Canagliflozin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Lipid Metabolism and Inhibiting Inflammation through Induction of Autophagy

Abstract

Purpose Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic diseases, including obesity and diabetes, and has gradually become the most common cause of chronic liver disease. We investigated the effects of sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin on NAFLD in high-fat diet (HFD)-induced obese mice and possible underlying mechanisms. Materials and Methods Male C57BL/6 mice were fed a normal-diet, HFD, or HFD with canagliflozin for 14 weeks. AML-12 hepatocytes were treated with canagliflozin. Expression of related pathways was assessed. Results Canagliflozin administration reduced body weight and fat mass, compared with HFD alone. Canagliflozin improved glucose and lipid metabolic disorders. Compared with HFD-fed mice, liver weight, serum alanine transaminase (ALT) levels, and hepatic lipid accumulation were decreased after canagliflozin administration. Additionally, canagliflozin upregulated lipolysis markers (CPT1a, ACOX1, and ACADM), downregulated lipogenesis markers (SREBP-1c and FASN), and suppressed the production of inflammatory cytokines (TNFα, MCP1, IL-1β, and IL-6), consistent with significantly increased LC3 II/I and Atg7 levels in the liver following canagliflozin treatment. In vitro, canagliflozin increased CPT1a, ACOX1, and ACADM expression, decreased SREBP-1c and FASN protein expression, and reduced TNFα, MCP1, IL-1β, and IL-6 mRNA levels in lipid mixture (LM)-induced hepatocytes in a dose-dependent manner. These changes were reversed by 3-MA, an autophagy inhibitor. Conclusion Our findings suggest that canagliflozin ameliorates the pathogenesis of NAFLD by regulating lipid metabolism and inhibiting inflammation, which may be associated with its promotion of autophagy.

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

“…First, SGLT2 inhibitors consistently enhance autophagic flux (including mitophagy) in the heart and kidney; the action to augment autophagy is seen in tissue harvested from chronically treated animals as well as in isolated cell cultures perfused with SGLT2 inhibitors (Table 1). [155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171][172][173] Second, SGLT2 inhibitors mute the generation of reactive oxygen species, enhance antioxidant mechanisms, and mitigate endoplasmic reticulum stress. 165,167,169,[174][175][176] Third, SGLT2 inhibitors accelerate the disposal of injured mitochondria, restore healthy mitochondrial function, and promote mitochondrial biogenesis 167,169 ; the increase in mitochondrial mass is a characteristic feature of the action of these drugs on electron microscopy.…”

Autophagy: A Cellular Guardian against Hepatic Lipotoxicity

“…Some of the well-described drugs that also show pro-autophagic activity in this class are metformin [ 87 ], rapamycin [ 88 ], statins [ 89 ], pioglitazone [ 90 ], fibrates [ 91 ], canagliflozin [ 92 ], verapamil [ 93 ], and carbamazepine [ 94 ].…”

Increased Hepatic ATG7 mRNA and ATG7 Protein Expression in Nonalcoholic Steatohepatitis Associated with Obesity

“…Given that NASH can be accompanied by fibrosis, the main risk factor for mortality due to hepatic causes of NAFLD [ 7 ], in recent years, there has been significant research into therapies aimed at controlling NASH. However, no Food and Drug Administration (FDA)-approved NAFLD-specific medications are currently available [ 8 ]. For this reason, it is very important to insist on the study of the pathogenic mechanisms involved in the progression of NAFLD/NASH to demonstrate possible therapeutic targets.…”

“…Given the suggested beneficial role that autophagy seems to have in NAFLD pathogenesis and given that there is not yet a specific drug approved by regulatory agencies to treat this hepatic disorder, drugs involving the autophagy system have begun to be investigated for the treatment of NAFLD [ 8 , 20 , 21 , 22 ]. In a recent study in animal models, it was suggested that the endocannabinoid system, which is known to be implicated in the pathogenesis of NAFLD, might mediate its role through autophagy mechanisms [ 23 ].…”