Introduction

Laboratory of Human Nutrition studies the physiology of digestion and absorption of nutrients. The main theme is "mechanisms of pancreatic bicarbonate secretion". Cystic fibrosis and chronic pancreatitis involve indigestion and malnutrition due to impaired bicarbonate secretion by pancreatic ductal epithelium. Our laboratory is trying to clarify molecular pathogenesis of the diseases by mutli-faceted approach.

Research Projects

1. Cellular and molecular mechanisms for pancreatic bicarbonate secretion.

Moisturization and alkalinization of mucosal epithelia is fundamental to mucosal defense and nutrients absorption. We are investigating cellular and molecular mechanisms for HCO3- secretion by mucosal epithelial cells by using isolated pancreatic duct segments. Human, dog, and guinea-pig pancreatic ductal epithelium produces alkaline isotonic fluid containing as much as 140 mM HCO3- in response to secretin stimulation. Pancreas consists of exocrine and endocrine pancreas. The exocrine pancreas consists of acinar cells and duct cells; the former synthesizes and secretes digestive enzymes and the latter produces HCO3--rich fluid secretion. We isolate interlobular duct segments (diameter: ~100 μm) from the pancreas of small animals and microperfuse the lumen with artificial pancreatic juice (Figure 1). Mechanisms for HCO3- transport were examined by monitoring changes in pH, various ion concentrations, volume, and membrane potential in intra- and extra-cellular microenvironment in native and polarized epithelium. We simulate various in vivo conditions that apical membrane faces high HCO3-. Figure 2 is a model of pancreatic HCO3- secretion based on experimental data accumulated in our laboratory. Various ion channels/transporters are localized to basolateral or apical membranes, which accomplish vectorial HCO3- transport. The key molecule is the CFTR (cystic fibrosis transmembrane conductance regulator) anion channel localized to the apical membrane of mucosal epithelia which is related to the next project.

2. Pathophysiology of cystic fibrosis and its related diseases.

Cystic fibrosis is an autosomal recessive genetic disease caused by mutations of CFTR. CFTR is a key molecule for Cl- and HCO3- transport by epithelia cells. Dysfunction of CFTR impairs anion and water transport in bronchial and intestinal mucosa, pancreatic duct, bile duct, sweat duct, and vas deferens, which results in thick mucus/luminal fluid, then obstruction of the lumen and recurrent mucosal infection. Severe cases of cystic fibrosis show meconium ileus, recurrent respiratory tract infection, and digestive disturbance. Cystic fibrosis is the most common genetic disease in Europeans but is rare in Asian population (The incidence in Japanese is ~1 per 600,000.) Our group is the office for registry and nationwide epidemiological survey of cystic fibrosis and is responsible for genetic diagnosis of cystic fibrosis. Recent studies suggest that mild dysfunction of CFTR is a risk of chronic pancreatitis, male infertility, chronic sinusitis, diffuse panbronchiolitis. Our group is investigating the risk of particular CFTR mutations/polymorphisms for idiopathic and chronic pancreatitis.

3. Fatty-acid receptors in the intestine

When long chain lipids in the diet enter the lumen of upper small intestine, enteroendocrine (EEC) cells in the duodenal epithelium secrete cholecystokinin (CCK). CCK acts in a paracrine manner to activate vagal afferents and also as a circulating hormone to induce pancreatic enzyme secretion, gall-bladder contraction, and slower gastric emptying. These actions coordinate maximally to achieve efficient digestion and nutrient absorption (Figure 3). Little has been known how CCK-secreting EEC (I cells) sense intraluminal lipids. Recently, there has been the identification of candidate receptors for extracellular fatty acids. Ligand-hunting for orphan G protein-coupled receptors (GPRs) revealed that GPR40, GPR41, GPR43, and GPR120 are apparent receptors for fatty acids. GPR40 is activated by a relatively wide range of saturated and unsaturated fatty acids and thus may represent the main sensor of dietary fatty acids. In our laboratory, we are trying to clarify fatty-acid sensing mechanism in the intestine.

