The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus

Abstract

Background: Diabetes mellitus (DM) is considered as a risk factor for the progress of liver diseases.After tissue damage, there is the highest amplitude of ubiquitously sterile inflammatory response in the liver, resulting in a major clinical consequence concerning a high prevalence of steatohepatitis in DM patients. This study aimed to investigate the inhibitory efficacy of dapagliflozin (DAPA), a sodium glucose cotransporter-2 (SGLT2) inhibitor, on experimental steatohepatitis with DM.Methods: DM-steatohepatitis model was established by dual intraperitoneal injection of streptozotocin (STZ) and feeding with the high-fat diet (HFD) in apolipoprotein E-deficient (ApoE -/-) mice (n=40). The mice were concurrently treated with DAPA (1 mg/kg/d) by gavage for 12 weeks.Results: In ApoE -/mice, dual HFD/STZ dramatically induced hepatic damage and inflammation as compared with HFD alone. DAPA treatment was effective to protect from hepatic damage and inflammation in dual HFD/STZ treated ApoE -/mice. DAPA also significantly the probability decreased the blood glucose, hepatic lipid accumulation, liver steatosis, and fibrotic response in dual HFD/STZ treated ApoE -/mice. Further mechanistic investigations indicated that the protection of DAPA on diabetic liver injury was associated with the suppressed production of hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) and the inhibited activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome.Conclusions: These data demonstrate the efficacy of DAPA for protecting liver damage, inflammation and steatosis from experimental steatohepatitis with DM, and indicate a possible involvement of the inhibited activity of ROS-NLRP3 inflammasome.

Dapagliflozin Restores Impaired Autophagy and Suppresses Inflammation in High Glucose-Treated HK-2 Cells

“…Lipopolysaccharide (LPS)-induced NF-κB can bind to the NLRP3 promoter to directly regulate its expression in human macrophages [21], which indicates that NLRP3 is a downstream gene of NF-κB. Multiple studies have shown that SGLT2 inhibition suppresses the NLRP3 inflammasome in different diabetic animal models [26,27,[54][55][56]. Dapagliflozin suppressed the activation of the NLRP3 inflammasome in diabetic myocardial tissues [26] and reduced the production of IL-1β in aortic and liver tissues [54,55].…”

“…Multiple studies have shown that SGLT2 inhibition suppresses the NLRP3 inflammasome in different diabetic animal models [26,27,[54][55][56]. Dapagliflozin suppressed the activation of the NLRP3 inflammasome in diabetic myocardial tissues [26] and reduced the production of IL-1β in aortic and liver tissues [54,55]. AMPK can suppress inflammatory signaling [25] and NLRP3 activation [57,58].…”

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

“…Expression of NLPR3 and caspase-1 proteins as well as the release of mature interleukins 1β and 18 were markedly reduced in dapagliflozin-treated HFD/STZ ApoE −/− animals. Treatment with dapagliflozin attenuated the activation of NLRP3 inflammasome especially in the animals with diabetes [ 58 ].…”

“…Liver: reduced oxidative stress by means of decreased level of MDA and sustained enzymatic activity of superoxide dismutase [ 54 , 58 ]…”

Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases

“…ROS-induced chronic inflammation is a promoter of cancer initiation and tumorigenesis [ 40 , 200 ]. Dapagliflozin or empagliflozin can inhibit the activity of the ROS-induced NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome [ 201 , 202 ]. Furthermore, canagliflozin and tofogliflozin demonstrated anti-inflammatory and chemopreventive effects in nonalcoholic steatohepatitis- and diethylnitrosamine-induced HCC models, respectively [ 188 , 189 , 190 ].…”