Dapagliflozin uncouples the anti-inflammatory and lipogenic effects of pioglitazone in valproic acid-induced steatohepatitis in rats: Lipid-sensing nuclear receptors (LXRα and PPARγ) as the molecular nexus between hepatoprotection and lipogenesis.

Valproic acid (VPA) is a foundation antiepileptic medication, implicated in dose-dependent hepatotoxicity via mitochondrial dysfunction, progression of oxidative-inflammatory cascade, and steatosis. LXRα/PPARγ are crucial regulators of hepatic lipogenesis, representing a pertinent therapeutic target. Dapagliflozin, a SGLT2 inhibitor and pioglitazone, a PPARγ agonist, are emerging therapies for metabolic hepatic steatosis; however, while pioglitazone confers notable anti-inflammatory benefits, its hepatic PPARγ signaling remains a recognized concern. The current study targets the individual or combined modulatory effects of both drugs on the hepatic LXRα and PPARγ pathways in VPA-induced steatohepatitis in rats. Forty male Sprague-Dawley rats were randomized into five groups: Control, VPA (500 mg/kg/d given orally), PIO + VPA (10 mg/kg/d pioglitazone), DAPA + VPA (1 mg/kg/d dapagliflozin), and COMB (1 mg/kg/d dapagliflozin and 10 mg/kg/d pioglitazone). All prophylactic treatments were orally given 1 h prior to VPA. Spectrophotometry, RT-PCR, histopathological and immunohistochemical parameters were used to assess hepatic injury across groups. The results indicated that hepatocytes are nudged toward increased lipogenesis in the VPA group via activation of hepatic PPARγ (P < 0.001), LXRα (P < 0.01), SREBP1c (P < 0.001), and perilipin 2 (P < 0.05). VPA was associated with impaired LFTs, dyslipidemia, altered MDA/GSH equilibrium, and intense NF-κB immunoreactivity (all P < 0.001), besides significant fibrosis (P < 0.001) and elevated histopathology scores (P < 0.01). Relative to VPA, PIO + VPA exhibited significant hepatic anti-inflammatory and antioxidative benefits, restoring LFTs (P < 0.001) and MDA/GSH equilibrium (P < 0.001), alongside inhibiting NF-κB immunoreactivity (P < 0.001), however; it failed to significantly improve histopathological scores or lipogenic effectors (P > 0.05). Relative to VPA, DAPA + VPA and COMB groups showed a downregulation of hepatic lipogenic effectors (PPARγ at P < 0.001, LXRα at P < 0.01, SREBP1c at P < 0.001, and perilipin 2 at P < 0.05), with additional improvement of histopathological scores (P < 0.05), fibrosis (P < 0.001), and lipid profiles (P < 0.001) while simultaneously restoring LFTs and hepatic redox status (P < 0.001). Within the scope of the available literature, this study is the first to elucidate the divergent effects of pioglitazone and dapagliflozin on VPA-induced steatosis through the intricate hepatic LXRα/PPARγ signaling, underscoring the pronounced hepatoprotective capacity of dapagliflozin, effectively rescuing pioglitazone's pro-steatotic signaling.