Transcriptomic and metabolomic analyses reveal that lobeglitazone ameliorates hepatic steatosis in rats concurrent with regulation of mitochondrial pyruvate metabolism.

Background

AND

Purpose

Lobeglitazone is a thiazolidinedione and PPARγ agonist that improves metabolic parameters and hepatic steatosis, but its mechanisms are not fully understood. This study investigated the effects of lobeglitazone on hepatic transcriptomic and metabolic profiles in a rat model of obesity and Type 2 diabetes mellitus. EXPERIMENTAL APPROACH Male Otsuka Long-Evans Tokushima fatty rats were fed a high-fat, high-carbohydrate (HF/HC) diet for 15 weeks and treated with lobeglitazone or vehicle. Metabolic parameters, liver function and histology were assessed. RNA sequencing was conducted to identify changes in hepatic gene expression, and metabolomic profiling was performed on liver and plasma samples. Mechanistic validation was conducted in HepG2 cells using siRNA-mediated PPARγ knockdown. KEY

Results

Lobeglitazone treatment improved glucose tolerance and decreased plasma triglyceride and total cholesterol levels. Histological analyses indicated reduced hepatic steatosis, ballooning and lobular inflammation, reflecting protection against hepatic steatosis. RNA sequencing revealed 334 DEGs between the HF/HC-lobeglitazone and HF/HC groups, with pathway enrichment analyses indicating modulation of pathways related to central carbon metabolism. Five pyruvate metabolism-associated genes were down-regulated by lobeglitazone. Quantitative PCR confirmed selected transcriptomic changes, although mitochondrial pyruvate carrier (MPC) 1 and 2 mRNA levels were not significantly altered. In contrast, MPC1 and MPC2 protein levels were markedly reduced. Metabolomics showed increased hepatic and plasma pyruvate, amino acids involved in pyruvate production and hydroxybutyrates, suggesting reduced mitochondrial pyruvate flux. Functional assays demonstrated decreased mitochondrial pyruvate levels following lobeglitazone treatment. PPARγ knockdown abolished lobeglitazone-induced down-regulation of MPC proteins.

Conclusions

AND IMPLICATIONS Lobeglitazone treatment was associated with improved hepatic steatosis and liver-associated metabolic parameters, accompanied by transcriptional and metabolomic changes related to mitochondrial pyruvate metabolism. These findings are correlative and provide new insights into the hepatic actions of lobeglitazone in metabolic disease.