Faculty Members

Faculty	Position	Department
Hiroshi Ishiguro	Professor	Human Nutrition
Akiko Yamamoto	Professor	Human Nutrition

Bibliography

• 2016

  1. Mochimaru Y, Yamamoto A, Nakakuki M, Yamaguchi M, Taniguchi I, Ishiguro H, Caffeine inhibits fluid secretion by interlobular ducts from guinea-pig pancreas. Pancreas, 2016 (in press)
  2. Ito T, Ishiguro H, Ohara H, Kamisawa T, Sakagami J, Sata N, Takeyama Y, Hirota M, Miyakawa H, Igarashi H, Lee L, Fujiyama T, Hijioka M, Ueda K, Tachibana Y, Sogame Y, Yasuda H, Kato R, Kataoka K, Shiratori K, Sugiyama M, Okazaki K, Kawa S, Tando Y, Kinoshita Y, Watanabe M, Shimosegawa T. Evidence-based clinical practice guidelines for chronic pancreatitis 2015. J Gastroenterol, 2016; 51: 85-92.

• 2015

  1. Kondo S, Fujiki K, Ko SB, Yamamoto A, Nakakuki M, Ito Y, Shcheynikov N, Kitagawa M, Naruse S, Ishiguro H, Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. Am J Physiol Gastrointest Liver Physiol, 2015; 309: G260-9.

• 2014

  1. Ishiguro H. HCO3- secretion by SLC26A3 and mucosal defence in the colon. Acta Physiol (Oxf), 2014; 211: 17-9.

• 2013

  1. Ko SB, Azuma S, Yokoyama Y, Yamamoto A, Kyokane K, Niida S, Ishiguro H, Ko MS. Inflammation increases cells expressing ZSCAN4 and progenitor-cell markers in the adult pancreas. Am J Physiol Gastrointest Liver Physiol, 2013; 304: G1103-16.

• 2012

  1. Nakakuki M, Fujiki K, Yamamoto A, Ko SB, Yi L, Ishiguro M, Yamaguchi M, Kondo S, Maruyama S, Yanagimoto K, Naruse S, Ishiguro H. Detection of a large heterozygous deletion and a splicing defect in the CFTR transcripts from nasal swab of a Japanese case of cystic fibrosis. J Hum Genet, 2012; 57: 427-33.
  2. Song Y, Yamamoto A, Steward MC, Ko SB, Stewart AK, Soleimani M, Liu BC, Kondo T, Jin CX, Ishiguro H. Deletion of Slc26a6 alters the stoichiometry of apical Cl-/HCO3- exchange in mouse pancreatic duct. Am J Physiol Cell Physiol, 2012; 303: C815-24.
  3. Ishiguro H, Yamamoto A, Nakakuki M, Yi L, Ishiguro M, Yamaguchi M, Kondo S, Mochimaru Y. Physiology and pathophysiology of bicarbonate secretion by pancreatic duct epithelium. Nagoya J Med Sci, 2012; 74: 1-18.

• 2011

  1. Ishiguro H, Steward MC, Yamamoto A. Microperfusion and micropuncture analysis of ductal secretion. In: The Pancreapedia Exocrine Pancreas Knowledge Base 2011. University of Michigan Library. (DOI: 10.3998/panc.2011.16)

• 2010

  1. Ko SB, Mizuno N, Yatabe Y, Yoshikawa T, Ishiguro H, Yamamoto A, Azuma S, Naruse S, Yamao K, Muallem S, Goto H. Corticosteroids correct aberrant CFTR localization in the duct and regenerate acinar cells in autoimmune pancreatitis. Gastroenterology, 2010; 138: 1988-96.

• 2009

  1. Ishiguro H, Steward MC, Naruse S, Ko SB, Goto H, Case RM, Kondo T, Yamamoto A. CFTR functions as a bicarbonate channel in pancreatic duct cells. J Gen Physiol, 2009; 133: 315-26.
  2. Steward MC, Ishiguro H. Molecular and cellular regulation of pancreatic duct cell function. Curr Opin Gastroenterol, 2009; 25: 447-53.

Research Keywords

Epithelial transport of bicarbonate、Cystic fibrosis and its CFTR-related diseases、Fatty-acid receptors in the intestine

Private Page

Call for graduate students

Hiroshi Ishiguro and Akiko Yamamoto are faculty members of Research Center of Health, Physical Fitness, and Sports (Higashiyama campus). The laboratory of Human Nutrition is located at the 2nd floor of the Building for Medical Research (Tsurumai campus). Now 4 graduate students belong to our laboratory. We welcome students who are interested in the gastrointestinal and nutritional physiology.