Published online Jul 27, 2020. doi: 10.4254/wjh.v12.i7.350
Peer-review started: February 27, 2020
First decision: April 22, 2020
Revised: May 20, 2020
Accepted: June 2, 2020
Article in press: July 27,2020
Published online: July 27, 2020
The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin has been reported to improve liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood. To our knowledge, this is the first report to show that the therapeutic effects of the SGLT2 inhibitor ipragliflozin are associated with activation of sirtuin 1 (SIRT1) signaling in the liver.
SGLT2 inhibitors are reportedly effective in fatty liver model mice as well as human nonalcoholic fatty liver disease patients. The mechanisms still need to be elucidated. Evaluating the mechanisms further may help identify molecules related to ameliorating fatty liver, allowing us to develop novel therapeutic strategies for fatty liver in the future.
The main objectives were to investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice. Another objective was to evaluate the effect of ipragliflozin on β-oxidation, oxidative stress, inflammatory cytokine, and macrophage infiltration in the liver. Our study confirms the ameliorative effects of SGLT2 inhibitors on liver steatosis and the previously proposed mechanisms, and proposes a new mechanism, which can promote further research.
Obese (ob/ob) mice and their littermates received a normal chow diet or a normal chow diet plus 2 doses of ipragliflozin for 4 weeks. We examined lipid accumulation, β-oxidation, oxidative stress, inflammatory cytokine, and macrophage infiltration in the liver. Ob/ob mice were suitable for this experiment as they developed fatty liver even when they received normal chow. In addition, we used two control mouse groups, ob/ob control mice that received ipragliflozin and ob/ob littermates. In particular, SIRT1 signaling in the liver as a new candidate mechanism by which SGLT2 inhibitors improve liver steatosis was also assessed.
Amelioration of hepatic lipid accumulation by SGLT2 inhibitors was confirmed in our obese mouse model with ipragliflozin. Ipragliflozin-induced SIRT1 upregulation and SIRT1 signaling, which we propose might be involved in the mechanism by which ipragliflozin induces improvement of liver steatosis. The hypothesis should be further verified with different SGLT2 inhibitors in additional models and human samples. The observed effects of ipragliflozin on oxidative stress and macrophage infiltration, which were inconsistent with previous studies in the liver, need to be further evaluated.
The new findings in our study are that SIRT1 signaling may be involved in
the mechanism of ipragliflozin-induced improvement of liver steatosis in ob/ob mice. Thus, our study offers a new mechanism of ipragliflozin-induced improvement of liver steatosis. To be more specific, our proposed theory (hypothesis) is that activation of SIRT1 signaling due to ipragliflozin may ameliorate liver steatosis in ob/ob mice. This hypothesis and new phenomena were confirmed in our obese mouse model. In summary, the liver steatosis-attenuating effects of ipragliflozin in ob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway. The original insights into our results are that temporary calorie loss due to urinary glucose excretion caused by ipragliflozin may stimulate hepatic SIRT1, which might also be partly due to the activation of phospho-AMP-activated protein kinase in our mouse model. Our study provides additional evidence of SGLT2 inhibitor-induced improvement of liver steatosis; thus, we think that SGLT2 inhibitors are likely to be beneficial in diabetes mellitus patients with fatty liver in clinical practice.
We take particular note of the role of SIRT1 as it plays important roles in controlling energy homeostasis and longevity in mammals and because the regulation of SIRT1 expression affects fatty liver. Thus, new target molecules that may be involved in amelioration of liver steatosis by SGLT2 inhibitors may be associated with energy homeostasis and longevity. We propose that future research should confirm our hypothesis using different animal models and human samples with different SGLT2 inhibitors or by confirming that upregulation or downregulation of SIRT1 signaling by the different methods used in our model or previous studies alters hepatic lipid accumulation. Genetically engineered mice, such as SIRT1 knockout mice, may be one of the best ways to confirm our results, and could be used to evaluate ipragliflozin-induced improvement of liver steatosis.