby inhibiting the proliferation and the growth of MCF-7 and MDA-MB-231 cells, which are, respectively, models of early- and late-stage breast cancer (25). A large-scale screening of the GLUT family of transporters in malignant vs. normal human tissues and cells showed that GLUT5 was highly overexpressed in 27% of cancerous tissues tested, including tumors in brain, breast, colon, liver, lung, testis, and uterus (61). In situ RT-PCR and ultrastructural immunohistochemistry confirmed GLUT5 expression‎ in breast cancer. In contrast, GLUT6 and -9 are clearly not overexpressed in human cancer of various tissues, whereas GLUT1 is expressed in cancers of a wide range of tissues but expression‎ in each tissue is modest. The extensive expression‎ of the glucose/fructose transporter GLUT2, and the fact that in most of the tumor cells overexpressing GLUT5 the rate of fructose uptake is exacerbated, indicate that fructose may be a preferred substrate providing energy required for the growth and proliferation of tumor cells (61, 89). This increase of GLUT5 could indicate preferential utilization of fructose by cancer cells. However, the link between fructose and tumor cell growth remains unclear. Interestingly, it was observed over 50 years ago that cancer cells maintain a high rate of glycolysis even in the presence of oxygen, a phenomenon called the Warburg effect (7, 123, 152). One of the major regulatory steps in glycolysis involves conversion of fructose 6-phosphate to fructose-1,6-bisphosphate by phosphofructokinase-1 (PFK-1). The activity of PFK-1 is allosterically controlled by fructose-2,6-bisphosphate, the product of the enzymatic activity of a dual kinase/phosphatase family of enzymes (PFKFB1–4) that is also increased in a significant number of tumor types (6). Fructose is known to stimulate the intestinal expression‎ of PFKFB1 (38), but it is not known whether fructose leads to increased levels of fructose 2,6-bisphosphate. However, it is clear that the rate of glycolysis can be stimulated by fructose because its entrance into glycolysis skips the two main regulatory enzymes (glucokinase and PFK-1) (67). Either the presence of GLUT5 leads to a greater use of fructose by neoplastic cells, or increased usage of fructose leads to a higher abundance of GLUT5. Clearly, the role of fructose in enhanced glycolysis observed in cancer cells requires further study.

Future Research

GLUT5 is found in many tissues, and its expression‎ and activity are clearly regulated under normal and are altered under pathological conditions (Fig. 2). The increasing importance of fructose in human nutrition and disease calls for additional studies that hopefully will increase our understanding of the role of the fructose transporter GLUT5 in health and disease.

Fig. 2.

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Multiple regulatory parameters of GLUT5 expression‎ and protein abundance and activity under physiological (light shading) and pathological (darker shading) conditions in small intestine, kidney, adipocytes, skeletal muscle, and brain.

Estimates of fructose concentrations in plasma, urine, and cerebrospinal and intracellular fluids, as well as kinetic properties of GLUT5 in other tissues, are needed to better understand the role of GLUT5 in fructose metabolism and the role of fructose in GLUT5 regulation.

GLUT5 is expressed in only a limited number of tissues seemingly capable of or preferentially metabolizing fructose, and there exist two major categories of transcriptional and/or posttranscriptional regulation of GLUT5. In the apical membrane of polarized cells (e.g., enterocytes and renal cells), GLUT5 is acutely and specifically regulated by its own substrate, whereas in the other tissues, like adipocytes, fructose seems to have no acute effect. The signaling cascade regulating this specific and acute regulation in epithelial cells of GLUT5 by fructose is not known and can be compared with signals regulating substrate-independent modulation of GLUT5 in other tissues. The subcellular redistribution of GLUT5 following different stimuli also merits attention.

In Caco2 cells and in highly proliferative cancer cells, GLUT5 expression‎ is significant enough that it appears to be a good marker of malignancy or high proliferation rate. This suggests that cancerous cells lose the inhibitory factor(s) that blocks intensive GLUT5 expression‎ in normal cells. The mechanisms underlying GLUT5 induction in cancer need to be identified.

Until now, the developmentally regulated biological factor(s) allowing luminal fructose to enhance GLUT5 expression‎ after but not before 14 days of age has not been identified. Moreover, related factors that trigger diurnal rhythms of GLUT5 expression‎ in adults are not known. The mechanisms underlying and the factors involved in the glucocorticoid-allowed, fructose-induced regulation of GLUT5 in suckling rats need further study.

Information about ontogenetic development of human intestinal GLUT5 is needed to increase our understanding not only of the role fructose plays in intestinal fructose malabsorption but also of the correlation between fructose malabsorption and infant colic.

GRANTS

We are grateful for financial support from the National Science Foundation (IOS-0722365, IBN-0235011, IBN-9985808), the National Institutes of Health (R-DK-075617A), and the Foundation of UMDNJ.

Acknowledgments

We thank Drs. X. Cui, M. Dudley, E. David, J. Jiang, I. Monteiro, and R. Shu and all former students and collaborators for their contributions to our work on GLUT5. We also thank Dr. T. Kawasaki, Teikyo University School of Medicine, Japan, for providing unpublished data.

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