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. 2016 Jan 5;11(1):e0146337.
doi: 10.1371/journal.pone.0146337. eCollection 2016.

The Selective SGLT2 Inhibitor Ipragliflozin Has a Therapeutic Effect on Nonalcoholic Steatohepatitis in Mice

Yasushi Honda  1 , Kento Imajo  1 , Takayuki Kato  1 , Takaomi Kessoku  1 , Yuji Ogawa  1 , Wataru Tomeno  1 , Shingo Kato  1 , Hironori Mawatari  1 , Koji Fujita  1 , Masato Yoneda  1 , Satoru Saito  1 , Atsushi Nakajima  1
Affiliations

The Selective SGLT2 Inhibitor Ipragliflozin Has a Therapeutic Effect on Nonalcoholic Steatohepatitis in Mice

Yasushi Honda et al. PLoS One. .

Abstract

Background & aims: In recent years, nonalcoholic steatohepatitis (NASH) has become a considerable healthcare burden worldwide. Pathogenesis of NASH is associated with type 2 diabetes mellitus (T2DM) and insulin resistance. However, a specific drug to treat NASH is lacking. We investigated the effect of the selective sodium glucose cotransporter 2 inhibitor (SGLT2I) ipragliflozin on NASH in mice.

Methods: We used the Amylin liver NASH model (AMLN), which is a diet-induced model of NASH that results in obesity and T2DM. AMLN mice were fed an AMLN diet for 20 weeks. SGLT2I mice were fed an AMLN diet for 12 weeks and an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks.

Results: AMLN mice showed steatosis, inflammation, and fibrosis in the liver as well as obesity and insulin resistance, features that are recognized in human NASH. Ipragliflozin improved insulin resistance and liver injury. Ipragliflozin decreased serum levels of free fatty acids, hepatic lipid content, the number of apoptotic cells, and areas of fibrosis; it also increased lipid outflow from the liver.

Conclusions: Ipragliflozin improved the pathogenesis of NASH by reducing insulin resistance and lipotoxicity in NASH-model mice. Our results suggest that ipragliflozin has a therapeutic effect on NASH with T2DM.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Ipragliflozin improved steatosis and decreased lipid content in the liver.
(A) Liver sections from BD mice, AMLN mice and SGLT2I mice. Hematoxylin and eosin (H&E) staining, (B) oil red O staining. Magnification, 200×. Scale bars: 200 μm. (C) Triglyceride (TG) and free fatty acid (FFA) content was measured in the livers of BD, AMLN, and SGLT2I mice (n = 4–6). Results are the mean ± SD. Significance was tested using the Student’s t-test (*p<0.05).
Fig 2
Fig 2. Ipragliflozin improved liver inflammation and suppressed hepatocyte apoptosis.
TUNEL-stained paraffin-embedded sections of liver tissue from BD, AMLN, and SGLT2I mice. Magnification, 400×. Scale bars: 100 μm. The number of apoptotic cells per field was counted in BD, AMLN, and SGLT2I mice (n = 5–8). Results are the mean ± SD. Significance was determined using the Student’s t-test (*p<0.05).
Fig 3
Fig 3. Ipragliflozin improved fibrosis.
(A) Liver sections from BD, AMLN and SGLT2I mice. Masson’s trichrome (MT), (B) Sirius red (SR) staining. Areas of SR staining in the liver of BD, AMLN, and SGLT2I mice (n = 5–8). (C) Expression of collagen 1α1 mRNA, and α-smooth muscle actin α (α-SMA) mRNA in BD, AMLN, and SGLT2I mice (n = 5–8). (D) α-SMA-stained paraffin-embedded sections of liver tissue from BD, AMLN, and SGLT2I mice. Areas of α-SMA staining in the livers of BD, AMLN, and SGLT2I mice (n = 5–8). Magnification, 200×. Scale bars: 200 μm. Results are the mean ± SD. Significance was determined using the Student’s t-test (*p<0.05).
Fig 4
Fig 4. Ipragliflozin accelerated β-oxidation and export of very-low-density lipoprotein.
Expression of mRNA of acetyl-CoA carboxylase (ACC), sterol regulatory element-binding protein 1c (SREBP1c), peroxisome proliferator activated receptor α (PPARα), carnitine palmitoyltransferase 1A (CPT1A), and microsomal triglyceride transfer protein (MTTP) in BD, AMLN, and SGLT2I mice (n = 5–8). Results are the mean ± SD. Significance was determined using the Student’s t-test (*p<0.05).
Fig 5
Fig 5. Mechanism of the effect of ipragliflozin on NASH in AMLN and SGLT2I mice (schematic).
TGs, triglycerides; FFAs, free fatty acids.
See this image and copyright information in PMC

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