Combined Treatment with Sodium-Glucose Cotransporter-2 Inhibitor (Canagliflozin) and Dipeptidyl Peptidase-4 Inhibitor (Teneligliptin) Alleviates NASH Progression in A Non-Diabetic Rat Model of Steatohepatitis.
Takahiro OzutsumiTadashi NamisakiNaotaka ShimozatoKosuke KajiYuki TsujiDaisuke KayaYukihisa FujinagaMasanori FurukawaKeisuke NakanishiShinya SatoYasuhiko SawadaSoichiro SaikawaKoh KitagawaHiroaki TakayaHideto KawarataniMitsuteru KitadeKei MoriyaRyuichi NoguchiTakemi AkahaneAkira MitoroHitoshi YoshijiPublished in: International journal of molecular sciences (2020)
Hepatocellular carcinoma (HCC) is the strongest independent predictor of mortality in non-alcoholic steatohepatitis (NASH)-related cirrhosis. The effects and mechanisms of combination of sodium-dependent glucose cotransporter inhibitor and canagliflozin (CA) and dipeptidyl peptidase-4 inhibitor and teneligliptin (TE) on non-diabetic NASH progression were examined. CA and TE suppressed choline-deficient, L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. CA alone or with TE significantly decreased proinflammatory cytokine expression. CA and TE significantly attenuated hepatic lipid peroxidation. In vitro studies showed that TE alone or with CA inhibited cell proliferation and TGF-β1 and α1 (I)-procollagen mRNA expression in Ac-HSCs. CA+TE inhibited liver fibrogenesis by attenuating hepatic lipid peroxidation and inflammation and by inhibiting Ac-HSC proliferation with concomitant attenuation of hepatic lipid peroxidation. Moreover, CA+TE suppressed in vivo angiogenesis and oxidative DNA damage. CA or CA+TE inhibited HCC cells and human umbilical vein endothelial cell (HUVEC) proliferation. CA+TE suppressed vascular endothelial growth factor expression and promoted increased E-cadherin expression in HUVECs. CA+TE potentially exerts synergistic effects on hepatocarcinogenesis prevention by suppressing HCC cell proliferation and angiogenesis and concomitantly reducing oxidative stress and by inhibiting angiogenesis with attenuation of oxidative stress. CA+TE showed chemopreventive effects on NASH progression compared with single agent in non-diabetic rat model of NASH, concurrent with Ac-HSC and HCC cell proliferation, angiogenesis oxidative stress, and inflammation. Both agents are widely, safely used in clinical practice; combined treatment may represent a potential strategy against NASH.
Keyphrases
- oxidative stress
- vascular endothelial growth factor
- cell proliferation
- endothelial cells
- dna damage
- protein kinase
- type diabetes
- poor prognosis
- signaling pathway
- induced apoptosis
- wound healing
- coronary artery disease
- squamous cell carcinoma
- ischemia reperfusion injury
- risk assessment
- risk factors
- metabolic syndrome
- amino acid
- radiation therapy
- diabetic rats
- transforming growth factor
- cell death
- epithelial mesenchymal transition
- drug delivery
- cell cycle
- weight loss
- cancer therapy
- endoplasmic reticulum stress
- smoking cessation
- fatty acid
- liver injury
- insulin resistance
- heat shock protein
- case control
- type iii