Exendin‑4, a glucagon‑like peptide‑1 receptor agonist, modulates hepatic fatty acid composition and Δ‑5‑desaturase index in a murine model of non‑alcoholic steatohepatitis

  • Authors:
    • Takumi Kawaguchi
    • Minoru Itou
    • Eitaro Taniguchi
    • Michio Sata
  • View Affiliations

  • Published online on: June 27, 2014     https://doi.org/10.3892/ijmm.2014.1826
  • Pages: 782-787
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Abstract

Glucagon‑like peptide‑1 (GLP‑1) is involved in the development of non‑alcoholic steatohepatitis (NASH), which is characterized by fatty acid imbalance. The aim of this study was to investigate the effects of the GLP‑1 receptor (GLP‑1R) agonist, exendin‑4 (Ex‑4), on hepatic fatty acid metabolism and its key enzyme, Δ‑5‑desaturase, in a murine model of NASH. NASH was induced in db/db mice fed a methionine‑choline deficient (MCD) diet. Ex‑4 (n=4) or saline [control (CON); n=4] was administered intraperitoneally for 8 weeks. Steatohepatitis activity was evaluated by non‑alcoholic fatty liver disease (NAFLD) activity score. Hepatic fatty acid composition and Δ‑5‑desaturase index were analyzed by gas chromatography. Ex‑4 treatment significantly reduced body weight and the NAFLD activity score. Hepatic concentrations of long‑chain saturated fatty acids (SFAs) were significantly higher in the Ex‑4 group compared to the CON group (23240±955 vs. 31710±8436 µg/g•liver, P<0.05).Ex‑4 significantly reduced hepatic n‑3 polyunsaturated fatty acid (PUFA)/n‑6 PUFA ratio compared to the CON group (13.83±3.15 vs. 8.73±1.95, P<0.05). In addition, the hepatic Δ‑5‑desaturase index was significantly reduced in the Ex‑4 group compared to the CON group (31.1±12.4 vs. 10.5±3.1, P<0.05). In conclusion, the results showed that Ex‑4 improved steatohepatitis in a murine model of NASH. Furthermore, Ex‑4 altered hepatic long‑chain saturated and PUFA composition and reduced the Δ‑5‑desaturase index. Thus, Ex‑4 may improve NASH by regulating hepatic fatty acid metabolism.

Introduction

The incidence of non-alcoholic steatohepatitis (NASH) is rapidly increasing worldwide (14). NASH can be caused by various pathogenic mechanisms, including overeating, physical inactivity, diabetes mellitus, and medications (5,6). The gut directly links to the liver through the portal vein and is involved in the development of NASH (7,8). The gut secretes various hormones in the portal vein and regulates hepatic metabolism (911). Glucagon-like peptide-1 (GLP-1) is a gut hormone and is known to affect lipid metabolism in hepatocytes (9,11).

Exendin-4 (Ex-4) is a long-acting GLP-1 receptor (GLP-1R) agonist. GLP-1R occurs in the pancreatic islets, kidney, lung, heart, stomach, intestine, thyroid gland, and numerous regions of the peripheral and central nervous system (1214). GLP-1R also occurs in hepatocytes, and treatment with Ex-4 substantially reduces triglyceride stores in hepatoma cells (15). Similarly, GLP-1R agonist reduces steatosis severity in certain animal models of NASH (1619). Findings of previous studies have also shown that reduced hepatic accumulation of triglycerides is mediated by GLP-1R agonist upregulation of hepatic 3-phosphoinositide-dependent kinase-1 activity, protein kinase C ζ activity, peroxisome proliferator-activated receptor α activity, and fatty acid β-oxidation (1519).

