Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling

Abstract

BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors are newly developed oral antidiabetic drugs. SGLT2 is primarily expressed in the kidneys and reabsorbs approximately 90% of the glucose filtered by the renal glomeruli. SGLT2 inhibitors lower glucose levels independently of insulin action by facilitating urinary glucose excretion. The SGLT2 inhibitor ipragliflozin has reportedly improved liver steatosis in animal models and clinical studies. However, the mechanisms by which SGLT2 inhibitors improve liver steatosis are not fully understood. AIM To investigate the ameliorative effects of ipragliflozin on liver steatosis and the mechanisms of these effects in obese mice. METHODS We analyzed 8-wk-old male obese ( ob/ob ) mice that were randomly divided into a group receiving a normal chow diet and a group receiving a normal chow diet supplemented with ipragliflozin (3 mg/kg or 10 mg/kg) for 4 wk. We also analyzed their lean sex-matched littermates receiving a normal chow diet as another control group. Body weight and liver weight were evaluated, and liver histology, immunoblotting, and reverse transcription-polymerase chain reaction analyses were performed. RESULTS Hepatic lipid accumulation was significantly ameliorated in ob/ob mice treated with 10 mg/kg ipragliflozin compared to untreated ob/ob mice irrespective of body weight changes. Ipragliflozin had no appreciable effects on hepatic oxidative stress-related gene expression levels or macrophage infiltration, but significantly reduced hepatic interleukin-1β (IL-1β) mRNA expression levels. Ipragliflozin increased both the mRNA and protein expression levels of sirtuin 1 (SIRT1) in the liver. The hepatic mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), peroxisome proliferator-activated receptor α (PPARα), and fibroblast growth factor-21 (FGF21) were also significantly higher in ipragliflozin-treated ob/ob mice than in untreated ob/ob mice. CONCLUSION Our study suggests that the liver steatosis-ameliorating effects of ipragliflozin in ob/ob mice may be mediated partly by hepatic SIRT1 signaling, possibly through the PGC-1α/PPARα-FGF21 pathway.

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

“…The effect of SGLT2 inhibitors to reduce oxidative stress, enhance mitochondrial integrity, mute inflammatory pathways, and preserve cell viability is paralleled by an increase in expression or activity of AMPK, SIRT1, SIRT3, SIRT6, and PGC-1α and decreased activation of mTOR in diverse tissues under stress, particularly in experimentally induced cardiomyopathy and nephropathy (Figure 4 and Table 2). 48,54,57,76,77,87,110,157,158,161–171,174–219 The increase in AMPK and autophagic flux also explains the increase in ATP production that is seen in the heart and kidneys, both experimentally and clinically, after SGLT2 inhibition. 52,54,57,181,220…”

Exploring the modulatory effects of sotagliflozin on dyslipidemia in mice: The role of glucagon, fibroblast growth factor 21 and glucagon‐like peptide 1

“…Chronic use of SGLT-2 inhibitors is associated with GLP-1, glucagon and FGF-21 secretion. 31,[33][34][35][36] These peptides hormones are known to be critical regulators of fat metabolism. 14,15,19,20,43 The current preclinical investigation is the first to report the fate of these peptide hormones in response to the SGLT1/2 dual inhibition using sotagliflozin and its potential influence on fat metabolism.…”

“…The pleiotropic effects of SGLT‐2 inhibitors are thought to occur through various mechanisms 22,23 . Studies have reported enhanced glucagon secretion from pancreatic alpha cells, elevated circulating levels of FGF21, and secretion of incretin hormone GLP‐1 by SGLT‐2 inhibition 28–36 . Furthermore, long‐term clinical use of these agents reported improvement in plasma triglyceride levels and postprandial lipemia 37 …”

“…22,23 Studies have reported enhanced glucagon secretion from pancreatic alpha cells, elevated circulating levels of FGF21, and secretion of incretin hormone GLP-1 by SGLT-2 inhibition. [28][29][30][31][32][33][34][35][36] Furthermore, long-term clinical use of these agents reported improvement in plasma triglyceride levels and postprandial lipemia. 37 Chronic use of GLP-1 receptor agonists or DPP-IV inhibitors is reported to mitigate dyslipidemia.…”

PPARα in the Epigenetic Driver Seat of NAFLD: New Therapeutic Opportunities for Epigenetic Drugs?

“…Hence, SIRT1 activity is required to activate the transcription of PPARα target genes including FGF21 in the liver [ 86 ]. Moreover, it has been reported that natural compounds and drugs used for the treatment of NAFLD targeting the PPARα signaling pathway are dependent on SIRT1 activity [ 87 , 88 , 89 ]. Moreover, in both adipocytes and hepatocytes, it has been shown that the depletion of SIRT1 reduces the expression of several PPARα target genes related to lipid metabolism and mitochondrial biogenesis [ 90 , 91 ].…”