Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels.

Abstract

The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.