Fatty acids are an important triglyceride component. Fatty acids are a substrate of β-oxidation and yield large quantities of adenosine 5′-triphosphate (20). In addition, some polyunsaturated fatty acids (PUFAs) are a source of eicosanoids, which are biologically active substances. n-3 PUFAs are precursors of anti-inflammatory eicosanoids, including leukotriene B5, prostaglandin E3, and thromboxane B3 (21). On the other hand, n-6 PUFA are precursors of pro-inflammatory eicosanoids, including leukotriene B4, prostaglandin E2, and thromboxane B2 (21). A reduced n-3/n-6 PUFA ratio is a risk factor for chronic inflammatory diseases such as cardiovascular disease, inflammatory bowel disease, rheumatoid arthritis, and NASH (2224). Thus, besides quantitative abnormality in fatty acids, qualitative abnormality in fatty acids is an important pathogenesis of NASH.

The production of pro- and anti-inflammatory eicosanoids is regulated by desaturases, which are rate-limiting enzymes of n-3 and n-6 PUFA cascades (25). Δ-5-desaturase, also known as fatty acid desaturase 1, removes two hydrogen atoms from dihomo γ-linolenic acid and synthesizes arachidonic acid. Upregulation of Δ-5-desaturase activity promotes the production of pro-inflammatory eicosanoids (26). Notably, single-nucleotide polymorphisms in the Δ-5-desaturase gene are associated with circulating high sensitivity C-reactive protein levels in healthy young adults (27). Moreover, Δ-5-desaturase activity is associated with aging (28), development of type 2 diabetes mellitus (29), and NASH (30). However, the effects of Ex-4 on hepatic fatty acid composition and Δ-5-desaturase activity remain unclear.

The aim of this study was to investigate the effects of Ex-4 on severity of steatohepatitis, hepatic fatty acid composition, and Δ-5-desaturase index in a murine model of NASH.

Materials and methods

Materials

Reagents were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan) unless otherwise indicated.

Animals

NASH was induced in db/db mice fed a methionine-choline deficient (MCD) diet (31). Briefly, 5-week-old male db/db mice (BKS.Cg- + Leprdb/+Leprdb/Jcl*) weighing 15–20 g were purchased from CLEA Japan, Inc. (Tokyo, Japan). The mice were housed individually in an air-conditioned room at 22±3°C and 55±10% humidity with a 12-h light/dark cycle. The mice were fed a normal diet during a 1-week quarantine and acclimatization period, followed by the MCD diet (CLEA Japan, Inc.) and water ad libitum throughout the experimental period. All the rat experiments were conducted in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the University of Kurume Institutional Animal Care and Use Committee.

Treatment

Ex-4 (20 μg/kg; no. 24463, AnaSpec, Inc., Fremont, CA, USA) (Ex-4 group; n=4) or saline [control (CON) group; n=4] was administered intraperitoneally under anesthesia every morning for 8 weeks. At week 14, the mice were sacrificed by using ether anesthesia and the livers were obtained under anesthesia.

Measurement of body weight

Body weight was measured weekly, in the morning, through week 14.

Liver histology

Random histological sampling was performed throughout this study as previously described (32,33). Liver samples were fixed overnight in 10% buffered formalin and embedded in paraffin. All sections were cut at a thickness of 5 μm and stained with hematoxylin and eosin (H&E) (34,35).

Hepatic triglyceride content

Liver samples were fixed overnight in 10% buffered formalin. Sections were transferred to 70% ethanol and stained with Sudan IV (0.1% Sudan IV dissolved in equal parts acetone and 70% ethanol) to evaluate triglyceride content (36).

Non-alcoholic fatty liver disease (NAFLD) activity

NAFLD activity was evaluated by the NAFLD activity score, in which the following findings were evaluated semi-quantitatively: steatosis (0–3 points), lobular inflammation (0–2 points), hepatocellular ballooning (0–2 points), and fibrosis (0–4 points) (37).

Fatty acid composition

Total liver fatty acids were extracted according to Folch et al (38). Fatty acid methyl esters were isolated and quantified by gas chromatography furnished with a flame-ionization detector. The fatty acids measured (and expressed as μg/g•liver) were: lauric, myristic, myristoleic, palmitic, palmitoleic, stearic, oleic, linoleic, γ-linolenic, linolenic, arachidic, eicosenoic, eicosadienoic, 5,8,11-eicosatrienoic, dihomo γ-linolenic, arachidonic, eicosapentaenoic, behenic, erucic, docosatetraenoic, docosapentaenoic, lignoceric, docosahexaenoic, and nervonic acid.

