Sodium-glucose Cotransporter-2 Inhibition And Exercise Affect Pathways Related To Nonalcoholic Fatty Liver Disease

NAFLD/NASH prevalence is growing at an alarming rate. To date the only therapies for NAFLD/NASH are lifestyle modification, including exercise (EX). However, members of the sodium-glucose cotransporter-2 inhibitor (SGLT2i) class of type-2 diabetes medications may positively affect NAFLD/NASH. PURPOSE: Use whole genome RNAseq to identify pathways by which SGLT2i treatment alone and in combination with exercise oppose NAFLD/NASH. METHODS: A low-dose of streptozotocin (30 mg/kg) and high-fat feeding were used to induce hyperglycemic NAFLD in male Sprague-Dawley rats. Animals were randomized to the following conditions (n = 7-10/group): vehicle (0.5% methylcellulose) sedentary (VEH SED), VEH EX, canagliflozin (3 mg/kg/d) SED (SGLT2i SED), or SGLT2i EX for 12 weeks. EX ran for 60 min/d, 5d/wk, on a 10% incline at ~50% of maximal running speed from a graded exercise test. RESULTS: Principal component analysis showed distinct genetic patterns in the liver between VEH SED, SGLT2i SED, and SGLT2i EX. Whole genome RNAseq of the liver revealed that SGLT2i treatment alone positively regulated AMPK signaling, sirtuin pathways, and lipid oxidation, but downregulated oxidative stress pathways and mTOR signaling. Upon follow-up, SGLT2i had higher hepatic AMPK activation and ~ 22% lower pmTOR ser2448/mTOR (p < 0.05 VEH vs SGLT2i) within the liver. Hepatic mitochondrial (k = 0.24 vs 0.20, p < 0.05), cytosolic (k = 0.18 vs 0.13, p < 0.01), and mixed fraction (k = 0.18 vs 0.15, p < 0.05) protein synthesis rates, which are highly regulated by AMPK and mTOR signaling, were lower with SGLT2i than VEH. When SGLTL2i was compared to SGLT2i EX there was differential regulation of pathways related to liver steatosis, however there were no differences in protein expression of proteins related to lipid uptake and de novo lipogenesis, FAT/CD36 (1.02 vs 0.98) or pACC/ACC (1.01vs 1.08). CONCLUSION: SGLT2i treatment alone and in combination with exercise significantly affected several pathways associated with NAFLD/NASH. This work was supported by Pfizer Inc and NIH T32 DK064584