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Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats

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Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats J Nutr Sci Vitaminol, 65, 45–51, 2019 Alteration of Bile Acid Metabolism by a High-Fat Diet Is Associated with Plasma Transaminase Activities and Glucose Intolerance in Rats Reika YOSHITSUGU, Keidai KIKUCHI, Hitoshi IWAYA, Nobuyuki FUJII, Shota HORI, Dong Geun LEE and Satoshi ISHIZUKA* Laboratory of Nutritional Biochemistry, Research Group of Bioscience and Chemistry, Division of Fundamental Agriscience Research, Research Faculty of Agriculture, Hokkaido University, Sapporo 060–8589, Japan (Received July 3, 2018) Summary Ingestion of a high-fat (HF) diet is known to enhance bile acid (BA) secretion, but precise information about the BA molecular species is lacking, especially information on the conjugated BAs in enterohepatic circulation. As cholesterol is the precursor of BAs, we analyzed alterations of the entire BA metabolic pathway in response to a HF diet without the addition of cholesterol and BA in the diet. Additionally, we evaluated the relationships between BA metabolism and some disorders, such as plasma transaminase activities and glucose intolerance induced by the HF diet. Acclimated WKAH/HkmSlc male rats (3 wk old) were divided into two groups fed a control or the HF diet for 22 wk. Fasting blood glu- cose was measured during the experimental period, and an intraperitoneal glucose tolerance test was performed at week 21. As a result, ingestion of the HF diet selectively increased the concentration of taurocholic acid in the bile and small intestinal contents as well as deoxycholic acid in the large intestinal contents and feces. These results indicated a selec- tive increase of 12a-hydroxylated BA concentrations in response to the HF diet. Moreover, fecal 12a-hydroxylated BA concentration was positively correlated with cumulative energy intake, visceral adipose tissue weight, and glucose intolerance. The present study suggests that fecal 12a-hydroxylated BA is a non-invasive marker that can detect the early phase of glucose intolerance. Key Words bile acids, high-fat diet, energy intake, liver damage, glucose tolerance The expansion of noncommunicable diseases (NCDs) this instrumental analysis enables us to accurately eval- has increased, and overweight and unhealthy diets are uate BA metabolism, including conjugated BAs. factors associated with the incidence of disease (1). During the development of instrumental analysis, Consumption of an energy-dense diet is considered to information on BA metabolism has gradually been be related to NCDs. Actually, obesity (2) and various revealed. For example, BAs undergo deconjugation disorders (3), such as insulin resistance and dyslipid- and/or 7a-dehydroxylation by some intestinal bacte- emia, related to energy metabolism are observed in ani- ria (8). Aging increases the ratio of cholic acid (CA) to mal models fed a high-fat diet. Many researchers have chenodeoxycholic acid (CDCA) in rodents (9). The CA/ attempted to reveal the underlying mechanisms in the CDCA ratio in primary BAs in humans has not been development of these disorders, but these efforts are still systematically investigated. However, there are some underway. reports showing the BA composition in bile, serum, Ingestion of a high-fat diet promotes bile acid (BA) or feces, which enabled us to calculate the CA/CDCA secretion as shown by fecal excretion of secondary BAs ratio of 0.3–0.5 in infants until 72 h after birth (10), in animal and human studies (4, 5). In these studies, of ~0.5 in children ages 12–59 mo (11), and of .1.1 BAs were primarily analyzed by gas chromatography in adults 24–41 y of age (12). Taurocholic acid (TCA) (GC) and GC/mass spectrometry (MS). In this method, is the taurine-conjugated form, and deoxycholic acid deconjugation and derivatization steps of the extracted (DCA) is the 7a-dehydroxylated form of CA (13). Both BAs are necessary before analysis with GC/MS, which TCA and DCA possess an a-hydroxyl group in the ste- makes it difficult to distinguish unconjugated and con- roid ring. In rodents, there is an additional BA synthetic jugated BAs in the BA profile. Those preparatory steps pathway from CDCA to a- and b-muricholic acids in are not required in current methods with liquid chro- the liver (14). Considering the diversity of primary BA matography (LC)/MS (6, 7), and the whole BA profile synthesis, it is appropriate to use the term “proportion can be analyzed at the same time. The development of of 12a-hydroxylated BAs (12aBAs)” as a more general expression rather than the CA/CDCA ratio. * To whom correspondence should be addressed. BA metabolism is closely related to several disorders, E-mail: [email protected] such as carcinogenesis in the liver and intestine (15), 45 46 YOSHITSUGU R et al. type 2 diabetes (16) and cardiovascular diseases (17). Table 1. Diet composition. However, fundamental information on BA metabolism on a high-fat diet is still unclear despite the attention C HF that has been paid to the relationship between BAs and the development of NCDs. In this study, we assessed BA g/kg diet 1 metabolism in rats fed a high-fat diet and explored the Dextrin 529.5 299.5 Casein2 200.0 200.0 relationship between BA metabolism and several disor- Sucrose3 100.0 100.0 ders observed with high-fat diet consumption. Soybean oil4 70.0 70.0 MATERIALS AND METHODS Lard — 230.0 Cellulose5 50.0 50.0 Animals. The study was approved by the Institu- Mineral mixture6 35.0 35.0 tional Animal Care and Use Committee of National Vitamin mixture7 10.0 10.0 Corporation Hokkaido University (approved number: Choline bitartrate8 2.5 2.5 14-0026), and all animals were maintained in accor- L-Cystine8 3.0 3.0 dance with the Hokkaido University Manual for Imple- 1 TK-16 (Matsutani Chemical Industry Co., Ltd., Hyogo, menting Animal Experimentation. Wistar King A Hok- Japan). kaido male rats (3-wk-old NBRP Rat No: 0154) (WKAH/ 2 NZMP Acid Casein (Fonterra Co-Operative Group Lim- HkmSlc, Japan SLC, Inc., Shizuoka, Japan), an inbred ited, Auckland, New Zealand). strain of Wistar rats, were housed in an air-conditioned 3 Nippon Beet Sugar Manufacturing Co., Ltd., Tokyo, room at 2262˚C with 5565% humidity, and the light Japan period was from 8:00 to 20:00. The rats were housed 4 J-Oil Mills, Inc., Tokyo, Japan. individually in wire-bottomed cages and allowed ad libi- 5 Crystalline cellulose (Ceolus PH-102, Asahi Kasei tum access to diet and water. The rats were acclimatized Chemicals Corp., Tokyo, Japan). 6 with a control diet (C) based on the AIN-93G formulation AIN-93G mineral mixture (18). 7 AIN-93 vitamin mixture (18). (Table 1) (18) for 2 wk. The acclimatized rats (n520) 8 Wako Pure Chemical Industries, Ltd., Osaka, Japan. were then divided into two groups and were fed either a C (n510) or a high-fat diet (HF) (n510) (Table 1) for another 22 wk. Tail vein blood was collected every 2 wk from week 1 to week 15 and at week 21 during the test -muricholic acid (5b-cholanic acid-3a,6a,7b-triol, period after food deprivation for 16 h to measure fasting MCA), CDCA (5b-cholanic acid-3a,7a-diol), DCA plasma glucose concentration. Additionally, feces were (5b-cholanic acid-3a,12a-diol), hyocholic acid (5b- collected every 2 wk from week 2 to week 22 to measure cholanic acid-3a,6a,7a-triol, HCA), hyodeoxycholic fecal BA compositions. At week 22, bile juice was col- acid (5b-cholanic acid-3a,6a-diol, HDCA), ursodeoxy- lected through a polyvinyl catheter (SV-35; id 0.5 mm, cholic acid (5b-cholanic acid-3a,7a-diol, UDCA), litho- od 0.9 mm; Natsume Seisakusyo, Tokyo, Japan) inserted cholic acid (5b-cholanic acid-3a-ol, LCA), hyocholic into the common bile-pancreatic duct under anesthe- acid (5b-cholanic acid-3a,6a,7a,-triol, HCA), TCA (5b- sia with sodium pentobarbital (Somnopentyl, 50 mg/ cholanic acid-3a,7a,12a-triol-N-(2-sulphoethyl)-amide), kg body weight, Kyoritsu Seiyaku Corporation, Tokyo, tauro-a-muricholic acid (5b-cholanic acid-3a,6b,7a- Japan). Immediately after the bile collection for 10 min, triol-N-(2-sulphoethyl)-amide, TaMCA), tauro-b-muri- aortic blood was collected from the aorta abdominalis cholic acid (5b-cholanic acid-3a,6b,7b-triol-N-(2-sulpho- of the rats. An anticoagulant agent (heparin, 50 U/mL ethyl)-amide, TbMCA), tauro--muricholic acid (5b- blood, Nakarai Tesque, Inc., Kyoto, Japan) and a prote- cholanic acid-3a,6a,7b-triol-N-(2-sulphoethyl)-amide, ase inhibitor (aprotinin, 500 kIU/mL blood, Wako Pure TMCA), taurochenodeoxycholic acid (5b-cholanic acid- Chemical Industries, Ltd., Osaka, Japan) were added 3a,7a-diol-N-(2-sulphoethyl)-amide, TCDCA), tauro- to the collected blood, and the plasma was separated. deoxycholic acid (5a-cholanic acid-3a,12a-diol-N-(2- The rats were killed by exsanguination thereafter. The sulphoethyl)-amide, TDCA), taurohyodeoxycholic acid liver, visceral adipose tissues, and intestinal contents (5b-cholanic acid-3a,6a-diol-N-(2-sulphoethyl)-amide, (jejunum, ileum, cecum, and colon) were collected and THDCA), taurolithocholic acid (5b-cholanic acid-3a-ol- weighed. Feces were collected through the last day of N-(2-sulphoethyl)-amide, TLCA), glycocholic acid (5b- the experimental period. cholanic acid-3a,7a,12a-triol-N-(carboxymethyl)-amide, BA analysis. The levels of each BA in the bile, intesti- GCA), glycochenodeoxycholic acid (5b-cholanic acid- nal contents, and feces were extracted and measured as 3a,7a-diol-N-(carboxymethyl)-amide, GCDCA), gly- previously reported (6, 7). The individual BA concentra- codeoxycholic acid (5b-cholanic acid-3a,12a-diol-N- tions were measured with nordeoxycholic acid (23-nor- (car boxymethyl)-amide, GDCA), glycohyodeoxycholic acid 5b-cholanic acid-3a,12a-diol) as the internal standard.
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