Classification of fatty acids

Fatty acids were classified as follows: saturated fatty acids (SFAs), the sum of all identified SAFs; atherogenic SFAs, the sum of lauric, myristic, and palmitic acids; thrombogenic SFAs, the sum of myristic, palmitic, and stearic acids; medium SFAs, the sum of SFAs containing 11–16 carbon atoms; long SFAs, the sum of SFAs containing ≥16 carbon atoms; monounsaturated fatty acids (MUFAs), the sum of all identified MUFAs; PUFAs, the sum of all identified PUFAs; n-3 PUFAs, the sum of n-3 series PUFAs; n-6 PUFAs, the sum of n-6 series PUFA; Δ-5-desatulase index, arachidonic acid/γ-linolenic acid.

Statistical analysis

Data were expressed as mean ± SD. Differences between two groups were analyzed by the Wilcoxon test (JMP version 10.0.2, SAS Institute, Inc., Cary, NC). P≤0.05 was considered statistically significant.

Results

Effects of Ex-4 on body weight, appearance, and macroscopic appearance of the liver

In the CON group, body weight gradually increased to ~50 g at week 14 (Fig. 1A). In the Ex-4 group, body weight gain stopped 1 week after the Ex-4 treatment and reached a plateau at ~40 g at week 7 (Fig. 1A). Ex-4 significantly suppressed weight gain in MCD-fed db/db mice.

Representative mice from the CON and Ex-4 groups are shown in Fig. 1B. The mouse from the Ex-4 group was smaller and had a good coat of fur in comparison to the mouse from the CON group (Fig. 1B).

A representative macroscopic image of the liver of CON and Ex-4 mice is shown in Fig. 1C. CON livers exhibited xanthochromia with swelling, while the Ex-4 livers were brown, with no swelling (Fig. 1C).

Effects of Ex-4 on hepatic histology, hepatic triglyceride content, and the NAFLD activity score

Representative images of hepatic histology and Sudan IV staining are shown in Fig. 2A. Steatosis, lobular inflammation, and hepatocyte ballooning were milder in the Ex-4 group compared to the CON group (Fig. 2A). Obvious hepatic fibrosis was not evident in either group. Hepatic triglyceride content was depleted in the Ex-4 group in comparison to the CON group (Fig. 2A).

The NAFLD activity score was significantly lower in the Ex-4 group than in the CON group (Fig. 2B).

Effects of Ex-4 on hepatic SFA

There was no significant difference in the hepatic SFA content of the CON and Ex-4 groups (Table I). No significant difference between the groups was observed in the hepatic content of atherogenic, thrombogenic, and medium-chain SFA. However, long-chain SFA content was significantly higher in the Ex-4 group compared to the CON group (Table I).

Table I

Effects of Ex-4 on hepatic SFA.

Table I

Effects of Ex-4 on hepatic SFA.

SFA typeUnitCONEx-4P
SFAμg/g•liver17838±324827541±9273N.S.
 Atherogenicμg/g•liver13414±298122457±8670N.S.
 Thrombogenicμg/g•liver17605±324427210±9260N.S.
 Medium-chainμg/g•liver15233±355425186±9799N.S.
 Long-chainμg/g•liver23240±95531710±8436<0.05

[i] Ex-4, exendin-4; SFA, saturated fatty acid; CON, control; N.S., not significant.

We also examined the hepatic content of each long-chain SFA component and found no significant differences in the palmitic, stearic, behenic, and lignoceric acid. However, hepatic arachidic acid was significantly higher in the Ex-4 group compared to the CON group (Fig. 3A–E).

Effects of Ex-4 on hepatic MUFAs and PUFAs

Hepatic MUFA content did not significantly differ between groups (Table II). However, hepatic PUFA content was significantly higher in the Ex-4 group compared to the CON group. Similarly, hepatic n-6 PUFA content and the n-3 PUFA/n-6 PUFA ratio were significantly higher in the Ex-4 group compared to the CON group (Table II).

