Alogliptin alleviates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease by promoting CPT1a expression via Thr172 phosphorylation of AMPKα in the liver

Tobita,Hiroshi; Sato,Shuichi; Yazaki,Tomotaka; Mishiro,Tsuyoshi; Ishimura,Norihisa; Ishihara,Shunnji; Kinoshita,Yoshikazu

doi:10.3892/mmr.2018.8673

Alogliptin alleviates hepatic steatosis in a mouse model of nonalcoholic fatty liver disease by promoting CPT1a expression via Thr172 phosphorylation of AMPKα in the liver

Authors:
- Hiroshi Tobita
- Shuichi Sato
- Tomotaka Yazaki
- Tsuyoshi Mishiro
- Norihisa Ishimura
- Shunnji Ishihara
- Yoshikazu Kinoshita
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Affiliations: Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Shimane 693‑8501, Japan
Published online on: March 1, 2018 https://doi.org/10.3892/mmr.2018.8673
Pages: 6840-6846

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Abstract

Pioglitazone (PIO) has been reported to be effective for nonalcoholic fatty liver disease (NAFLD) and alogliptin (ALO) may have efficacy against NAFLD progression in patients with type 2 diabetes mellitus (T2DM). The present study examined the effectiveness of ALO in a rodent model of NAFLD and diabetes mellitus. KK‑Ay mice were used to produce an NAFLD model via administration of a choline‑deficient (CD) diet. To examine the effects of alogliptin, KK‑Ay mice were provided with a CD diet with 0.03% ALO and/or 0.02% PIO orally for 8 weeks. Biochemical parameters, pathological alterations and hepatic mRNA levels associated with fatty acid metabolism were assessed. Severe hepatic steatosis was observed in KK‑Ay mice fed with a CD diet, which was alleviated by the administration of ALO and/or PIO. ALO administration increased the hepatic carnitine palmitoyltransferase 1a (CPT1a) mRNA expression level and enhanced the Thr172 phosphorylation of AMP‑activated protein kinase α (AMPKα) in the liver. PIO administration tended to decrease the hepatic fatty acid synthase mRNA expression level and increase the serum adiponectin level. Homeostasis model of assessment‑insulin resistance values tended to improve with ALO and PIO administration. ALO and PIO alleviated hepatic steatosis in KK‑Ay mice fed with a CD diet. ALO increased hepatic mRNA expression levels associated with fatty acid oxidation. In addition, the results of the present study suggested that ALO promotes CPT1a expression via Thr172 phosphorylation of AMPKα.

