Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model

Yamane, Masafumi; Matono, Tomomitsu; Okano, Jun-ichi; Nagahara, Ran; Matsuki, Yukako; Okamoto, Toshiaki; Miyoshi, Katsuhiko; Sugihara, Takaaki; Nagahara, Takakazu; Koda, Masahiko; Isomoto, Hajime

doi:10.33160/yam.2019.03.005

Cited by 6 publications

(6 citation statements)

References 15 publications

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“…We observed ELD in renal tubules as well, which was prevented by ipragliflozin. This finding is in line with our previous report, which revealed less lipid deposition in hepatocytes in NASH model mice, treated with ipragliflozin [15]. In the clinical setting, it has been shown that inhibition of SGLT2 led to the reduction in epicardial fat accumulation, following the reduction in body weight and the improvement in lipid profile and glycemic control [20].…”

Section: Discussionsupporting

confidence: 91%

“…In addition to this effect, SGLT2 inhibitors improve glomerular hyperfiltration and insulin resistance [14]. We have also reported that ipragliflozin, an SGLT2 inhibitor, reduced ectopic fat accumulation in the liver and prevented liver fibrosis in NASH model mice [15]. This result indicates that this SGLT2 inhibitor has an additional effect besides glucose metabolism.…”

Section: Introductionmentioning

confidence: 81%

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Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules

Hosokawa

Takata

Sugihara

et al. 2019

IJMS

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Background: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed; however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin. Methods: Male FLS-ob/ob mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated. Results: The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis. Conclusions: ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 81%

Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules

Hosokawa

Takata

Sugihara

et al. 2019

IJMS

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“…Traditional murine models used to study hepatic fibrosis often include choline- and methionine-deficient diets or carbon tetrachloride-induced models [ 15 – 17 ]. Not just induced ones but genetically modified models have also been widely investigated to study hepatic fibrosis [ 18 , 19 ]. However, these models do not represent the entire spectrum of the pathophysiologies seen in human NASH.…”

Section: Discussionmentioning

confidence: 99%

Steatosis is involved in the progression of kidney disease in a high-fat-diet-induced non-alcoholic steatohepatitis mouse model

et al. 2022

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Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health issues associated with the metabolic syndrome. Although NASH is a known risk factor of CKD, the mechanisms linking these two diseases remain poorly understood. We aimed to investigate alterations in the kidney complicated with dyslipidemia in an established NASH mouse model. Male C57BL6/J mice were fed with control diet or high-fat diet (HFD), containing 40% fat, 22% fructose, and 2% cholesterol for 16 weeks. Metabolic characteristics, histological changes in the kidney, endoplasmic reticulum (ER) stress, apoptosis, and fibrosis were evaluated by histological analysis, immunoblotting, and quantitative reverse transcription-polymerase chain reaction. Levels of serum aspartate aminotransferase, alanine aminotransferase, alkali-phosphatase, total cholesterol, and urinary albumin were significantly higher in mice fed with HFD. Remarkable steatosis, glomerular hypertrophy, and interstitial fibrosis were also shown in in the kidney by leveraging HFD. Furthermore, HFD increased the mRNA expression levels of Casp3, Tgfb1, and Nfe2l2 and the protein level of BiP. We observed the early changes of CKD and speculate that the underlying mechanisms that link CKD and NASH are the induction of ER stress and apoptosis. Further, we observed the activation of Nfe2l2 in the steatosis-induced CKD mouse model. This NASH model holds implications in investigating the mechanisms linking dyslipidemia and CKD.

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“…Снижение степени выраженности стеатоза печени при лечении ипраглифлозином, возможно, связано с подавлением синтеза жирных кислот и их производных, служащих лигандами PPAR-α [46]. Поскольку PPAR-α регулирует катаболизм жирных кислот в печени, индуцируя синтез несколько белков, включая транспортный белок жирных кислот (FATP) и ацетил-КоА-синтазу длинноцепочечных жирных кислот [47], что способствует стеатозу печени, неожиданно оказалось, что уровни экспрессии мРНК PPAR-α значительно ингибировались приемом ипраглифлозина у мышей [48].…”

Section: ипраглифлозин и неалкогольная жировая болезнь печениunclassified

Effect of ipragliflozin on metabolic syndrome components and non-alcoholic fatty liver disease

2021

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Sodium-glucose cotransporter-2 inhibitors are the new drugs for the treatment of type 2 diabetes mellitus. Its mechanism of action is to increase the excretion of glucose in the urine due to inhibition of reabsorption in the proximal renal tubules, which leads to a decrease in blood glucose levels. These drugs also have pleiotropic effects including reduce body weight and blood pressure, improve the lipid profile (raising high-density lipoprotein cholesterol and lowering triglyceride levels), and reduce the risk of cardiovascular death and nephroprotection. Ipragliflozin, a new representative of the class of sodium glucose cotransporter-2 inhibitors, registered in Russia, has shown effectiveness in relation to glycemic control, reducing the levels of glycated hemoglobin and fasting plasma glucose both in monotherapy and in combination with other antihyperglycemic drugs. The PRIME-V and ILLUMINATE studies have demonstrated that ipragliflozin helps to reduce insulin resistance, body weight, BMI and waist circumference, total and LDL cholesterol. Positive effects of ipragliflozin on pancreatic β-cell mass and function have been shown in animal studies. Several studies have examined the beneficial effects of ipragliflozin on the course of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Significant reductions in ALT and GGT levels and a decrease in the absolute percentage of liver fat have been shown. Animal studies have confirmed the effect of ipragliflozin on the histological characteristics of NASH. The review presents data on the efficacy of ipragliflozin in relation to the components of the metabolic syndrome in patients with type 2 diabetes mellitus, and also discusses the likely mechanisms of a positive effect of the drug on the course of NASH in type 2 diabetes mellitus.

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Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model

Cited by 6 publications

References 15 publications

Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules

Ipragliflozin Ameliorates Endoplasmic Reticulum Stress and Apoptosis through Preventing Ectopic Lipid Deposition in Renal Tubules

Steatosis is involved in the progression of kidney disease in a high-fat-diet-induced non-alcoholic steatohepatitis mouse model

Effect of ipragliflozin on metabolic syndrome components and non-alcoholic fatty liver disease

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