Table II

Effects of Ex-4 on hepatic MUFAs and PUFAs.

Table II

Effects of Ex-4 on hepatic MUFAs and PUFAs.

Acid typeUnitCONEx-4P
MUFAμg/g•liver20355±670134965±14485N.S.
PUFAμg/g•liver18410±79125986±8050<0.05
n-3 PUFAμg/g•liver2218.5±415.81992.4±288.7N.S.
n-6 PUFAμg/g•liver16166±94323937±7845<0.05
n-3 PUFA/n-6 PUFARatio13.83±3.158.73±1.95<0.05

[i] Ex-4, exendin-4; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; CON, control; N.S., not significant.

We also assessed the hepatic content of each n-6 PUFA component and found no significant difference in arachidonic acid. However, the hepatic content of linoleic acid, γ-linolenic acid, and dihomo γ-linolenic acid was significantly higher in the Ex-4 group compared to the CON group (Fig. 4A–D). By contrast, hepatic Δ-5-desaturase index in the Ex-4 group was approximately one-third of that in the CON group. Ex-4 treatment significantly reduced hepatic Δ-5-desaturase index compared to the CON group (Fig. 4E).

Discussion

Results of this study have shown that Ex-4 inhibited body weight gain and improved NASH in MCD diet-fed db/db mice. Ex-4 also altered hepatic fatty acid composition with a decrease in Δ-5-desaturase index. Thus, Ex-4 may improve NASH by altering the hepatic fatty acid composition in a murine model of NASH.

The effects of the GLP-1R agonist Ex-4 on NASH were examined. The results showed that Ex-4 significantly suppressed body weight gain and the NAFLD activity score in MCD diet-fed db/db mice. GLP-1R expression is downregulated in a NASH rat model as well as in patients with NASH (16). Moreover, GLP-1R agonist improves NASH in various animal models, including high-fat diet-fed rats (16), ob/ob mice (17,18), and diabetic male ApoE(−/−) mice (19). The GLP-1R agonist also reduced body weight and the NAFLD activity score in patients with NASH (39). Thus, our results are consistent with previous reports in this regard. Possible mechanisms for GLP-1R agonist-induced NASH improvement include the upregulation of insulin sensitivity, peroxisome proliferator-activated receptor α activity, and fatty acid β-oxidation (15,16,40,41). However, the effects of GLP-1R agonist in hepatic fatty acid composition remain unclear.

In general, long-chain SFAs promote inflammation and progression of NAFLD (42,43). However, results of this study have shown that Ex-4 significantly increased the hepatic content of long-chain SFAs, in particular the arachidic and lignoceric acids. Although the reason for the discrepancy between previous reports and our findings remains unclear, certain SFAs, including arachidic and lignoceric acids are not correlated with insulin resistance, a feature of NASH (44). Furthermore, arachidic acid improves lipid metabolism by enhancing apoB secretion (45). Lignoceric acid is a precursor of ceramide, thus an increase in hepatic lignoceric acid content indicates a decrease in ceramide synthesis. Recently, Kurek et al showed that inhibition of ceramide synthesis reduces hepatic lipid accumulation in a rat model of NAFLD (46). This finding suggests that Ex-4 improves lipid metabolism through alterations in arachidic and lignoceric acids in a murine model of NASH.

