Tofogliflozin Attenuates Renal Lipid Deposition and Inflammation via PPARα restoration in Diet-induced Steatohepatitic mice. (RNA-Seq)

Aims: We have previously demonstrated hepatic, cardiac, and skin inflammation in high-fat diet-induced steatotic liver disease model. However, the molecular mechanism in the kidney in this model is still not clear. It has been recently reported that SGLT2 inhibitors improved chronic kidney disease (CKD). Therefore, we evaluated the effect of tofogliflozin on renal lipid metabolism and inflammation in this model. Methods: Male 8-10-week-old C57Bl/6 mice were fed high-fat/high-cholesterol/high-sucrose/bile acid (HF/HC/HS/BA) diet with 0.015% tofogliflozin (Tofo group) or HF/HC/HS/BA diet alone (Cont group). After eight weeks, serum lipid profiles and histology, lipid content, mRNA/microRNA and protein expression levels in the kidney were examined. Results: The Tofo group showed significant reduction in body weight (26.9±0.9 vs 24.5±1.0 g; p<0.001) and kidney weight compared to the Cont group. Renal cholesterol (9.1±1.6 vs 7.5±0.7 mg/g; p<0.05) and non-esterified fatty acid (NEFA) (12.0±3.0 vs 8.4±1.5 µEq/g; p<0.01) were significantly decreased in the Tofo group. Transmission electron microscopy revealed a decreasedd number of lipid droplets. mRNA sequencing analysis revealed that fatty acid metabolism-related genes were upregulated and NFκB signaling pathway-related genes were downregulated in the Tofo group. microRNA sequencing analysis indicated that miR-21a was downregulated and miR-204 was upregulated in the Tofo group. Interestingly, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and CPT1 in the Tofo group. Conclusions: Tofogliflozin decreased renal cholesterol and NEFA content and improved inflammation through the regulation of PPARα and miR-21a.