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1	Bellentani S: The epidemiology of non-alcoholic fatty liver disease. Liver Int. 1:81–84. 2017. View Article : Google Scholar
2	Dai W, Ye L, Liu A, Wen SW, Deng J, Wu X and Lai Z: Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: A meta-analysis. Medicine (Baltimore). 96:e81792017. View Article : Google Scholar : PubMed/NCBI
3	Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, et al: Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 149:389–397. 2015. View Article : Google Scholar : PubMed/NCBI
4	Rafig N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T and Younossi ZM: Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 7:234–238. 2009. View Article : Google Scholar : PubMed/NCBI
5	Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, et al: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 362:1675–1685. 2010. View Article : Google Scholar : PubMed/NCBI
6	Da Silva Morais A, Lebrun V, Abarca-Quinones J, Brichard S, Hue L, Guigas B, Viollet B and Leclercq IA: Prevention of steatohepatitis by pioglitazone: Implication of adiponectin-dependent inhibition of SREBP-1c and inflammation. J Hepatol. 50:489–500. 2009. View Article : Google Scholar : PubMed/NCBI
7	Yilmaz Y, Yonal O, Deyneli O, Celikel CA, Kalayci C and Duman DG: Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg. 75:240–244. 2012.PubMed/NCBI
8	Mashitani T, Noguchi R, Okura Y, Namisaki T, Mitoro A, Ishii H, Nakatani T, Kikuchi E, Moriyasu H, Matsumoto M, et al: Efficacy of alogliptin in preventing non-alcoholic fatty liver disease progression in patients with type 2 diabetes. Biomed Rep. 4:183–187. 2016. View Article : Google Scholar : PubMed/NCBI
9	Nonogaki K, Nozue K and Oka Y: Social isolation affects the development of obesity and type 2 diabetes in mice. Endocrinology. 148:4658–4666. 2007. View Article : Google Scholar : PubMed/NCBI
10	Haluzik MM, Lacinova Z, Dolinkova M, Haluzikova D, Housa D, Horinek A, Vernerova Z, Kumstyrova T and Haluzik M: Improvement of insulin sensitivity after peroxisome proliferator-activated receptor-alpha agonist treatment is accompanied by paradoxical increase of circulating resistin levels. Endocrinology. 147:4517–4524. 2006. View Article : Google Scholar : PubMed/NCBI
11	Rinella ME, Elias MS, Smolak RR, Fu T, Borensztajn J and Green RM: Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet. J Lipid Res. 49:1068–1076. 2008. View Article : Google Scholar : PubMed/NCBI
12	Rozen S and Skaletsky H: Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 132:365–386. 2000.PubMed/NCBI
13	Raabe M, Véniant MM, Sullivan MA, Zlot CH, Björkegren J, Nielsen LB, Wong JS, Hamilton RL and Young SG: Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J Clin Invest. 103:1287–1298. 1999. View Article : Google Scholar : PubMed/NCBI
14	Okumura K, Ikejima K, Kon K, Abe W, Yamashina S, Enomoto N, Takei Y and Sato N: Exacerbation of dietary steatohepatitis and fibrosis in obese, diabetic KK-A(y) mice. Hepatol Res. 36:217–228. 2006. View Article : Google Scholar : PubMed/NCBI
15	Boettcher E, Csako G, Pucino F, Wesley R and Loomba R: Meta-analysis: Pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 35:66–75. 2012. View Article : Google Scholar : PubMed/NCBI
16	Gastaldelli A, Harrison S, Belfort-Aguiar R, Hardies J, Balas B, Schenker S and Cusi K: Pioglitazone in the treatment of NASH: The role of adiponectin. Aliment Pharmacol Ther. 32:769–775. 2010. View Article : Google Scholar : PubMed/NCBI
17	Kon K, Ikejima K, Hirose M, Yoshikawa M, Enomoto N, Kitamura T, Takei Y and Sato N: Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem Biophys Res Commun. 291:55–61. 2002. View Article : Google Scholar : PubMed/NCBI
18	Klein T, Fujii M, Sandel J, Shibazaki Y, Wakamatsu K, Mark M and Yoneyama H: Linagliptin alleviates hepatic steatosis and inflammation in a mouse model of non-alcoholic steatohepatitis. Med Mol Morphol. 47:137–149. 2014. View Article : Google Scholar : PubMed/NCBI
19	Kern M, Klöting N, Niessen HG, Thomas L, Stiller D, Mark M, Klein T and Blüher M: Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. PLoS One. 7:e387442012. View Article : Google Scholar : PubMed/NCBI
20	Aroor AR, Habibi J, Ford DA, Nistala R, Lastra G, Manrique C, Dunham MM, Ford KD, Thyfault JP, Parks EJ, et al: Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function. Diabetes. 64:1988–2001. 2015. View Article : Google Scholar : PubMed/NCBI
21	Orellana-Gavaldà JM, Herrero L, Malandrino MI, Pañeda A, Sol Rodríguez-Peña M, Petry H, Asins G, Van Deventer S, Hegardt FG and Serra D: Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation. Hepatology. 53:821–832. 2011. View Article : Google Scholar : PubMed/NCBI
22	Ben-Shlomo S, Zvibel I, Shnell M, Shlomai A, Chepurko E, Halpern Z, Barzilai N, Oren R and Fishman S: Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase. J Hepatol. 54:1214–1223. 2011. View Article : Google Scholar : PubMed/NCBI
23	Steinberg GR and Kemp BE: AMPK in health and disease. Physiol Rev. 89:1025–1078. 2009. View Article : Google Scholar : PubMed/NCBI
24	Kim JH, Kang SI, Shin HS, Yoon SA, Kang SW, Ko HC and Kim SJ: Sasa quelpaertensis and p-coumaric acid attenuate oleic acid-induced lipid accumulation in HepG2 cells. Biosci Biotechnol Biochem. 77:1595–1598. 2013. View Article : Google Scholar : PubMed/NCBI
25	Dahlhoff C, Worsch S, Sailer M, Hummel BA, Fiamoncini J, Uebel K, Obeid R, Scherling C, Geisel J, Bader BL and Daniel H: Methyl-donor supplementation in obese mice prevents the progression of NAFLD, activates AMPK and decreases acyl-carnitine levels. Mol Metab. 3:565–580. 2014. View Article : Google Scholar : PubMed/NCBI