Although hepatic MUFA content was not altered by Ex-4 treatment, hepatic PUFA content was increased. Ex-4 increased the hepatic content of n-6 PUFAs such as linoleic acid, γ-linolenic acid, and dihomo γ-linolenic acid. These n-6 PUFAs are precursors of pro-inflammatory eicosanoids and are involved in the development of NASH (22,47). Thus, our findings are different from those of previous studies. However, a possible explanation for the discrepancy is an Ex-4-induced alteration in n-6 PUFA metabolism. Δ-5-desaturase is a rate-limiting enzyme of n-6 PUFA metabolism that increases the production of pro-inflammatory eicosanoids (48). An oligonucleotide microarray analysis using human liver tissue showed that Δ-5-desaturase is upregulated in patients with NASH (30). In this study, we have found that the Δ-5-desaturase index was significantly reduced by Ex-4 treatment, indicating that Ex-4 inhibits Δ-5-desaturase activity and subsequently suppresses the production of pro-inflammatory eicosanoids (Fig. 5). In addition, the inhibition of Δ-5-desaturase activity increases hepatic contents of dihomo γ-linolenic acid, which is a precursor of anti-inflammatory eicosanoids (Fig. 5). López-Vicario et al recently showed that a Δ-5-desaturase inhibitor, CP-24879, significantly reduces intracellular lipid accumulation and inflammatory injury in hepatocytes in vitro (30), supporting our hypothesis. Thus, our findings together with those of previous studies suggest that suppression of Δ-5-desaturase activity could be a new therapeutic strategy for NASH.

In conclusion, the results of the present study have shown that Ex-4 suppressed body weight gain and improved steatohepatitis in a murine model of NASH. Ex-4 also altered hepatic fatty acid composition with a decrease in Δ-5-desaturase index. These findings suggest that Ex-4 improves NASH by modulating hepatic fatty acid metabolism.

Acknowledgements

This study was supported, in part, by Health and Labour Sciences Research Grants for Research on Hepatitis from the Ministry of Health, Labour and Welfare of Japan.

Abbreviations:

GLP-1

glucagon-like peptide-1

NASH

non-alcoholic steatohepatitis

Ex-4

exendin-4

GLP-1R

GLP-1 receptor

NAFLD

non-alcoholic fatty liver disease

PUFA

polyunsaturated fatty acid

MCD

methionine-choline deficient

SFA

saturated fatty acid

MUFA

monounsaturated fatty acid

References

1 

Williams CD, Stengel J, Asike MI, et al: Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 140:124–131. 2011. View Article : Google Scholar

2 

Ono M and Saibara T: Clinical features of nonalcoholic steatohepatitis in Japan: Evidence from the literature. J Gastroenterol. 41:725–732. 2006. View Article : Google Scholar : PubMed/NCBI

3 

Sumida Y, Yoneda M, Hyogo H, et al: A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol. 46:257–268. 2011. View Article : Google Scholar

4 

Eguchi Y, Hyogo H, Ono M, et al: Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 47:586–595. 2012. View Article : Google Scholar

5 

Nakahara T, Hyogo H, Yoneda M, et al: Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. Nov 26–2013.(Epub ahead of print).

6 

Angulo P: Nonalcoholic fatty liver disease. N Engl J Med. 346:1221–1231. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Imajo K, Fujita K, Yoneda M, et al: Hyperresponsivity to low-dose endotoxin during progression to nonalcoholic steatohepatitis is regulated by leptin-mediated signaling. Cell Metab. 16:44–54. 2012. View Article : Google Scholar : PubMed/NCBI

8 

Smith K: Microbiota: Gut microbiota produce alcohol in patients with NASH. Nat Rev Gastroenterol Hepatol. 9:6872012. View Article : Google Scholar : PubMed/NCBI

9 

Mells JE and Anania FA: The role of gastrointestinal hormones in hepatic lipid metabolism. Semin Liver Dis. 33:343–357. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Itou M, Kawaguchi T, Taniguchi E, et al: Altered expression of glucagon-like peptide-1 and dipeptidyl peptidase IV in patients with HCV-related glucose intolerance. J Gastroenterol Hepatol. 23:244–251. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Itou M, Kawaguchi T, Taniguchi E and Sata M: Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol. 19:2298–2306. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Drucker DJ: The biology of incretin hormones. Cell Metab. 3:153–165. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Gier B, Butler PC, Lai CK, Kirakossian D, DeNicola MM and Yeh MW: Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab. 97:121–131. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Broide E, Bloch O, Ben-Yehudah G, Cantrell D, Shirin H and Rapoport MJ: GLP-1 receptor is expressed in human stomach mucosa: analysis of its cellular association and distribution within gastric glands. J Histochem Cytochem. 61:649–658. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Gupta NA, Mells J, Dunham RM, et al: Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 51:1584–1592. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al: Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 31:1285–1297. 2011. View Article : Google Scholar

17 

Trevaskis JL, Griffin PS, Wittmer C, et al: Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 302:G762–G772. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Dhanesha N, Joharapurkar A, Shah G, et al: Treatment with exendin-4 improves the antidiabetic efficacy and reverses hepatic steatosis in glucokinase activator treated db/db mice. Eur J Pharmacol. 714:188–192. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Panjwani N, Mulvihill EE, Longuet C, et al: GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(−/−) mice. Endocrinology. 154:127–139. 2013.PubMed/NCBI

20 

Stumpf PK: Metabolism of fatty acids. Annu Rev Biochem. 38:159–212. 1969. View Article : Google Scholar

21 

Calder PC: N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids. 38:343–352. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Patterson E, Wall R, Fitzgerald GF, Ross RP and Stanton C: Health implications of high dietary omega-6 polyunsaturated Fatty acids (Review). J Nutr Metab. 2012:e5394262012. View Article : Google Scholar

23 

Puri P, Baillie RA, Wiest MM, et al: A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 46:1081–1090. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Puri P, Wiest MM, Cheung O, et al: The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology. 50:1827–1838. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Poudel-Tandukar K, Sato M, Ejima Y, et al: Relationship of serum fatty acid composition and desaturase activity to C-reactive protein in Japanese men and women. Atherosclerosis. 220:520–524. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Chuang LT, Thurmond JM, Liu JW, Mukerji P, Bray TM and Huang YS: Effect of conjugated linoleic acid on Delta-5 desaturase activity in yeast transformed with fungal Delta-5 desaturase gene. Mol Cell Biochem. 265:11–18. 2004. View Article : Google Scholar

27 

Roke K, Ralston JC, Abdelmagid S, et al: Variation in the FADS1/2 gene cluster alters plasma n-6 PUFA and is weakly associated with hsCRP levels in healthy young adults. Prostaglandins Leukot Essent Fatty Acids. 89:257–263. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Maniongui C, Blond JP, Ulmann L, Durand G, Poisson JP and Bézard J: Age-related changes in delta 6 and delta 5 desaturase activities in rat liver microsomes. Lipids. 28:291–297. 1993. View Article : Google Scholar : PubMed/NCBI

29 

Kröger J and Schulze MB: Recent insights into the relation of Δ5 desaturase and Δ6 desaturase activity to the development of type 2 diabetes. Curr Opin Lipidol. 23:4–10. 2012.

30 

López-Vicario C, González-Périz A, Rius B, et al: Molecular interplay between Δ5/Δ6 desaturases and long-chain fatty acids in the pathogenesis of non-alcoholic steatohepatitis. Gut. 63:344–355. 2014.

31 

Yamaguchi K, Yang L, McCall S, et al: Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 45:1366–1374. 2007. View Article : Google Scholar

32 

Kawaguchi T, Sakisaka S, Sata M, Mori M and Tanikawa K: Different lobular distributions of altered hepatocyte tight junctions in rat models of intrahepatic and extrahepatic cholestasis. Hepatology. 29:205–216. 1999. View Article : Google Scholar : PubMed/NCBI

33 

Kawaguchi T, Sakisaka S, Mitsuyama K, et al: Cholestasis with altered structure and function of hepatocyte tight junction and decreased expression of canalicular multispecific organic anion transporter in a rat model of colitis. Hepatology. 31:1285–1295. 2000. View Article : Google Scholar

34 

Kawaguchi T, Yoshida T, Harada M, et al: Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 165:1499–1508. 2004. View Article : Google Scholar : PubMed/NCBI

35 

Kawaguchi T, Ide T, Taniguchi E, et al: Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 102:570–576. 2007. View Article : Google Scholar : PubMed/NCBI

36 

Krishna SM, Seto SW, Moxon JV, et al: Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model. Am J Pathol. 181:706–718. 2012. View Article : Google Scholar

37 

Kleiner DE, Brunt EM, Van Natta M, et al: Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 41:1313–1321. 2005. View Article : Google Scholar : PubMed/NCBI

38 

Folch J, Lees M and Sloane Stanley GH: A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 226:497–509. 1957.PubMed/NCBI

39 

Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N and Harrison SA: Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol. 105:2707–2709. 2010. View Article : Google Scholar : PubMed/NCBI

40 

Ding X, Saxena NK, Lin S, Gupta NA and Anania FA: Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology. 43:173–181. 2006. View Article : Google Scholar : PubMed/NCBI

41 

Gupta NA, Kolachala VL, Jiang R, et al: The glucagon-like peptide-1 receptor agonist Exendin 4 has a protective role in ischemic injury of lean and steatotic liver by inhibiting cell death and stimulating lipolysis. Am J Pathol. 181:1693–1701. 2012. View Article : Google Scholar : PubMed/NCBI

42 

Leamy AK, Egnatchik RA and Young JD: Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog Lipid Res. 52:165–174. 2013. View Article : Google Scholar : PubMed/NCBI

43 

Matsumori R, Miyazaki T, Shimada K, et al: High levels of very long-chain saturated fatty acid in erythrocytes correlates with atherogenic lipoprotein profiles in subjects with metabolic syndrome. Diabetes Res Clin Pract. 99:12–18. 2013. View Article : Google Scholar

44 

Kusunoki M, Tsutsumi K, Nakayama M, et al: Relationship between serum concentrations of saturated fatty acids and unsaturated fatty acids and the homeostasis model insulin resistance index in Japanese patients with type 2 diabetes mellitus. J Med Invest. 54:243–247. 2007. View Article : Google Scholar

45 

Arrol S, Mackness MI and Durrington PN: The effects of fatty acids on apolipoprotein B secretion by human hepatoma cells (HEP G2). Atherosclerosis. 150:255–264. 2000. View Article : Google Scholar : PubMed/NCBI

46 

Kurek K, Piotrowska DM, Wiesiolek-Kurek P, et al: Inhibition of ceramide de novo synthesis reduces liver lipid accumulation in rats with nonalcoholic fatty liver disease. Liver Int. Sep 25–2013.(Epub ahead of print).

47 

Araya J, Rodrigo R, Videla LA, et al: Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond). 106:635–643. 2004. View Article : Google Scholar

48 

de Gomez Dumm IN, de Alaniz MJ and Brenner RR: Effect of dietary fatty acids on delta 5 desaturase activity and biosynthesis of arachidonic acid in rat liver microsomes. Lipids. 18:781–788. 1983.PubMed/NCBI

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Kawaguchi T, Itou M, Taniguchi E and Sata M: Exendin‑4, a glucagon‑like peptide‑1 receptor agonist, modulates hepatic fatty acid composition and Δ‑5‑desaturase index in a murine model of non‑alcoholic steatohepatitis. Int J Mol Med 34: 782-787, 2014
APA
Kawaguchi, T., Itou, M., Taniguchi, E., & Sata, M. (2014). Exendin‑4, a glucagon‑like peptide‑1 receptor agonist, modulates hepatic fatty acid composition and Δ‑5‑desaturase index in a murine model of non‑alcoholic steatohepatitis. International Journal of Molecular Medicine, 34, 782-787. https://doi.org/10.3892/ijmm.2014.1826
MLA
Kawaguchi, T., Itou, M., Taniguchi, E., Sata, M."Exendin‑4, a glucagon‑like peptide‑1 receptor agonist, modulates hepatic fatty acid composition and Δ‑5‑desaturase index in a murine model of non‑alcoholic steatohepatitis". International Journal of Molecular Medicine 34.3 (2014): 782-787.
Chicago
Kawaguchi, T., Itou, M., Taniguchi, E., Sata, M."Exendin‑4, a glucagon‑like peptide‑1 receptor agonist, modulates hepatic fatty acid composition and Δ‑5‑desaturase index in a murine model of non‑alcoholic steatohepatitis". International Journal of Molecular Medicine 34, no. 3 (2014): 782-787. https://doi.org/10.3892/ijmm.2014.1826